- Meta -Non-flat substituents: A novel molecular design to improve aqueous solubility in small molecule drug discovery
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Aqueous solubility is a key requirement for small-molecule drug candidates. Here, we investigated the regioisomer-physicochemical property relationships of disubstituted benzenes. We found that meta-isomers bearing non-flat substituents tend to possess the lowest melting point and the highest thermodynamic aqueous solubility among the regioisomers. The examination of pharmaceutical compounds containing a disubstituted benzene moiety supported the idea that the introduction of a non-flat substituent at the meta position of a benzene substructure would be a promising approach for medicinal chemists aiming to improve the thermodynamic aqueous solubility of drug candidates, even though it might not be universally effective. This journal is
- Ichikawa, Yuki,Hiramatsu, Michiaki,Mita, Yusuke,Makishima, Makoto,Matsumoto, Yotaro,Masumoto, Yui,Muranaka, Atsuya,Uchiyama, Masanobu,Hashimoto, Yuichi,Ishikawa, Minoru
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p. 446 - 456
(2021/01/29)
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- Preparation of a novel bridged bis(β-cyclodextrin) chiral stationary phase by thiol-ene click chemistry for enhanced enantioseparation in HPLC
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A bridged bis(β-cyclodextrin) ligand was firstly synthesized via a thiol-ene click chemistry reaction between allyl-ureido-β-cyclodextrin and 4-4′-thiobisthiophenol, which was then bonded onto a 5 μm spherical silica gel to obtain a novel bridged bis(β-cyclodextrin) chiral stationary phase (HTCDP). The structures of HTCDP and the bridged bis(β-cyclodextrin) ligand were characterized by the 1H nuclear magnetic resonance (1H NMR), solid state 13C nuclear magnetic resonance (13C NMR) spectra spectrum, scanning electron microscope, elemental analysis, mass spectrometry, infrared spectrometry and thermogravimetric analysis. The performance of HTCDP in enantioseparation was systematically examined by separating 21 chiral compounds, including 8 flavanones, 8 triazole pesticides and 5 other common chiral drugs (benzoin, praziquantel, 1-1′-bi-2-naphthol, Tr?ger's base and bicalutamide) in the reversed-phase chromatographic mode. By optimizing the chromatographic conditions such as formic acid content, mobile phase composition, pH values and column temperature, 19 analytes were completely separated with high resolution (1.50-4.48), in which the enantiomeric resolution of silymarin, 4-hydroxyflavanone, 2-hydroxyflavanone and flavanone were up to 4.34, 4.48, 3.89 and 3.06 within 35 min, respectively. Compared to the native β-CD chiral stationary phase (CDCSP), HTCDP had superior enantiomer separation and chiral recognition abilities. For example, HTCDP completely separated 5 other common chiral drugs, 2 flavanones and 3 triazole pesticides that CDCSP failed to separate. Unlike CDCSP, which has a small cavity (0.65 nm), the two cavities in HTCDP joined by the aryl connector could synergistically accommodate relatively bulky chiral analytes. Thus, HTCDP may have a broader prospect in enantiomeric separation, analysis and detection. This journal is
- Gong, Bolin,Guo, Siyu,Zhang, Ning
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p. 35754 - 35764
(2021/12/02)
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- Preparation method of (R)-bicalutamide intermediate
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The invention relates to a method for preparing an (R)-bicalutamide intermediate. The method comprises the following steps: taking methacrylic acid as a raw material, and obtaining the (R)-bicalutamide intermediate through several steps of esterification, hydroxylation and sulfonation, namely, (R)-3-(4-fluorophenylsulfydryl)-2-hydroxy-2-methylpropionic acid. (R)-bicalutamide with enantioselectivity of more than 99% can be obtained by two simple follow-up reactions of the intermediate. The preparation method has the advantages of easily available starting materials, high reaction yield, easy operation in reaction, high enantioselectivity and wide industrial application prospects.
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- Design and synthesis of novel bicalutamide and enzalutamide derivatives as antiproliferative agents for the treatment of prostate cancer
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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.
