AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Mastoparan

 Uncategorized  Comments Off on Mastoparan
Jul 082016
 

STR3

Mastoparan, Peptide (H-INLKALAALAKKIL-NH2)

IUPAC Condensed

H-Ile-Asn-Leu-Lys-Ala-Leu-Ala-Ala-Leu-Ala-Lys-Lys-xiIle-Leu-NH2

LINUCS
[][L-Leu-NH2]{[(1+2)][L-xiIle]{[(1+2)][L-Lys]{[(1+2)][L-Lys]{[(1+2)][L-Ala]{[(1+2)][L-Leu]{[(1+2)][L-Ala]{[(1+2)][L-Ala]{[(1+2)][L-Leu]{[(1+2)][L-Ala]{[(1+2)][L-Lys]{[(1+2)][L-Leu]{[(1+2)][L-Asn]{[(1+2)][L-Ile]{}}}}}}}}}}}}}}
Sequence
INLKALAALAKKXL
HELM

PEPTIDE1{I.N.L.K.A.L.A.A.L.A.K.K.[*N[C@H](C(=O)*)C(C)CC |$_R1;;;;;_R2;;;;$|].L.[am]}$$$$

Mastoparan
Ile – Asn – Leu – Lys – Ala – Leu – Ala – Ala – Leu – Ala – Lys – Lys – Ile – Leu -NH2
(2S)-N-[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-2-[[(2S,3S)-2-amino-3-methylpentanoyl]amino]butanediamide
Mastoparan; Mast cell degranulating peptide (Vespula lewisii); NSC351907; CAS 72093-21-1;
Molecular Formula: C70H131N19O15
Molecular Weight: 1478.90744 g/mol
  • 18: PN: WO0181408 SEQID: 37 claimed protein
  • 18: PN: WO2010069074 SEQID: 16 claimed protein
  • L-Leucinamide, L-isoleucyl-L-asparaginyl-L-leucyl-L-lysyl-L-alanyl-L-leucyl-L-alanyl-L-alanyl-L-leucyl-L-alanyl-L-lysyl-L-lysyl-L-isoleucyl-
  • Mastoparan 1
  • NSC 351907

Description

Mastoparan (Vespula lewisii) has been shown to cause an increase in the production of Arachidonic Acid (sc-200770) catalyzed by PLA2 from porcine pancreas and bee venom. This compound also displays toxicity by regulating G proteins via mimicking of G-protein-coupled receptors. Additionally, Mastoparan has been reported as a stimulator of insulin release by pancreatic islets, which acts through GTP-binding proteins and PLA2. In other experiments, this agent has demonstrated the ability to cause exocytosis of rat peritoneal mast cells and also stimulate the accumulation of inositol phosphates in hepatocytes. Additionally, Mastoparan has been noted to act as a mitogen in Swiss 3T3 cells and stimulate pertussis toxin-sensitive Arachidonate release without phosphoinositide breakdown. Mastoparan (Vespula lewisii) is an inhibitor of CaM. Mastoparan (Vespula lewisii) is an activator of Heterotrimeric G Protein and PLA2.
Technical Information
Physical State: Solid
Derived from: Synthetic. Originally isolated from wasp venom (Vespula lewisii)
Solubility: Soluble in water (2.6 mg/ml), and 100% ethanol.
Storage: Store at -20° C
Refractive Index: n20D 1.53
IC50: Na+,K+-ATPase: IC50 = 7.5 µM

Mastoparan is a peptide toxin from wasp venom. It has the chemical structure Ile-Asn-Leu-Lys-Ala-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2.[2]

The net effect of mastoparan’s mode of action depends on cell type, but seemingly always involves exocytosis. In mast cells, this takes the form of histamine secretion, while in platelets and chromaffin cells release serotonin and catecholamines are found, respectively. Mastoparan activity in the anterior pituitary gland leads to prolactin release.

In the case of histamine secretion, the effect of mastoparan takes place via its interference with G protein activity. By stimulating theGTPase activity of certain subunits, mastoparan shortens the lifespan of active G protein. At the same time, it promotes dissociation of any bound GDP from the protein, enhancing GTP binding. In effect, the GTP turnover of G proteins is greatly increased by mastoparan. These properties of the toxin follow from the fact that it structurally resembles activated G protein receptors when placed in a phospholipid environment. The resultant G protein-mediated signaling cascade leads to intracellular IP3 release and the resultant influx of Ca2+.

In an experimental study conducted by Tsutomu Higashijima and his counterparts, mastoparan was compared to melittin, which is found in bee venom.[2] Mainly, the structure and reaction to phosphate was studied in each toxin. Using Circular Dichroism (CD), it was found that when mastoparan was exposed to methanol, an alpha helical form existed. It was concluded that strong intramolecular hydrogen bonding occurred. Also, two negative bands were present on the CD spectrum. In an aqueous environment, mastoparan took on a nonhelical, unordered form. In this case, only one negative band was observed on the CD spectrum. Adding phosphate buffer to mastoparan resulted in no effect.

Melittin produced a different conformational change than mastoparan. In an aqueous solution, melittin went from a nonhelical form to an alpha helix when phosphate was added to the solution. The binding of melittin to the membrane was believed to result fromelectrostatic interactions, not hydrophobic interactions.

Infections caused by multidrug resistant bacteria are currently an important problem worldwide. Taking into account data recently published by the WHO, lower respiratory infections are the third cause of death in the world with around 3.2 million deaths per year, this number being higher compared to that related to AIDS or diabetes mellitus [1]. It is therefore important to solve this issue, although the perspectives for the future are not very optimistic. During the last 30 years an enormous increase has been observed of superbugs isolated in the clinical setting, especially from the group called ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.) which show high resistance to all the antibacterial agents available [2]. We will focus on Acinetobacter baumannii, the pathogen colloquially called “iraquibacter” for its emergence in the Iraq war. It is a Gram-negative cocobacillus and normally affects people with a compromised immune system, such as patients in the intensive care unit (ICU) [3] and [4]. Together with Escherichia coliand P. aeruginosa, A. baumannii are the most common cause of nosocomial infections among Gram-negative bacilli. The options to treat infections caused by this pathogen are diminishing since pan-drug resistant strains (strains resistant to all the antibacterial agents) have been isolated in several hospitals [5]. The last option to treat these infections is colistin, which has been used in spite of its nephrotoxic effects [6]. The evolution of the resistance of A. baumannii clinical isolates has been established by comparing studies performed over different years, with the percentage of resistance to imipenem being 3% in 1993 increasing up to 70% in 2007. The same effect was observed with quinolones, with an increase from 30 to 97% over the same period of time[7]. In Spain the same evolution has been observed with carbapenems; in 2001 the percentage of resistance was around 45%, rising to more than 80% 10 years later [8]. Taking this scenario into account, there is an urgent need for new options to fight against this pathogen. One possible option is the use of antimicrobial peptides (AMPs) [9],[10] and [11], and especially peptides isolated from a natural source [12]. One of the main drawbacks of using peptides as antimicrobial agents is the low stability or half-life in human serum due to the action of peptidases and proteases present in the human body[13], however there are several ways to increase their stability, such as using fluorinated peptides [14] and [15]. One way to circumvent this effect is to study the susceptible points of the peptide and try to enhance the stability by protecting the most protease labile amide bonds, while at the same time maintaining the activity of the original compound. Another point regarding the use of antimicrobial peptides is the mechanism of action. There are several mechanisms of action for the antimicrobial peptides, although the global positive charge of most of the peptides leads to a mechanism of action involving the membrane of the bacteria [16]. AMPs has the ability to defeat bacteria creating pores into the membrane [17], also acting as detergents [18], or by the carpet mechanism [19]. We have previously reported the activity of different peptides against colistin-susceptible and colistin-resistant A. baumannii clinical isolates, showing that mastoparan, a wasp generated peptide (H-INLKALAALAKKIL-NH2), has good in vitro activity against both colistin-susceptible and colistin-resistant A. baumannii [20]. Therefore, the aim of this manuscript was to study the stability of mastoparan and some of its analogues as well as elucidate the mechanism of action of these peptides.

Paper

European Journal of Medicinal Chemistry

Volume 101, 28 August 2015, Pages 34–40

Research paper

Sequence-activity relationship, and mechanism of action of mastoparan analogues against extended-drug resistantAcinetobacter baumannii

  • a ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic – Universitat de Barcelona, Barcelona, Spain
  • b Biomedical Institute of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
  • c Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain
  • d Department of Clinical Microbiology, CDB, Hospital Clinic, School of Medicine, University of Barcelona, Barcelona, Spain
  • e Department of Organic Chemistry, University of Barcelona, Barcelona, Spain

http://www.sciencedirect.com/science/article/pii/S0223523415300933

doi:10.1016/j.ejmech.2015.06.016

Highlights

•The most susceptible position of mastoparan is the peptide bond between isoleucine and asparagine.
•The positive charge present in the N-terminal play an important role in the antimicrobial activity of the peptides.
•Mastoparan and its enantiomer version exhibit a mechanism of action related to the membrane disruption of bacteria.
•Three of the mastoparan analogues synthesized have good activity against highly resistant Acinetobacter baumannii.
•Two of the active analogues showed a significant increase in the human serum stability compared to mastoparan.

