2-Hydroxy-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)-3-((2-(trifluoromethyl)phenyl)thio)propanamide
Purified by flash column
chromatography eluting with n-hexane/EtOAc
100:0 v/v increasing to n-hexane/EtOAc
70:30 v/v. Obtained in 57% yield as a pale yellow sticky solid.
1H-NMR
(CDCl3): d 9.00 (bs, 1H), 7.93-7.90 (m,
2H), 7.72-7.69 (m, 2H), 7.49-7.46 (m, 2H), 7.24-7.21 (m, 1H), 4.00 (d, J= 14.3
Hz, 1H), 3.57 (s, 1H), 3.21 (d, J= 14.3 Hz, 1H), 1.57 (s, 3H).
19F-NMR (CDCl3): d -60.17
(s, 3F), -60.07 (s, 3F).
13C-NMR (CDCl3): d 172.7,
141.0, 134.0, 132.6, 132.3, 127.4, 126.7, 126.6, 126.6, 122.7, 121.8, 118.0,
117.9, 75.1, 45.3, 26.1.
MS [ESI, m/z]: 469.3 [M+H]+,
491.0 [M+Na]+.
EI-HMRS (M-H)- found 467.0489, calculated for C18H13N2O4F6S
467.0500.
HPLC (method 1): retention time = 22.44 min.
1H-NMR (CDCl3): d 9.00 (bs, 1H), 7.93-7.90 (m, 2H), 7.72-7.69 (m, 2H), 7.49-7.46 (m, 2H), 7.24-7.21 (m, 1H), 4.00 (d, J= 14.3 Hz, 1H), 3.57 (s, 1H), 3.21 (d, J= 14.3 Hz, 1H), 1.57 (s, 3H).
1H NMR
19F-NMR (CDCl3): d -60.17 (s, 3F), -60.07 (s, 3F).
19F-NMR
13C-NMR (CDCl3): d 172.7, 141.0, 134.0, 132.6, 132.3, 127.4, 126.7, 126.6, 126.6, 122.7, 121.8, 118.0, 117.9, 75.1, 45.3, 26.1.
13C-NMRDr Marcella Bassetto
Post Doctoral Research Associate
- bassettom@cardiff.ac.uk
- https://www.researchgate.net/profile/Marcella_Bassetto
- http://marcellabassetto.blogspot.in/
Paper
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.
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, 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.
“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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