AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
May 062017
 

Novel diarylheptanoids as inhibitors of TNF-α production

Sameer Dhurua, Dilip Bhedia, Dnyaneshwar Gophanea, Kiran Hirbhagata, Vijaya Nadara, Dattatray Morea, Sapna Parikha, Roda Dalala, Lyle C. Fonsecaa, Firuza Kharasa, Prashant Y. Vadnala, Ram A. Vishwakarmaa, H. Sivaramakrishnana*

 

aDepartment of Medicinal Chemistry, Piramal Life Sciences Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon (E), Mumbai 400 063, India

bDepartment of Pharmacology, Piramal Life Sciences Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon (E), Mumbai 400 063, India 

Bioorg. Med. Chem. Lett. 21 (2011) 3784–3787

 

[Link: http://pubs.rsc.org/en/content/articlelanding/2013/cc/c2cc36389e#!divAbstract]

 

Graphical abstract

 

Synthesis and anti-inflammatory activity of novel diarylheptanoids [5-hydroxy-1-phenyl-7-(pyridin-3-yl)-heptan-3-ones and 1-phenyl-7-(pyridin-3-yl)hept-4-en-3-ones] as inhibitors of tumor necrosis factor-α (TNF-α production is described in the present article. The key reactions involve the formation of a β-hydroxyketone by the reaction of substituted 4-phenyl butan-2-ones with pyridine-3-carboxaldehyde in presence of LDA and the subsequent dehydration of the same to obtain the α,β-unsaturated ketones. Compounds 4i, 5b, 5d, and 5g significantly inhibit lipopolysaccharide (LPS)-induced TNF-α production from human peripheral blood mononuclear cells in a dose-dependent manner. Of note, the in vitro TNF-α inhibition potential of 5b and 5d is comparable to that of curcumin (a naturally occurring diarylheptanoid). Most importantly, oral administration of 4i, 5b, 5d, and 5g (each at 100 mg/kg) but not curcumin (at 100 mg/kg) significantly inhibits LPS-induced TNF-α production in BALB/c mice. Collectively, our findings suggest that these compounds may have potential therapeutic implications for TNF-α-mediated auto-immune/inflammatory disorders.

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Scheme 1. Synthetic scheme

 

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Table 1.

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Table 2.

 

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Highlights

 

  • Designed and synthesized a novel series of diarylheptanoids.
  • Compounds 4i, 5b, 5d, and 5g significantly inhibit in vitro TNF-α production from human cells.
  • Oral administration of these compounds significantly inhibits TNF-α production in mice.
  • These compounds may have potential therapeutic implications for TNF- α -mediated auto-immune/inflammatory diseases.

 

ABOUT GUEST BLOGGER

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Dr. Dnyaneshwar B. Gophane, Ph. D.

Post doc fellow at Purdue university and university of Iceland

Email, gophane@gmail.com

 

Dr. Dnyaneshwar B. Gophane completed his B.Sc. (Chemistry) at Anand college of science, Pathardi (Ahmednagar, Maharashtra, India) in 2000 and M.Sc. (Organic Chemistry) at Department of Chemistry, University of Pune (India) in 2003. From 2003 to 2008, he worked in research and development departments of pharmaceutical companies like Dr. Reddy’s Laboratories and Nicholas Piramal India Limited, where he involved in synthesizing novel organic compounds for in vitro and in vivo screening and optimizing process for drug molecule syntheses. In 2008, Dnyaneshwar joined Prof. Sigurdsson’s laboratory for his Ph.D. study at the University of Iceland. His Ph.D. thesis mainly describes syntheses of nitroxide spin-labeled and fluorescent nucleosides and their incorporation into DNA and RNA using phosphoramidite chemistry. These modified nucleosides are useful probes for studying the structure and dynamics of nucleic acids by EPR and fluorescence spectroscopies. In 2014, after finishing his Ph.D., he worked as post doc fellow in same laboratory and mainly worked on spin labelling of RNA. At the university of Purdue in his second post doc, he was totally dedicated to syntheses of small molecules for anti-cancer activity and modification of cyclic dinucleotides for antibacterial activity. During his research experience, he has authored 8 international publications in peer reviewed journals like Chemical Communications, Chemistry- A European Journal, Journal of organic chemistry and Organic and Biomolecular Chemistry.

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May 032017
 

Hydrogen-bonding controlled rigidity of an isoindoline-derived nitroxide spin label for nucleic acids

Dnyaneshwar B. Gophane and Snorri Th. Sigurdsson* 

a Department of Chemistry, Science Institute, University of Iceland, Dunhaga 3, 107 Reykjavik, Iceland 

Chem. Commun., 2013, 49, 999—1001

[Link: http://pubs.rsc.org/en/content/articlelanding/2013/cc/c2cc36389e#!divAbstract]

 

Graphical abstract

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Two new nitroxide-modified nucleosides, OxU and ImU, were synthesized and incorporated into DNA. ImU has lower mobility in duplex DNA due to an intramolecular hydrogen bond.