Abstract

The treatment of some infectious diseases can currently be very challenging since the spread of multi-, extended- or pan-resistant bacteria has considerably increased over time. On the other hand, the number of new antibiotics approved by the FDA has decreased drastically over the last 30 years. The main objective of this study was to investigate the activity of wasp peptides, specifically mastoparan and some of its derivatives against extended-resistant Acinetobacter baumannii. We optimized the stability of mastoparan in human serum since the specie obtained after the action of the enzymes present in human serum is not active. Thus, 10 derivatives of mastoparan were synthetized. Mastoparan analogues (guanidilated at the N-terminal, enantiomeric version and mastoparan with an extra positive charge at the C-terminal) showed the same activity against Acinetobacter baumannii as the original peptide (2.7 μM) and maintained their stability to more than 24 h in the presence of human serum compared to the original compound. The mechanism of action of all the peptides was carried out using a leakage assay. It was shown that mastoparan and the abovementioned analogues were those that released more carboxyfluorescein. In addition, the effect of mastoparan and its enantiomer against A. baumannii was studied using transmission electron microscopy (TEM). These results suggested that several analogues of mastoparan could be good candidates in the battle against highly resistant A. baumannii infections since they showed good activity and high stability.

Graphical abstract

Image for unlabelled figure

References

  1.  PDB: 2CZP​; Todokoro Y, Yumen I, Fukushima K, Kang SW, Park JS, Kohno T, Wakamatsu K, Akutsu H, Fujiwara T (August 2006). “Structure of Tightly Membrane-Bound Mastoparan-X, a G-Protein-Activating Peptide, Determined by Solid-State NMR”. Biophys. J. 91 (4): 1368–79. doi:10.1529/biophysj.106.082735. PMC 1518647. PMID 16714348.
  2.  Higashijima T, Uzu S, Nakajima T, Ross EM (May 1988). “Mastoparan, a peptide toxin from wasp venom, mimics receptors by activating GTP-binding regulatory proteins (G proteins)”. J. Biol. Chem. 263 (14): 6491–4. PMID 3129426.

 

Reference

    • V.N. Yewale, World Health Organization
    • WHO’s First Global Report on Antibiotic Resistance Reveals Serious, Worldwide Threat to Public Health
    • World Heal. Organ, Geneva (2014
    • H.W. Boucher, G.H. Talbot, J.S. Bradley, J.E. Edwards, D. Gilbert, L.B. Rice, M. Scheld, B. Spellberg, J. Bartlett
    • Bad bugs, No drugs: no ESKAPE! An update from the infectious diseases Society of America
    • Clin. Infect. Dis., 48 (2009), pp. 1–12
    • L. Dijkshoorn, A. Nemec, H. Seifert
    • An increasing threat in hospitals: multidrug resistant Acinetobacter baumannii
    • Nat. Rev. Microbiol., 5 (2007), pp. 939–951
    • I. Roca, P. Espinal, X. Vila-Farrés, J. Vila
    • The Acinetobacter baumannii oxymoron: commensal hospital dweller turned pan-drug-resistant menace
    • Front. Microbiol., 23 (3) (2012), p. 148
    • J. Vila, J. Pachón
    • Therapeutic options for Acinetobacter baumannii infections: an update
    • Expert. Opin. Pharmacother., 13 (2012), pp. 2319–2336
    • J. Li, R.L. Nation, R.W. Milne, J.D. Turnidge, K. Coulthard
    • Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria
    • Int. J. Antimicrob. Agents, 25 (2005), pp. 11–25
    • J. Vila, J. Pachón
    • Therapeutic options for Acinetobacter baumannii infections
    • Expert. Opin. Pharmacother., 9 (2008), pp. 587–599
    • F. Fernández-Cuenca, M. Tomás-Carmona, F. Caballero-Moyano, G. Bou, L. Martínez-Martínez, J. Vila, J. Pachón, J.M. Cisneros, J. Rodríguez-Baño, A. Pascual, grupo del proyecto GEIH-REIPI-Ab 2010
    • In vitro activity of 18 antimicrobial agents against clinical isolates of Acinetobacter spp. Multicenternational study GEIH-REIPI-Ab 2010
    • Enferm. Infecc. Microbiol. Clin., 31 (2013), pp. 4–9
    • X. Vila-Farrés, E. Giralt, J. Vila
    • Update of peptides with antibacterial activity
    • Curr. Med. Chem., 19 (2012), pp. 6188–6198
    • V. Dhople, A. Krukemeyer, A. Ramamoorthy
    • The human beta-defensin-3, an antibacterial peptide with multiple biological functions
    • Biochim. Biophys. Acta, 1758 (2006), pp. 1499–1512
    • L.M. Gottler, A. Ramamoorthy
    • Structure, membrane orientation, mechanism, and function of pexiganan–a highly potent antimicrobial peptide designed from magainin
    • Biochim. Biophys. Acta, 1788 (2009), pp. 1680–1686
    • J.M. Conlon, A. Sonnevend, T. Pál, X. Vila-Farrés
    • Efficacy of six frog skin-derived antimicrobial peptides against colistin-resistant strains of theAcinetobacter baumannii group
    • Int. J. Antimicrob. Agents, 39 (2012), pp. 317–320
    • H. Meng, K. Kumar
    • Antimicrobial activity and protease stability of peptides containing fluorinated amino acids
    • J. Am. Chem. Soc., 129 (2007), pp. 15615–15622
    • E.N. Marsh, B.C. Buer, A. Ramamoorthy
    • Bad bugs, no drugs: no ESKAPE! An update from the infectious diseases Society of Ame
    • Mol. Biosyst., 5 (2009), pp. 1143–1147
    • L.M. Gottler, R. de la Salud Bea, C.E. Shelburne, A. Ramamoorthy, E.N. Marsh
    • Using fluorous amino acids to probe the effects of changing hydrophobicity on the physical and biological properties of the beta-hairpin antimicrobial peptide protegrin-1
    • Biochemistry, 47 (2008), pp. 9243–9250
    • M. Wenzel, A.I. Chiriac, A. Otto, D. Zweytick, C. May, C. Schumacher, R. Gust, H.B. Albada, M. Penkova, U. Krämer, R. Erdmann, N. Metzler-Nolte, S.K. Straus, E. Bremer, D. Becher, H. Brötz-Oesterhelt, H.G. Sahl, J.E. Bandow
    • Small cationic antimicrobial peptides delocalize peripheral membrane proteins
    • Proc. Natl. Acad. Sci. U. S. A., 111 (2014), pp. E1409–E1418
    • D.K. Lee, J.R. Brender, M.F. Sciacca, J. Krishnamoorthy, C. Yu, A. Ramamoorthy
    • A. Lipid composition-dependent membrane fragmentation and pore-forming mechanisms of membrane disruption by pexiganan (MSI-78)
    • Biochemistry, 52 (2013), pp. 3254–3263
    • D.K. Lee, A. Bhunia, S.A. Kotler, A. Ramamoorthy
    • Detergent-type membrane fragmentation by MSI-78, MSI-367, MSI-594, and MSI-843 antimicrobial peptides and inhibition by cholesterol: a solid-state nuclear magnetic resonance study
    • Biochemistry, 54 (2015), pp. 1897–1907
    • R.F. Epand, W.L. Maloy, A. Ramamoorthy, R.M. Epand
    • Probing the “charge cluster mechanism” in amphipathic helical cationic antimicrobial peptides
    • Biochemistry, 49 (2010), pp. 4076–4084
    • X. Vila-Farres, C. Garcia de la Maria, R. López-Rojas, J. Pachón, E. Giralt, J. Vila
    • In vitro activity of several antimicrobial peptides against colistin-susceptible and colistin-resistant Acinetobacter baumannii
    • Clin. Microbiol. Infect., 18 (2012), pp. 383–387

Patent IDDatePatent TitleUS20160672612016-03-10SERCA INHIBITOR AND CALMODULIN ANTAGONIST COMBINATION

Mastoparan
Mastoparan.png

Solution structure of mastoparan from Vespa simillima xanthoptera.[1]
Identifiers
Symbol Mastoparan_2
Pfam PF08251
InterPro IPR013214
TCDB 1.C.32
OPM superfamily 160
OPM protein 2czp

///////Peptide, Antimicrobial peptide, Mastoparan, Acinetobacter baumannii,  NSC351907,  72093-21-1, NSC 351907

CCC(C)C(C(=O)NC(CC(=O)N)C(=O)NC(CC(C)C)C(=O)NC(CCCCN)C(=O)NC(C)C(=O)NC(CC(C)C)C(=O)NC(C)C(=O)NC(C)C(=O)NC(CC(C)C)C(=O)NC(C)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(CC(C)C)C(=O)N)N

