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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
SYNTHESIS
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].
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.
•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
A university spokesman described Prof McGuigan as ‘exceptionally gifted’
A top cancer scientist has died from the disease – after a lifetime of research looking for a cure.
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 Echo
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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