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.

 

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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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