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New bicalutamide/enzalutamide derivatives as antiproliferative agents for the treatment of prostate cancer

 cancer  Comments Off on New bicalutamide/enzalutamide derivatives as antiproliferative agents for the treatment of prostate cancer
Jul 082016
 

STR1.jpg

3,3,3-trifluoro-2-hydroxy-N-(4-nitro-3-(trifluoromethyl)phenyl)-2-(((2-(trifluoromethyl)phenyl)thio)methyl)propanamide

Cas 1929605-82-2

MF C18 H11 F9 N2 O4 S,  MW 522.34
New bicalutamide and enzalutamide derivatives as antiproliferative agents for the treatment of prostate cancer
School of Pharmacy and Pharmaceutical Sciences, Redwood Building, King Edward VII Avenue, CF10 3NB, Cardiff, Wales, UK

Dr Marcella Bassetto

Dr Marcella Bassetto

Post Doctoral Research Associate

bassettom@cardiff.ac.uk
https://www.researchgate.net/profile/Marcella_Bassetto
http://marcellabassetto.blogspot.in/
Cardiff University
Cardiff University
School of Pharmacy and Pharmaceutical Sciences
Cardiff, Wales, United Kingdom

SYNTHESIS

Synthetic strategy used in the synthesis of 52. Reagents and conditions: (a) NaH ...

Scheme .

Synthetic strategy used in the synthesis of 52. Reagents and conditions: (a) NaH (1 equiv.), THF, 0 °C to RT, 3 h; (b) KCN (1.2 equiv.), 25% H2SO4, 0 °C to RT, 20 h; c) HCl, AcOH, reflux, 24 h; (d) 8, SOCl2(1.3 equiv.), DMA, RT, 72 h.

3-Bromo-1,1,1-trifluoroacetone (48) was coupled with thiophenol 47 to afford 49, which was then converted into cyano derivative 50 using potassium cyanide and 25% sulfuric acid [16]. Intermediate 51 was obtained after refluxing 50 in concentrated HCl and glacial acetic acid. Coupling of 51 with commercially available 4-nitro-3-(trifluoromethyl)aniline 8yielded the desired amide 52.

 Synthesis of 1,1,1-rifluoro-3-((2-(trifluoromethyl)phenyl)thio)propan-2-one (49)

To a mixture of NaH (10.47 mmol) in 10 mL anhydrous THF was added a solution of 2-(trifluoromethyl)benzenethiol (10.47 mmol) in 2mL anhydrous THF at 0 °C. This mixture was stirred for 20 min. 3-Bromo-1,1,1-trifluoropropan-2-one was then added dropwise to the mixture at 0 °C, the reaction was warmed to r.t. and stirred for 12 h. The mixture was filtered trough celite, the filtered pad was washed with THF, and the filtrate was evaporated to dryness. The residue was purified by flash column chromatography eluting with n-hexane/EtOAc 100:0 v/v increasing to n-hexane/EtOAc 85:15 v/v to give a pale yellow oil in 93% yield. 1H-NMR (CDCl3): d 7.76-7.69 (m, 2H), 7.60-7.53 (m, 1H), 7.42-7.38 (m, 1H), 3.44 (s, 2H). 19F-NMR (CDCl3): d -59.91 (s, 3F), -85.26 (s, 3F). 13C-NMR (CDCl3): d 189.6, 137.7, 135.9, 134.5, 133.2, 130.6, 129.6 (q, J= 26.3 Hz), 127.0 (q, J= 3.8 Hz), 124.3 (q, J= 4.1 Hz), 124.0 (q, J= 3.7 Hz), 94.4 (q, J= 30.4 Hz), 40.4.

Synthesis of    3,3,3-trifluoro-2-hydroxy-2-(((2-(trifluoromethyl)phenyl)thio)methyl)propanenitrile (50)

A 20% aqueous solution of H2SO4 (3.4 mL) was added dropwise to a mixture of 49 (11.03 mmol) and KCN (13.24 mmol) in 5 mL H2O at 0 °C. The reaction mixture was warmed to r.t. and stirred for 20 h. The mixture was then diluted with water (50 mL) and extracted with Et2O (3 x 150 mL). The organic extracts were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography eluting with n-hexane/EtOAc 100:0 v/v increasing to n-hexane/EtOAc 95:5 v/v to give a pale yellow oil in 86% yield. 1H-NMR (CDCl3): d 7.80 (d, J= 7.8 Hz, 1H), 7.77-7.76 (m, 1H), 7.72-7.59 (m, 1H), 7.52-7.49 (m, 1H), 4.36 (bs, 1H), 3.58 (d, J= 14.6 Hz, 1H), 3.44 (d, J= 14.6 Hz, 1H). 19F-NMR (CDCl3): d -57.08 (s, 3F), -79.51 (s, 3F). 13C-NMR (CDCl3): d 135.4, 132.8, 132.5 (q, J= 30.1 Hz), 129.1, 128.7 (q, J= 5.5 Hz), 126.7, 124.9, 124.6, 122.6, 122.4, 120.4, 114.0, 71.4 (q, J= 32.9), 40.75.

1.1.1        Synthesis         of         3,3,3-trifluoro-2-hydroxy-2-(((2-(trifluoromethyl)phenyl)thio)methyl)propanoic acid (51)

A mixture of 51 (6.89 mmol), concentrated HCl (23.4 mL) and AcOH (4.1 mL) was refluxed o.n. with vigorous stirring. The mixture was then diluted with water (100 mL) and extracted with Et2O (4 x 100 mL), which was in turn washed with sat. aq. NaHCO3 (4 x 100 mL). The water solution was acidified with concentrated HCl to pH 1 and extracted with Et2O (4x 150 mL). The Et2O extracts were dried over Na2SO4, filtered and concentrated to dryness to give a pale yellow waxy solid in 41% yield. 1H-NMR (CDCl3): d 9.57 (bs, 1H), 7.70 (d, J= 7.7 Hz, 1H), 7.67 (d, J= 7.7 Hz, 1H), 7.54-7.51 (m, 1H), 7.39-7.36 (m, 1H), 3.60 (s, 2H). 19F-NMR (CDCl3): d -60.10 (s, 3F), -77.7 (s, 3F). 13C-NMR (CDCl3): d 172.0, 134.1, 134.0, 131.2 (q, J= 30.1 Hz), 127.5, 126.7 (q, J= 5.6 Hz), 124.2 (q, J= 121.9 Hz), 121.9 (q, J= 126.7 Hz), 78.2 (q, J= 28.7 Hz), 37.7.

Synthesis of 3,3,3-trifluoro-2-hydroxy-N-(4-nitro-3-(trifluoromethyl)phenyl)-2-(((2-(trifluoromethyl)phenyl)thio)methyl)propanamide (52)

Thionyl chloride (1.16 mmol) was added dropwise to a stirring solution of 51 in anhydrous DMA at -10 °C under Ar atmosphere. The reaction mixture was stirred for 1 h, then a solution of 8 in 2 mL anhydrous DMA was added dropwise. The reaction mixture was warmed to r.t. and stirred for 72 h. The mixture was then diluted with sat. aq. NaHCO3 (40 mL) and extracted with Et2O (3 x 40 mL). The organic extracts were filtered trough celite, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash column chromatography eluting with n-hexane/EtOAc 100:0 v/v increasing to n-hexane/EtOAc 80:20 v/v to give a pale yellow solid in 13% yield.

1H-NMR (CDCl3): d 8.93 (bs, 1H), 7.94 (d, J= 8.8 Hz, 1H), 7.87 (d, J= 2.2 Hz, 1H), 7.72 (d, J= 8.1 Hz, 1H), 7.69 (dd, J= 8.8 Hz, 2.2 Hz, 1H), 7.50-7.47 (m, 2H), 7.26-7.23 (m, 1H), 4.41 (s, 1H), 4.19 (d, 14.7 Hz, 1H), 3.45 (d, J= 14.7 Hz, 1H).

19F-NMR (CDCl3): d -59.7 (s, 3F), -60.12 (s, 3F), -77.4 (s, 3F).

13C-NMR (CDCl3): d 164.6, 143.8, 140.0, 134.7, 132.6, 131.1 (q, J= 29.8 Hz), 130.5, 128.3, 126.8 (q, J= 5.5 Hz), 126.7, 125.2 (q, J= 36.3 Hz), 124.5, 123.9, 122.6, 122.4, 122.2, 121.7, 120.4, 118.2 (q, J= 5.8 Hz), 76.3 (q, J= 27.8 Hz), 38.5.

MS [ESI, m/z]: 523.0 [M+H]+.

EI-HMRS (M-H)– found 521.0215, calculated for C18H0N2O4F9S 521.0218.

HPLC (method 1): retention time = 23.84 min.