Abstract 

Nucleosides spin-labelled with isoindoline-derived benzimidazole (ImU) and benzoxazole (OxU) moieties were synthesized and incorporated into DNA oligonucleotides. Both labels display limited mobility in duplex DNA but ImU was less mobile, which was attributed to an intramolecular hydrogen bond between the N-H of the imidazole and O4 of the uracil nucleobase.

Scheme 1. Literature methods for synthesis of diamino isoindoline 6.

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Scheme 2. Improved synthesis of diamino isoindoline 6.

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Scheme 3. Synthesis of benzimidazole derivative phosphoramidites 10.

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Scheme 4. Synthesis of benzoxazole derivative phosphoramidites 14.

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Highligts

 

  • Synthesized novel nitroxide-labelled benzimidazole (ImU) and benzoxazole (OxU) derivatives of 2′-deoxyuridine as spin probes for nucleic acids.
  • Both ImU and OxU had limited mobility in duplex DNA, in particular ImU, indicating that rotation around the single bond linking the spin label to the uracil is restricted.
  • ImU is the first example of using intramolecular hydrogen-bonding to restrict spin label mobility.
  • ImU should not only be a good label for accurate distance measurements in oligonucleotides, but also yield information about the relative orientation of the labels.


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ABOUT GUEST BLOGGER

 

Dr. Dnyaneshwar B. Gophane, Ph. D.

Post doc fellow at Purdue university and university of Iceland

Email, gophane@gmail.com

Dr. Dnyaneshwar Gophane

Phone: +917083553405 and +917558215379

Dr. Dnyaneshwar B. Gophane completed his B.Sc. (Chemistry) at Anand college of science, Pathardi (Ahmednagar, Maharashtra, India) in 2000 and M.Sc. (Organic Chemistry) at Department of Chemistry, University of Pune (India) in 2003. From 2003 to 2008, he worked in research and development departments of pharmaceutical companies like Dr. Reddy’s Laboratories and Nicholas Piramal India Limited, where he involved in synthesizing novel organic compounds for in vitro and in vivo screening and optimizing process for drug molecule syntheses. In 2008, Dnyaneshwar joined Prof. Sigurdsson’s laboratory for his Ph.D. study at the University of Iceland. His Ph.D. thesis mainly describes syntheses of nitroxide spin-labeled and fluorescent nucleosides and their incorporation into DNA and RNA using phosphoramidite chemistry.

These modified nucleosides are useful probes for studying the structure and dynamics of nucleic acids by EPR and fluorescence spectroscopies. In 2014, after finishing his Ph.D., he worked as post doc fellow in same laboratory and mainly worked on spin labelling of RNA. At the university of Purdue in his second post doc, he was totally dedicated to syntheses of small molecules for anti-cancer activity and modification of cyclic dinucleotides for antibacterial activity. During his research experience, he has authored 8 international publications in peer reviewed journals like Chemical Communications, Chemistry- A European Journal, Journal of organic chemistry and Organic and Biomolecular Chemistry.

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Apr 292017
 

Image for unlabelled figure

As a GUEST BLOGGER, myself Dr Pravin Patil,  presenting my paper as below

A New Combination of Cyclohexylhydrazine and IBX for Oxidative Generation of Cyclohexyl Free Radical and Related Synthesis of Parvaquone

 Pravin C Patil*a and Krishnacharya G Akamanchi

Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai-400 019.

aPresent address: Department of Chemistry, University of Louisville, Louisville, KY, USA.

*Corresponding Author: Email-pravinchem@gmail.com

Tetrahedron Letters 2017, 58 (19), 1883-1886 (Recently published)

[Link: http://www.sciencedirect.com/science/article/pii/S004040391730429X]

 

Graphical Abstract:

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Abstract: The present paper demonstrate a single-step and straightforward synthesis of parvaquone through intermediacy of cyclohexyl radical generated from novel combination of cyclohexylhydrazine and o-iodoxybenzoic acid and subsequently trapped by 2-hydroxy-1,4-naphthoquinone. Formation of cyclohexyl free radical using this new combination was reaffirmed by cyclohexylation of readily available 2-amino-1, 4-naphthoquinone.

