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

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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

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.

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

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.

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.

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    • 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.
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    • 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
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    • 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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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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