 

clips

Prostate cancer (PC) is a leading cause of male death worldwide and it is the most frequently diagnosed cancer among men aged 65–74 [1]. The prognosis varies greatly, being highly dependent on a number of factors such as stage of diagnosis, race and age. Currently, PC treatment includes androgen deprivation, surgery, radiation, endocrine therapy and radical prostatectomy.

PC cell growth is strongly dependent on androgens, therefore blocking their effect can be beneficial to the patient’s health. Such outcomes can be achieved by antagonism of the androgen receptor (AR) using anti-androgen drugs, which have been extensively explored either alone or in combination with castration [2]. Flutamide (Eulexin®) (1) (in its active form as hydroxyflutamide (2)), bicalutamide (Casodex®) (3), nilutamide (Niladron®) (4) and enzalutamide (previously called MDV3100) (Xtandi®) (5) are all non-steroidal androgen receptor antagonists approved for the treatment of PC (Fig. 1). In many cases, after extended treatment over several years, these anti-androgens become ineffective and the disease may progress to a more aggressive and lethal form, known as castration resistant prostate cancer (CRPC). The major cause of this progressive disease is the emergence of different mutations on the AR, which cause the anti-androgen compounds to function as agonists, making them tumour-stimulating agents[3].

Structure of anti-androgen small molecules approved by FDA or in clinical ...

Fig. 1.

Structure of anti-androgen small molecules approved by FDA or in clinical development for the treatment of PC.

Flutamide (Eulexin®) (1)
(in its active form as hydroxyflutamide (2)),
bicalutamide (Casodex®) (3),
nilutamide (Niladron®) (4) and

enzalutamide (previously called MDV3100) (Xtandi®) (5)

Among the drugs used for the treatment of PC, bicalutamide and enzalutamide selectively block the action of androgens while presenting fewer side effects in comparison with other AR antagonists [4], [5] and [6]. The structure of these molecules is characterised by the presence of a trifluoromethyl substituted anilide, which appears to be critical for biological activity (Fig. 1). As a means to improve the anti-proliferative activity of these compounds, and in order to exploit the well established potential of the fluorine atom in enhancing the pharmacological properties and drug-like physicochemical characteristics of candidate compounds [7], [8] and [9], a wide array of diverse new structures has been rationally designed and synthesised, through the introduction of fluoro-, trifluoromethyl- and trifluoromethoxy groups in diverse positions of both aromatic rings of the parent scaffolds. Our modifications resulted in a marked improvement of in vitro anti-proliferative activities on a range of human PC cell lines (VCap, LNCaP, DU-145 and 22RV1). In addition, we probed full versus partial AR antagonism for our new compounds.

Paper

Image for unlabelled figure

European Journal of Medicinal Chemistry

Volume 118, 8 August 2016, Pages 230–243

Research paper

Design and synthesis of novel bicalutamide and enzalutamide derivatives as antiproliferative agents for the treatment of prostate cancer

School of Pharmacy and Pharmaceutical Sciences, Redwood Building, King Edward VII Avenue, CF10 3NB, Cardiff, Wales, UK

This work is dedicated to the memory of Prof. Chris McGuigan, a great colleague and scientist, invaluable source of inspiration and love for research.
doi:10.1016/j.ejmech.2016.04.052
E-mail address: Ferlas1@cardiff.ac.uk (Dr. S. Ferla)

Highlights

•Synthesis of novel fluorinated bicalutamide and enzalutamide analogs.
•Anti-proliferative activity in four human prostate cancer cell lines improved up to 50 folds.
•Full AR antagonist effect exhibited by the new compounds.
•Activity switch from partial agonist to full AR antagonist for enobosarm scaffold.
•AR open conformation homology model and molecular modeling studies.

Abstract

Prostate cancer (PC) is one of the major causes of male death worldwide and the development of new and more potent anti-PC compounds is a constant requirement. Among the current treatments, (R)-bicalutamide and enzalutamide are non-steroidal androgen receptor antagonist drugs approved also in the case of castration-resistant forms. Both these drugs present a moderate antiproliferative activity and their use is limited due to the development of resistant mutants of their biological target.

Insertion of fluorinated and perfluorinated groups in biologically active compounds is a current trend in medicinal chemistry, applied to improve their efficacy and stability profiles. As a means to obtain such effects, different modifications with perfluoro groups were rationally designed on the bicalutamide and enzalutamide structures, leading to the synthesis of a series of new antiproliferative compounds. Several new analogues displayed improved in vitro activity towards four different prostate cancer cell lines, while maintaining full AR antagonism and therefore representing promising leads for further development.

Furthermore, a series of molecular modelling studies were performed on the AR antagonist conformation, providing useful insights on potential protein-ligand interactions.

http://www.sciencedirect.com/science/article/pii/S0223523416303452

 

Top cancer scientist dies of the disease he spent his life trying to cure

Professor Chris McGuigan, 57, of Cardiff University, was trying to invent new drugs to use in the fight against the disease

Professor Chris McGuigan
A university spokesman described Prof McGuigan as ‘exceptionally gifted’

Professor Chris McGuigan, 57, was trying to invent new drugs to use in the fight against the disease.

But the tragic scientist, who was head of medicinal chemistry at Cardiff University’s School of Pharmacy and Pharmaceutical Sciences, died after his own fight with cancer.

A spokesman for Cardiff University said: “Professor McGuigan had been at the heart of scientific research for more than 30 years. He was an exceptionally gifted inventor and chemist.

“His loss will be felt cross the university and the wider scientific community.

South Wales EchoPatricia Price
Prof McGuigan invented four new experimental drugs that were used in human clinical trials

“He had a strong drive to use his scientific ideas for social good, working tirelessly to address medical needs where they were unmet.

“Our thoughts are with his family, friends and close colleagues at this very sad time.”

Prof McGuigan’s research led him to try and develop new drugs for cancer, HIV, hepatitis B and C, shingles, measles, influenza and central nervous system (CNS) disease.

He also invented four new experimental drugs that were used in human clinical trials.

Prof McGuigan, who lived in Cardiff, is survived by wife Maria, 50, and his two young daughters Phoebe and Grace.

References

    • J. Ferlay, H.-R. Shin, F. Bray, D. Forman, C. Mathers, D.M. Parkin
    • Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008
    • Int. J. Cancer, 127 (2010), pp. 2893–2917
    • G.J.C.M. Kolvenbag, P. Iversen, D.W.W. Newling
    • Antiandrogen monotherapy: a new form of treatment for patients with prostate cancer
    • Urology, 58 (2001), pp. 16–22
    • H.I. Scher, W.K. Kelly
    • Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer
    • J. Clin. Oncol., 11 (1993), pp. 1566–1572
    • P. Reid, P. Kantoff, W. Oh
    • Antiandrogens in prostate cancer
    • Investig. New Drugs, 17 (1999), pp. 271–284
    • J. Anderson
    • The role of antiandrogen monotherapy in the treatment of prostate cancer
    • BJU Int., 91 (2003), pp. 455–461
    • M.P. Wirth, O.W. Hakenberg, M. Froehner
    • Antiandrogens in the treatment of prostate cancer
    • Eur. Urol., 51 (2007), pp. 306–313
    • D. O’Hagan, D.B. Harper
    • Fluorine-containing natural products
    • J. Fluor. Chem., 100 (1999), pp. 127–133
    • B.E. Smart
    • Fluorine substituent effects on bioactivity
    • J. Fluor. Chem., 109 (2001), pp. 3–11
    • J. Wang, M. Sánchez-Roselló, J.L. Aceña, C. del Pozo, A.E. Sorochinsky, S. Fustero, V.A. Soloshonok, H. Liu
    • Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade 2001–2011
    • Chem. Rev., 114 (2014), pp. 2432–2506
    • K.D. James, N.N. Ekwuribe
    • A two-step synthesis of the anti-cancer drug (R,S)-Bicalutamide
    • Synthesis, 7 (2002), pp. 850–852
    • B.-C. Chen, R. Zhao, S. Gove, B. Wang, J.E. Sundeen, M.E. Salvati, J.C. Barrish
    • Nucleohilic aromatic substitution of methacrylamide anion and its application to the synthesis of the anticancer drug bicalutamide
    • J. Org. Chem., 26 (2003), pp. 10181–10182
    • Pizzatti, E.; Vigano, E.; Lussana, M.; Landonio, E. Procedure for the synthesis of bicalutamide. U.S. Patent 0,041,161, February 23, 2006.
    • I.D. Cockshott
    • Bicalutamide: clinical pharmacokinetics and metabolism
    • Clin. Pharmacokinet., 13 (2004), pp. 855–878
    • Dalton, T.J.; Miller, D.D.; Yin, D.; He, Y. Selective androgen receptor modulators and methods of use thereof. U.S. Patent 6,569,896 B2 May 27, 2003.
    • H. Tucker, G.J. Chesterson
    • Resolution of the nonsteroidal antiandrogen 4′-cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3′-(trifluoromethyl)-propionanilide and the determination of the absolute configuration of the active enantiomer
    • J. Med. Chem., 31 (1988), pp. 885–887
    • Y. He, D. Yin, M. Perera, L. Kirkovsky, N. Stourman, W. Li, J.T. Dalton, D.D. Miller
    • Novel nonsteroidal ligands with binding affinity and potent functional activity for the androgen receptor
    • Eur. J. Med. Chem., 37 (2002), pp. 619–634