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Scheme: Literature methods for synthesis of parvaquone

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Scheme:  IBX mediated oxidative arylation towards synthesis of 1 (Parvaquone)

 

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Scheme :  Cyclohexyl radical mediated postulated mechanism for formation of Parvaquone, 1

Synthesis of 2-cyclohexyl-3-hydroxy-1,4-naphthoquinone (parvaquone) (1): To a solution of 3 (1.0 g, 5.74 mmol) in acetonitrile (20 mL) was added IBX (3.80 g, 13.6 mmol) in one lot and stirred for 5 min at room temperature. To this was added dropwise a solution of 8 (0.78 g, 6.8 mmol) dissolved in 10 mL of acetonitrile over the course of 20 min. During the addition of 8 exotherm (up to 35 °C) was observed with evolution of nitrogen gas in the form of bubbles. Reaction progress was monitored by TLC (using mobile phase, hexane: ethyl acetate/5:95). After satisfactory TLC, water (20 mL) was added to the reaction mixture and acetonitrile was evaporated using rotary evaporator. To the residue obtained was added dichloromethane (30 mL). Oganic layer was separated and washed with saturated sodium bicarbonate solution followed by saturated solution of sodium sulphite. Separated organic layer was dried over anhydrous sodium sulphate and evaporated to obtain crude 1 which was further purified by column chromatography (mobile phase – hexane: ethyl acetate/5:95) to afford 1 as yellow solid, (0.88 g, 60% yield); mp 136-138 °C (lit.18 135-136°C); FT-IR (KBr): 3585, 3513, 3071, 2926, 2853, 1666, 1604, 1590 cm-1;

1H NMR (300 MHz; CDCl3): δ 8.10-8.06 (d, J = 12 Hz, 2H), 7.74-7.67 (d, J = 22 Hz, 2H, 7.45 (s, 1H, OH), 3.11-3.03 (t, J = 16 Hz, 1H), 1.99-1.34 (m, 10H); 13C NMR (75 MHz; CDCl3): δ 184.5, 181.9, 152.8, 135.1, 134.9, 132.7, 129.2, 127.9, 126.9, 125.9, 35.1, 29.2, 26.7, 25.9.

Highlights

  • New method of generating cyclohexyl radical by using IBX and cyclohexylhydrazine.
  • Parvaquone synthesized in 60% yield using metal, hazardous peroxide free conditions.
  • Described method has advantages of single step and mild reaction conditions.
  • The mechanism for cyclohexyl radical mediated synthesis of parvaquone is postulated.

 

please note………

Image result for A new combination of cyclohexylhydrazine and IBX for oxidative generation of cyclohexyl free radical and related synthesis of parvaquone

 

ABOUT GUEST BLOGGER

Dr. Pravin C. Patil

Dr. Pravin C. Patil

Postdoctoral Research Associate at University of Louisville

Email, pravinchem@gmail.com

    see…….http://oneorganichemistoneday.blogspot.in/2017/04/dr-pravin-patil.html

    Dr. Pravin C Patil completed his B.Sc. (Chemistry) at ASC College Chopda (Jalgaon, Maharashtra, India) in 2001 and M.Sc. (Organic Chemistry) at SSVPS’S Science College Dhule in North Maharashtra University (Jalgaon, Maharashtra, India) in year 2003. After M.Sc. degree he was accepted for summer internship training program at Bhabha Atomic Research Center (BARC, Mumbai) in the laboratory of Prof. Subrata Chattopadhyay in Bio-organic Division. In 2003, Dr. Pravin joined to API Pharmaceutical bulk drug company, RPG Life Science (Navi Mumbai, Maharashtra, India) and worked there for two years. In 2005, he enrolled into Ph.D. (Chemistry) program at Institute of Chemical Technology (ICT), Matunga, Mumbai, aharashtra, under the supervision of Prof. K. G. Akamanchi in the department of Pharmaceutical Sciences and Technology.

    After finishing Ph.D. in 2010, he joined to Pune (Maharashtra, India) based pharmaceutical industry, Lupin Research Park (LRP) in the department of process development. After spending two years at Lupin as a Research Scientist, he got an opportunity in June 2012 to pursue Postdoctoral studies at Hope College, Holland, MI, USA under the supervision of Prof. Moses Lee. During year 2012-13 he worked on total synthesis of achiral anticancer molecules Duocarmycin and its analogs. In 2014, he joined to Prof. Frederick Luzzio at the Department for Chemistry, University of Louisville, Louisville, KY, USA to pursue postdoctoral studies on NIH sponsored project “ Structure based design and synthesis of Peptidomimetics targeting P. gingivalis.

    During his research experience, he has authored 23 international publications in peer reviewed journals and inventor for 4 patents.

    //////////////Parvaquone, guest blogger, pravin patil

     

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