 

///////////1929605-82-2, bicalutamide and enzalutamide derivatives, antiproliferative agents,  treatment of prostate cancer,  School of Pharmacy and Pharmaceutical Sciences, Redwood Building, King Edward VII Avenue, CF10 3NB, Cardiff, Wales, UK

 

FC(F)(F)c1cc(ccc1[N+]([O-])=O)NC(=O)C(O)(CSc2ccccc2C(F)(F)F)C(F)(F)F

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HAO 472

 china  Comments Off on HAO 472
Jul 082016
 

 

STR1

 

STR1.CF3COOH

 

 

STR1.jpg

 

HAO 472

PHASE 1 CHINA

 

 

PRoject Name: HAO472 treatment Phase I clinical trial in relapsed / refractory AML,  M2b type of AML

The main purpose: to determine HAO472 treatment of relapsed / refractory C the maximum tolerated dose (MTD). Secondary objectives: 1) evaluation of drug safety and tolerability; 2) study HAO472 in pharmacokinetic characteristics of the human body; 3) the effectiveness of HAO472 treatment of relapsed / refractory M2b type of AML.

Introduction Test

Acute myelogenous leukemia

HAO472

Phase I

Test Number: CTR20150246

Sponsor Name:

Jiangsu Hengrui Medicine Co., Ltd. 1/
2 Ruijin Hospital, Shanghai Jiaotong University School of Medicine /
3 Jiangsu Hengrui Medicine Co., Ltd. /
4 Shanghai Hengrui Medicine Co., Ltd. /

Microsoft Word - 2016-6-8_Manuscrpit_Review on Oridonin analogs

Natural products have historically been, and continue to be, an invaluable source for the discovery of various therapeutic agents. Oridonin, a natural diterpenoid widely applied in traditional Chinese medicines, exhibits a broad range of biological effects including anticancer and anti-inflammatory activities. To further improve its potency, aqueous solubility and bioavailability, the oridonin template serves as an exciting platform for drug discovery to yield better candidates with unique targets and enhanced drug properties. A number of oridonin derivatives (e.g. HAO472) have been designed and synthesized, and have contributed to substantial progress in the identification of new agents and relevant molecular mechanistic studies toward the treatment of human cancers and other diseases. This review summarizes the recent advances in medicinal chemistry on the explorations of novel oridonin analogues as potential anticancer therapeutics, and provides a detailed discussion of future directions for the development and progression of this class of molecules into the clinic.

Highlights

Oridonin displays significant anticancer activities via multi-signaling pathways.

Recent advances in medicinal chemistry of oridonin-like compounds are presented.

The article summarizes the SAR and mechanism studies of relevant drug candidates.

The milestones and future direction of oridonin-based drug discovery are discussed.

European Journal of Medicinal Chemistry

Volume 122, 21 October 2016, Pages 102–117

Review article

Discovery and development of natural product oridonin-inspired anticancer agents

  • a Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, 77555, United States
  • b Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States
doi:10.1016/j.ejmech.2016.06.015

 

Major milestones achieved in oridonin-inspired drug discovery and development.

 

 

////////Natural product, Oridonin, Diterpenoids, Anticancer agents, Drug discovery, Chemical biology, AML, HAO 472, relapsed / refractory AML. Jiangsu Hengrui Medicine Co., Ltd, PHASE1, LEUKEMIA

 

C[C@H](N)C(=O)O[C@]15OC[C@@]2([C@H](O)CCC(C)(C)[C@@H]2[C@H]1O)[C@H]3CC[C@@H]4C(=C)C(=O)[C@@]35C4O

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Eldecalcitol, an active vitamin D3 analog used to treat osteoporosis

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Jul 072016
 

 

 

 

Eldecalcitol

(1S,2S,3S,5Z)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-2-(3-hydroxypropoxy)-4-methylidenecyclohexane-1,3-diol

(1R,2R,3R,5Z,7E)-2-(3-Hydroxypropyloxy)-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol

AC1O5QQ2;   CAS 104121-92-8;  AN-3697; ED 71, Edirol®
Molecular Formula: C30H50O5
Molecular Weight: 490.715 g/mol

APPROVED JAPAN , 2011-01-21, Chugai (Originator) , Roche,Taisho Toyama

Eldecalcitol was approved by Pharmaceuticals and Medicals Devices Agency of Japan (PMDA) on January 21, 2011. It was developed by Chugai Pharmaceutical (a member of Roche) and marketed as Edirol® by Chugai Pharmaceutical and Taisho.

Eldecalcitol is an orally active vitamin D analogue leading to greater absorption of bind calcium. It is usually used to treat osteoporosis.

Edirol® is available as capsule for oral use, containing 0.5 μg or 0.75 μg of free Eldecalcitol, and the recommended dose is 0.75 μg once daily.

ED-71, a vitamin D analog, is a more potent inhibitor of bone resorption than alfacalcidol in an estrogen-deficient rat model of osteoporosis. ED-71, effectively and safely increased lumbar and hip bone mineral density (BMD) in osteoporotic patients who also received vitamin D3 supplementation.

Eldecalcitol is a drug used in Japan for the treatment of osteoporosis.[1] It is an analog of vitamin D.[2] Osteoporosis is a common bone disease among the older generation, with an estimated prevalence of over 200 million people.[1] This condition often results in bone fractures due to abnormally low bone mass density, and is a leading cause of disability, especially among developed countries with longer average life spans. Osteoporosis is more common in women than with men.

 

 

AC1O5QQ2.pngEldecalcitol

Discovery

Chugai Pharmaceutical/Roche are the originators of the medicinal drug eldecalcitol through Taisho Pharmaceutical Holdings and Chugai Pharmaceutical. The trade name of eldecalcitol is Edirol, and its Chemical Abstracts Service (CAS) registry number is 104121-92-8. Eldecalcitol was approved for use in Japan on January 2011. The approval came from the Japanese Ministry of Health, Labor, and Welfare for the objective of a treatment for osteoporosis.[3]

Effects

Clinical trials have suggested that eldecalcitol, a vitamin D analog, has strong effects to reduce calcium reabsorption into the body from bones, therefore increasing bone mineral density, and to increase calcium absorption in intestines.[4] In animals, eldecalcitol inhibits the activity of osteoclasts for the function to reduce bone degradation for calcium, while still able to maintain osteoblast function so as to not hinder bone formation.[5] Unlike other vitamin D analogs, eldecalcitol does not significantly suppress parathyroid hormone levels, promising a better treatment for osteoporosis in comparison to other medications.[6] Bone mineral density increases with eldecalcitol use, in addition to strengthening bone structure. This occurs due to the function of the eldecalcitol drug, which decreases bone reabsorption as observed through a bone reabsorption marker. Bone geometry assessments show that eldecalcitol increases cortical bone area in patients with osteoporosis more so than other vitamin D analogs, such as alfacalcidol. There was also the maintenance of thickness of cortical bone mass, strongly indicating that eldecalcitol improves the strength and mass of bone, specifically cortical bone structure.[7] Adverse effects of eldecalcitol include an increase in blood and urinary calcium levels. Abnormally high levels of calcium can lead to problems associated with hypercalcemia.

Treatment for Osteoporosis

Eldecalcitol can be used for the treatment of hypocalcaemia or osteoporosis. Calcium absorption increases with the presence of eldecalcitol by the body, occurring in the intestines, which is useful for those who have low calcium levels. Eldecalcitol is more often used due to its effects to treat osteoporosis. In the aging population, the bone matrix becomes weakened through untreated osteoporosis. This leads to an increased risk of severe fractures that include spinal and hip fractures in addition to vertebral and wrist fractures. This creates a burden on the health care system due to a decline in the quality of life for the individuals that suffer from this condition. Some risk factors leading to the predisposition of developing osteoporosis are previous incidents of bone fractures and a reduction in bone mineral density.[1] These factors expectantly increase as age increases. Bone health is reliant on maintaining physiologically needed levels of calcium, where the body constantly maintains this calcium homeostasis through osteoblast and osteoclast activity. Osteoblast activity serves this function of maintaining appropriate calcium levels by depositing calcium in bones when blood calcium levels are above normal. In contrast, osteoclasts break down bone tissue to increase blood calcium levels if they are low.[8] This activity is performed after absorption of calcium by the body, which requires the actions of vitamin D. The active metabolite of vitamin D, calcitriol, performs its function through interactions with the calcitriol receptor. This nuclear hormone receptor is responsible for calcium absorption which, in turn, is involving in bone depletion and formation. The new analogs of vitamin D, such as eldecalcitol, are observed to have stronger effects in preventing bone loss, fractures, and falls in comparison to calcitriol.[9] Eldecalcitol is even more effective than its counterpart alfacalcidol, another vitamin D analog. Studies have shown eldecalcitol is more effective than alfacalcidol in preventing vertebral and wrist fractures, and even falls, with osteoporotic patients with vitamin D insufficiencies.[10] Eldecalcitol is also more effective at preventing fractures than vitamin D and calcium supplements.[1] Eldecalcitol increases calcium absorption for vitamin D deficient patients, and therefore could be used for osteoporosis treatment for all age groups.

Pharmacology

Analogs of vitamin D are being explored intensely for their regulatory effects on calcium metabolism with the purpose of treating osteoporosis, a skeletal disease associated with low bone mass and deterioration of bone tissue. Vitamin D is imperative for absorption of calcium to maintain bone strength.

Mechanism of Action

Eldecalcitol is an orally administered drug to patients, which binds to vitamin D receptors and binding protein for the goal of achieving greater specificity to bind calcium for its absorption. This greater affinity is 2.7-fold that of the active vitamin D form of calcitriol. Eldecalcitol is readily absorbed into the body, with a long elimination half-life of over eight hours, reaching maximum absorption in 3.4 hours.[1]

Dosage

Eldecalcitol is present in the form of pills for oral administration. In preclinical models with healthy male volunteers, oral doses of eldecalcitol ranged from 0.1 to 1.0 micrograms once daily to show an increase in bone mineral density.[11] Preclinical trials show improvements for doses at 0.5 and 0.75 micrograms, which are the recommended dosage amounts for the Edirol product as approved by the Japanese Ministry of Health, Labor, and Welfare for treating osteoporosis.[3]

Chemistry

The class of eldecalcitol is a vitamin D3 derivative. This molecule has a molecular weight of 490.71 grams per mole. The eldecalcitol analog of calcitriol, contains a hydroxypropyl group in the lower cyclohexane ring. The synthesis of eldecalcitol incorporates two units assembled together. The IUPAC names include (3S, 4S, 5R)-oct-1-en-7-yne-3,4,5-triol that is fused to a bicyclic system, (R)-6-((1R, 3aR, 7aR, E)-4-(bromomethylene)-7a-methyloctahydro-1H-inden-1-yl)-2-methylheptan-2-ol. The assembly process includes a Diels-Alder reaction to give the fully protected eldecalcitol. In order to get the parent molecule, the hydroxyl groups have to be deprotected. The chemistry of eldecalcitol allows for its binding 2.7-fold more potently than calcitriol. In addition, some vitamin D derivatives have been known to inhibit the serum parathyroid hormone. Eldecalcitol only weakly inhibits the serum parathyroid hormone, making it an even more appealing medicinal drug for its physiological uses in the treatment of osteoporosis.[3] Animal studies of eldecalcitol, in ovariectomized rats, show improvements in bone mass while lowering bone reabsorption to demonstrate its effectiveness in osteoporosis treatment.[5]

PAPER

Heterocycles,  Vol 92, No. 6, 2016, pp.1013-1029
Published online, 22nd March, 2016

DOI: 10.3987/REV-16-840
■ Diverse and Important Contributions by Medicinal Chemists to the Development of Pharmaceuticals: An Example of Active Vitamin D3 Analog, Eldecalcitol

Noboru Kubodera*

*International Institute of Active Vitamin D Analogs, 35-6, Sankeidai, Mishima, Shizuoka 411-0017, Japan

Abstract

Presented herein are diverse and important contributions by medicinal chemists to different stages of pharmaceutical development. The conceptual elements reviewed, which are intended for young chemists who engage in drug discovery research, draw upon the author’s experience in developing eldecalcitol, an active vitamin D3 analog used to treat osteoporosis. The review covers exploratory research for a lead candidate compound; process development for practical manufacturing; and synthesis of other compounds relevant to the program, such as tritiated compounds, postulated metabolites, and miscellaneous analogs for mode of action studies.

PAPER

Eldecalcitol [1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3], an analog of calcitriol (1α,25-dihydroxyvitamin D3), possesses a hydroxypropoxy substituent at the 2β-position of calcitriol. Eldecalcitol has potent biological effects on bone disease such as osteoporosis. The marketing of eldecalcitol has very recently started in Japan. In consideration of this, we have been investigating practical synthesis of eldecalcitol for industrial-scale production. Eldecalcitol was initially synthesized in a linear manner. The 27-step linear sequence was, however, suboptimal due to its lengthiness and low overall yield (ca. 0.03%). Next, we developed a convergent approach based on the Trost coupling reaction, in which the A-ring fragment (ene-yne part obtained in 10.4% overall yield) and the C/D-ring fragment (bromomethylene part obtained in 27.1% overall yield) are coupled to produce the triene system of eldecalcitol (15.6%). Although the overall yield of the convergent synthesis was better than that of the linear synthesis, significant improvements were still necessary. Therefore, additional biomimetic studies were investigated. Process development for the practical production of eldecalcitol is described herein.

http://ar.iiarjournals.org/content/32/1/303/F3.expansion.html

Convergent synthesis of eldecalcitol (5) by coupling A-ring fragment 37 with C/D-ring fragment 40. Reagents and conditions: a: HO(CH2)3OH/t-BuOK, 120°C. b: t-BuCOCl/pyridine/CH2Cl2, rt. c: H2/Pd(OH)2/MeOH, rt. d: Me2C(OMe)2/TsOH/acetone, rt. e: DMSO/(COCl)2/CH2Cl2, −60°C. f: CH2=CHMgBr/THF, −60°C. g: t-BuCOCl/Et3N/DMAP/CH2Cl2, rt. h: 1 M HCl/MeOH, rt. i: Ph3P/DEAD/benzene, reflux. j: LiC ≡ CTMS/BF3-OEt2, −78°C. k: 10 N NaOH/MeOH, rt. l: TBSOTf/Et3N/CH2Cl2, 0°C. m: TESOTf/Et3N/CH2Cl2, 0°C. n: O3/CH2Cl2/MeOH, −78°C then NaBH4/MeOH, −78°C. o: NMO/TPAP/4Ams/CH2Cl2, rt. p: Ph3P+CH2BrBr−/NaHMDS/ THF, −60°C to rt. q: (dba)3Pd2-CHCl3/PPh3/Et3N/toluene, reflux. r: TBAF/THF/toluene, reflux.

 

Industrial synthesis of alfacalcidol (4) and biomimetic synthesis of eldecalcitol (5) from cholesterol (42). Reagents and conditions: a: [Al(Oi-Pr)3]/cyclohexanone. b: DDQ/AcOEt. c: NaOEt/EtOH. d: NaBH4/MeOH/THF. e: Ac2O/DMPA/pyridine, rt. f: NBS/AIBN/n-hexane, reflux. g: γ-collidine/toluene, reflux. h: KOH/MeOH, rt. i: PTAD/CH2Cl2, rt. j: TBSCl/imidazole. k: MCPBA/CH2Cl2. l: DMI, 140°C. m: TBAF/THF. n: NaBH4/EtOH. o: 400 W high pressure mercury lamp/THF, 0°C then reflux without mercury lamp. p: HO(CH2)3OH/t-BuOK, 110°C. q: Microbial 25-hydroxylation.

 ROUTE1

1. US4666634A / EP184206A2.

2. Chem. Pharm. Bull. 1993, 41, 1111-1113.

3. Drug Evaluation Research 2011, 34, 224-229.


1. Anticancer. Res. 2012, 32, 303-310.

2. Drugs. Fut. 2005, 30, 450-461.


1. J. Am. Chem. Soc. 2001, 123, 3716-3722.


1. Bioorg. Med. Chem. Lett. 1997, 7, 2871-2874.

2. Anticance. Res. 2009, 29, 3571-3578.

3. Heterocycles 2009, 77, 323-331.

4. Heterocycles 2006, 70, 295-307.


1. EP0503630A1.

2. Drugs Fut. 2005, 30, 450-461.


1. Bioorg. Med. Chem. 1998, 6, 2517-2523.

References

  1. Sanford, M; McCormack, PL (2011). “Eldecalcitol: A review of its use in the treatment of osteoporosis”. Drugs 71 (13): 1755–70. doi:10.2165/11206790-000000000-00000. PMID 21902297.
  2. Hatakeyama, S; Yoshino, M (2010). “Synthesis and preliminary biological evaluation of 20-epieldecalcitol [20-epi-1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3: 20-epi-ED-71]”. The Journal of Steroid Biochemistry and Molecular Biology 121 (1–2): 25–28.doi:10.1016/j.jsbmb.2010.03.041. PMID 20304058.
  3. Robichaud; Stamford; Weinstein; McAlpine; Primeau; Lowe; Bernstein; Bronson; Manoj, Desai (2012). Annual Reports in Medicinal Chemistry 47 (1st ed.). San Diego: Elsevier Inc. pp. 529–531. ISBN 9780123964922.
  4. Nogachi, Y; Kawate, H; Nomura, M; Takayanagi, R (2013). “Eldecalcitol for the treatment of osteoporosis”. Europe PubMed Central 8: 1313–1321. doi:10.2147/CIA.S49825.
  5. Smith, S; Doyle, N; Boyer, M; Chouinard, L; Saito, H (2013). “Eldecalcitol, a vitamin D analog, reduces bone turnover and increases trabecular an cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys”. Bone 57 (1): 116–122.doi:10.1016/j.bone.2013.06.005. PMID 23774444.
  6. Harada, S; Uno, S; Takahashi, F; Saito, H (2010). “Eldecalcitol is less effective in suppressing parathyroid hormone compared to calcitriol in vivo“. The Journal of Steroid Biochemistry and Molecular Biology 121 (1–2): 281–283.doi:10.1016/j.jsbmb.2010.04.001. PMID 20398764.
  7. Nakamura, T; Takano, T; Fukunaga, M; Shiraki, M; Matsumoto, T (2013). “Eldecalcitol is more effective for the prevention of osteoporotic fractures than alfacalcidol”. Journal of Bone and Mineral Metabolism 31 (4): 417–422. doi:10.1007/s00774-012-0418-5.PMC 3709079. PMID 23575909.
  8. Matsuo, K; Irie, N (2008). “Osteoclast-osteoblast communication”. Archives of Biochemistry and Biophysics 473 (2): 201–209. doi:10.1016/j.abb.2008.03.027.PMID 18406338.
  9. Saito, H; Takeda, S; Amizuka, N (2013). “Eldecalcitol and calcitriol stimulates ‘bone minimodeling,’ focal bone formation without prior bone resorption, in rat trabecular bone”.The Journal of Steroid Biochemistry and Molecular Biology 136 (1): 178–182.doi:10.1016/j.jsbmb.2012.10.004.
  10. Matsumoto, T; Ito, M; Hayashi, Y; Hirota, T; Tanigawara, Y; Sone, T; Fukunaga, M; Shiraki, M; Nakamura, T (2011). “A new active vitamin D3 analog, eldecalcitol, prevents the risk of osteoporotic fractures—A randomized, active comparator, double-blind study”. Bone49 (4): 605–612. doi:10.1016/j.bone.2011.07.011. PMID 21784190.
  11. Harada, S; Mizoguchi, T; Kobayashi, Y; Nakamichi, Y; Takeda, S; Sakai, S; Takahashi, F; Saito, H; Yasuda, H; Udagawa, N; Suda, T; Takahashi, N (2012). “Daily administration of eldecalcitol (ED-71), an active vitamin D analog, increases bone mineral density by suppressing RANKL expression in mouse trabecular bone”. Journal of Bone and Mineral Research 27 (1): 461–473. doi:10.1002/jbmr.555.
No. Major Technical Classification Publication No. Patent No. Legal Status Filling Date Estimated Expiry Date
1 Preparation CN85108857A CN1008368B Granted/expired 1985/12/4 2005/12/4
2 Crystal CN1223639A CN1216861C Granted 1997/6/16 2017/6/16
3 Preparation CN1637017A CN1276927C
Patent ID Date Patent Title
US7927613 2011-04-19 Pharmaceutical co-crystal compositions
US7323580 2008-01-29 CRYSTALS OF A VITAMIN D DERIVATIVE AND A METHOD FOR THE PREPARATION THEREOF
US7235679 2007-06-26 Crystals of a vitamin D derivative and a method for the preparation thereof
EP0924199 2006-05-10 CRYSTALS OF VITAMIN D DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOF
US2005009794 2005-01-13 Crystals of a vitamin D derivative and a method for the preparation thereof
US6831183 2004-12-14 Crystals of a vitamin D derivative and a method for the preparation thereof
US6448421 2002-09-10 CRYSTALS OF VITAMIN D DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOF
Eldecalcitol
Eldecalcitol.svg
Systematic (IUPAC) name
(1S,2S,3S,5Z,7E)-2-(3-Hydroxypropoxy)-9,10-secocholesta-5,7,10-triene-1,3,25-triol
Clinical data
Trade names Edirol
Identifiers
CAS Number 104121-92-8
ATC code None
PubChem CID 6438982
ChemSpider 4943418
Chemical data
Formula C30H50O5
Molar mass 490.715 g/mol

///////////eldecalcitol, active vitamin D3 analog,  treat osteoporosis, AC1O5QQ2, 104121-92-8,   AN-3697, ED 71, ED-71, Edirol®, PMDA, JAPAN

O[C@H]1CC(\C(=C)[C@H](O)[C@H]1OCCCO)=C\C=C2/CCC[C@]3([C@H]2CC[C@@H]3[C@H](C)CCCC(O)(C)C)C

OR

CC(CCCC(C)(C)O)C1CCC2C1(CCCC2=CC=C3CC(C(C(C3=C)O)OCCCO)O)C

 

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ECA Guide on Visual Inspection: updated version for all participants of the Particles event

 regulatory  Comments Off on ECA Guide on Visual Inspection: updated version for all participants of the Particles event
Jul 072016
 

 

The advisory board of the ECA Visual Inspection Group has worked on an update of its visual inspection guide. All participants of the ECA Conference Particles in Parenterals 2016 will receive a copy for free. Read more.

see

http://www.gmp-compliance.org/eca_mitt_05360_15266,15265,Z-PEM_n.html

The advisory board of the ECA Visual Inspection Group has worked on an update of its visual inspection guide. All participants of the ECA Conference Particles in Parenterals 2016, 28-29 September 2016 in Barcelona will receive a copy for free.

The paper, which is much rather supposed to be a reference than a strict requirement, covers Manual and Automated Inspection issues including qualification, validation and revalidation in the following chapters:

  • Manual inspection
  • Automated inspection
  • Inspection of lyophilized product
  • Defect Classes
  • Evaluation of defect classes and trending
  • Batch release
  • Concerns regarding distributed product

The chapter on manual inspection has been extended to also address semi-automated inspection. The chapter on batch release now contains more information and explanation on AQL testing.

More information can also be found on the group’s webpage.

 

//////////ECA Guide, Visual Inspection,  updated version, Particles event

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FDA issues new Draft Guidance on Elemental Impurities

 regulatory  Comments Off on FDA issues new Draft Guidance on Elemental Impurities
Jul 072016
 

The recently issued FDA Guideline on Elemental Impurities as a draft describes the procedure for controlling elemental impurities for medicinal products with and without official USP monograph. Read in what cases the FDA expects the fulfilment of the requirements of the Guideline ICH Q3D respectively of the general USP Chapter <232> und <233>.

see

http://www.gmp-compliance.org/enews_05465_FDA-issues-new-Draft-Guidance-on-Elemental-Impurities_15332,S-AYL_n.html

The ICH Q3D “Guideline for Elemental Impurities” was issued in December 2014 and recommended for adoption in the regulations portfolio of the ICH regions Europe, USA and Japan according to the ICH step-by-step procedure (Step 5). With the publication of the “ICH guideline Q3D on elemental impurities” (EMA/CHMP/ICH/353369/2013) in August 2015 the European Medicines Agency (EMA) implemented this step and determined June 2016 (for medicinal products to be newly approved) and December 2017 (for already approved medicinal products) as the dates for the Guideline to come into effect. The FDA took over the ICH Q3D Guideline in September 2015.

On 30 June 2016 the FDA Guidance for Industry “Elemental Impurities in Drug Products” was issued as a draft and is now open for comments for a period of 60 days.

The requirements of the Guidance apply to

  • New compendial and noncompendial NDA or ANDA drug products
  • Drug products not approved under an NDA or ANDA – as, e.g., compendial and noncompendial nonprescription OTC products.

Compendial medicinal products are generally supposed to fulfil the requirements defined in the general USP Chapters <232> und <233>. However, in the following cases the provisions of ICH Q3D have to be met:

  • For noncompendial drug products,
  • For metallic impurities listed only in ICH Q3D but not in the general USP Chapters <232> and <233>.

Correspondingly these provisions do also apply for changes to approved medicinal products, made with the goal to fulfil the requirements of the chapters <232> and <233> respectively of ICH Q3D. For compendial medicinal products the result of the change must be the compliance with <232> and <233>, noncompendial products have to comply with the provisions of ICH Q3D.

The FDA generally considers these kind of changes as low risk with regard to negative effects on identity, strength, quality, purity or potency. For that reason they are not subject to the CBE change procedure and can be reported to the FDA as part of the annual report.

The general USP Chapter <232> only comprises the PDE values of 15 elements, while ICH Q3D covers 24 elements. Otherwise both chapters were adapted to ICH Q3D and issued in the second supplementary volume of USP 38-NF 33 on 1 December 2015. However, both chapters can only be applied to compendial products starting on 1 January 2018 – the date mentioned in the General Notices 5.60.30 “Elemental Impurities in USP Drug Products and Dietary Supplements”. This is nearly the date (December 2017) determined for the application of ICH Q3D respectively the European Guideline (EMA/CHMP/ICH 353369/2013).

///////////FDA, Draft Guidance, Elemental Impurities

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Discovery and development of natural product oridonin-inspired anticancer agents

 Uncategorized  Comments Off on Discovery and development of natural product oridonin-inspired anticancer agents
Jul 072016
 

Microsoft Word - 2016-6-8_Manuscrpit_Review on Oridonin analogs

Natural products have historically been, and continue to be, an invaluable source for the discovery of various therapeutic agents. Oridonin, a natural diterpenoid widely applied in traditional Chinese medicines, exhibits a broad range of biological effects including anticancer and anti-inflammatory activities. To further improve its potency, aqueous solubility and bioavailability, the oridonin template serves as an exciting platform for drug discovery to yield better candidates with unique targets and enhanced drug properties. A number of oridonin derivatives (e.g. HAO472) have been designed and synthesized, and have contributed to substantial progress in the identification of new agents and relevant molecular mechanistic studies toward the treatment of human cancers and other diseases. This review summarizes the recent advances in medicinal chemistry on the explorations of novel oridonin analogues as potential anticancer therapeutics, and provides a detailed discussion of future directions for the development and progression of this class of molecules into the clinic.

Highlights

Oridonin displays significant anticancer activities via multi-signaling pathways.

Recent advances in medicinal chemistry of oridonin-like compounds are presented.

The article summarizes the SAR and mechanism studies of relevant drug candidates.

The milestones and future direction of oridonin-based drug discovery are discussed.

European Journal of Medicinal Chemistry

Volume 122, 21 October 2016, Pages 102–117

Review article

Discovery and development of natural product oridonin-inspired anticancer agents

  • a Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, 77555, United States
  • b Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States
doi:10.1016/j.ejmech.2016.06.015

 

Major milestones achieved in oridonin-inspired drug discovery and development.

 

 

////////Natural product, Oridonin, Diterpenoids, Anticancer agents, Drug discovery, Chemical biology,

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Understanding the chemistry behind the antioxidant activities of butylated hydroxytoluene (BHT): A review

 Uncategorized  Comments Off on Understanding the chemistry behind the antioxidant activities of butylated hydroxytoluene (BHT): A review
Jul 062016
 

imageHighlights

Modification of BHT has a significant multivariate effect on antioxidant efficiency.

BDE is the key to rational design and development of antioxidants.
Antioxidant performance of BHT is mainly depending on 13 very crucial parameters.
MPAO is a promising way to increase antioxidant and pharmacological activities.

Abstract

Hindered phenols find a wide variety of applications across many different industry sectors. Butylated hydroxytoluene (BHT) is a most commonly used antioxidant recognized as safe for use in foods containing fats, pharmaceuticals, petroleum products, rubber and oil industries. In the past two decades, there has been growing interest in finding novel antioxidants to meet the requirements of these industries. To accelerate the antioxidant discovery process, researchers have designed and synthesized a series of BHT derivatives targeting to improve its antioxidant properties to be having a wide range of antioxidant activities markedly enhanced radical scavenging ability and other physical properties. Accordingly, some structure–activity relationships and rational design strategies for antioxidants based on BHT structure have been suggested and applied in practice. We have identified 14 very sensitive parameters, which may play a major role on the antioxidant performance of BHT. In this review, we attempt to summarize the current knowledge on this topic, which is of significance in selecting and designing novel antioxidants using a well-known antioxidant BHT as a building-block molecule. Our strategy involved investigation on understanding the chemistry behind the antioxidant activities of BHT, whether through hydrogen or electron transfer mechanism to enable promising anti-oxidant candidates to be synthesized.

 

European Journal of Medicinal Chemistry

Volume 101, 28 August 2015, Pages 295–312

Review article

Understanding the chemistry behind the antioxidant activities of butylated hydroxytoluene (BHT): A review

  • aNanotechnology & Catalysis Research Centre, (NANOCAT), University of Malaya, Block 3A, Institute of Postgraduate Studies Building, 50603 Kuala Lumpur, Malaysia
  • bDepartment of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
  • cDivision of Human Biology, Faculty of Medicine, International Medical University, 57000 Kuala Lumpur, Malaysia
  • dDrug Design and Development Research Group, Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
  • http://www.sciencedirect.com/science/article/pii/S022352341530101X

doi:10.1016/j.ejmech.2015.06.026

SEE

https://www.researchgate.net/publication/278050005_ChemInform_Abstract_Understanding_the_Chemistry_Behind_the_Antioxidant_Activities_of_Butylated_Hydroxytoluene_BHT_A_Review/figures

 

 

 

 

///////////Antioxidant, Butylated hydroxytoluene, Free radical, Reactive oxygen species, Phenol

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Kinetics of Rh(II)-Catalyzed α-Diazo-β-ketoester Decomposition and Application to the [3+6+3+6] Synthesis of Macrocycles on a Large Scale and at Low Catalyst Loadings

 Uncategorized  Comments Off on Kinetics of Rh(II)-Catalyzed α-Diazo-β-ketoester Decomposition and Application to the [3+6+3+6] Synthesis of Macrocycles on a Large Scale and at Low Catalyst Loadings
Jul 062016
 

STR1

 

 

 

Kinetics of Rh(II)-Catalyzed α-Diazo-β-ketoester Decomposition and Application to the [3+6+3+6] Synthesis of Macrocycles on a Large Scale and at Low Catalyst Loadings

†Department of Organic Chemistry and ‡Department of Inorganic and Analytical Chemistry, University of Geneva, 30 Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland
ACS Catal., 2016, 6, pp 4877–4881
DOI: 10.1021/acscatal.6b01283

 

Abstract Image

In the context of [3+6+3+6] macrocyclization reactions, precise kinetics of α-diazo-β-ketoester decomposition were measured by in situ infrared (IR) monitoring. Dirhodium complexes of Ikegami–Hashimoto type—and perchlorinated phthalimido derivatives in particular—performed better than classical achiral complexes. Clear correlations were found between speciation among dirhodium species and catalytic activity. With these results, novel cyclohexyl-derived catalysts were developed, affording good yields of macrocycles (up to 78%), at low catalyst loadings (from 0.01 mol % to 0.001 mol %) and on a large scale (from 1 g to 20 g).

STR1

 

STR1

 

STR1

 

///////acceptor-acceptor diazo reagents,  dirhodium complexes,  in situ IR monitoring,  kinetics, low catalyst loading,  multigram synthesis,  speciation,  ylides

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C–H Arylation of Heterocyclic N-Oxides Through in Situ Diazotisation Of Anilines without Added Promoters: A Green And Selective Coupling Process

 Uncategorized  Comments Off on C–H Arylation of Heterocyclic N-Oxides Through in Situ Diazotisation Of Anilines without Added Promoters: A Green And Selective Coupling Process
Jul 062016
 

STR1

 

A green and selective method for the generation of biaryl compounds through C–H arylation of heterocyclic N-oxides, in which the addition of ascorbic acid as a promoter is not required for either the generation of an aryldiazonium species or the subsequent arylation, is presented. Reaction conditions were optimized through multivariate data analysis, including orthogonal projections to latent structures (OPLS) and design of experiments (DoE) methodologies, resulting in further sustainability improvements, and were then applied to a range of substrates to establish the scope and limitations of the process. The reaction was studied using in situ infrared spectroscopy and a mechanism is presented that accounts for the available data from this and previous studies. The reaction was also performed on a multigram scale, with calorimetry studies to support further scale-up of this promoter-free transformation.

C–H Arylation of Heterocyclic N-Oxides Through in Situ Diazotisation Of Anilines without Added Promoters: A Green And Selective Coupling Process

† API Chemistry, GlaxoSmithKline Research and Development Ltd., Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
‡ WestCHEM, Department of Pure and Applied Chemistry, Thomas Graham Building, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K.
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00117

2-(4-(Ethoxycarbonyl)phenyl)pyridine N-Oxide

Orange solid (81 mg, 22% yield), mp 119–120 °C.
1H NMR (DMSO-d6, 400 MHz): δ 8.39–8.38 (m, 1H), 8.07 (d, 2H, J = 8.6 Hz), 8.00 (d, 2H, J = 8.6 Hz), 7.72–7.67 (m, 1H), 7.45–7.48 (m, 2H), 4.37 (q, 2H, J = 7.1 Hz), 1.36 (t, 3H, J = 7.1 Hz) ppm.
13C NMR (DMSO-d6, 100 MHz): δ 165.3 (CIV), 146.6 (CIV), 140.2, 137.2 (CIV), 130.2 (CIV), 129.6, 128.7, 127.7, 126.1, 125.5, 60.9, 14.1 ppm.
HRMS (ESI+): calculated for C14H14NO3 [M+H]+ 244.0960, found 244.0968.
STR1
STR1

//////C–H Arylation of Heterocyclic N-Oxides, Situ Diazotisation Of Anilines, Promoters, Green And Selective Coupling Process

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