- Bassetto, Marcella,Ferla, Salvatore,Pertusati, Fabrizio,Kandil, Sahar,Westwell, Andrew D.,Brancale, Andrea,McGuigan, Christopher
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p. 230 - 243
(2016/05/10)
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- ANDROGEN RECEPTOR ANTAGONISTS
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Disclosed herein are compositions and methods for modulating the androgen receptor.
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Paragraph 0327
(2016/04/26)
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- A new avenue toward androgen receptor pan-antagonists: C2 sterically hindered substitution of hydroxy-propanamides
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The androgen receptor (AR) represents the primary target for prostate cancer (PC) treatment even when the disease progresses toward androgen-independent (AIPC) or castration-resistant (CRPC) forms. Because small chemical changes in the structure of nonsteroidal AR ligands determine the pharmacological responses of AR, we developed a novel stereoselective synthetic strategy that allows sterically hindered C2-substituted bicalutamide analogues to be obtained. Biological and theoretical evaluations demonstrate that C2-substitution with benzyl and phenyl moieties is a new, valuable option toward improving pan-antagonist behavior. Among the synthesized compounds, (R)-16m, when compared to casodex, (R)-bicalutamide, and enzalutamide, displayed very promising in vitro activity toward five different prostate cancer cell lines, all representative of CPRC and AIPC typical mutations. Despite being less active than (R)-bicalutamide, (R)-16m also displayed marked in vivo antitumor activity on VCaP xenografts and thus it may serve as starting point for developing novel AR pan-antagonists.
- Guerrini, Andrea,Tesei, Anna,Ferroni, Claudia,Paganelli, Giulia,Zamagni, Alice,Carloni, Silvia,Di Donato, Marzia,Castoria, Gabriella,Leonetti, Carlo,Porru, Manuela,De Cesare, Michelandrea,Zaffaroni, Nadia,Beretta, Giovanni Luca,Del Rio, Alberto,Varchi, Greta
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p. 7263 - 7279
(2015/01/30)
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- Separation of racemic bicalutamide by an optimized combination of continuous chromatography and selective crystallization
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A racemic mixture of bicalutamide, a drug substance used in the treatment of prostate cancer, was separated by simulated moving bed chromatography, with the objective of maximizing throughput at reduced outlet purity. The enriched extract stream was purified further by a crystallization process exploiting a shift in the eutectic composition. The optimal purity in between both process steps was identified. The separation scheme developed was validated on a scale of 600 g, and the results were compared to those of state-of-the art and discussed. The investigated scheme revealed a wide range of promising coupling conditions while showing superior productivities and enhanced process robustness.
- Kaemmerer, Henning,Horvath, Zoltan,Lee, Ju Weon,Kaspereit, Malte,Arnell, Robert,Hedberg, Martin,Herschend, Bjoern,Jones, Matthew J.,Larson, Kerstin,Lorenz, Heike,Seidel-Morgensten, Andreas
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experimental part
p. 331 - 342
(2012/06/18)
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- NON-STEROIDAL COMPOUNDS FOR ANDROGEN RECEPTOR MODULATION
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The present invention concerns compounds of general Formula (I) : method of preparation and uses thereof.
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- Bacillus subtilis epoxide hydrolase-catalyzed preparation of enantiopure 2-methylpropane-1,2,3-triol monobenzyl ether and its application to expeditious synthesis of (R)-bicalutamide
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Expeditious synthesis of (R)-bicalutamide (1), a synthetic antiandrogen, from enantiopure 2-methylpropane-1,2,3-triol monobenzyl ether (4) was achieved. An engineered Bacillus subtilis epoxide hydrolase worked enantioselectively on the racemic epoxide (7) to provide the above starting material in highly enantiomerically enriched state.
- Fujino, Aya,Asano, Masayoshi,Yamaguchi, Hitomi,Shirasaka, Naoki,Sakoda, Akiko,Ikunaka, Masaya,Obata, Rika,Nishiyama, Shigeru,Sugai, Takeshi
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p. 979 - 983
(2008/02/04)
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- Syntheses of enantiomerically pure (R)- and (S)-bicalutamide
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The racemic antiandrogen bicalutamide is the leading antiandrogen used for the treatment of prostate cancer. The (R)-isomer possesses virtually all of the activity, but both isomers are metabolized by the liver. A convenient synthetic route to the active enantiomer would be an attractive option for patients who are hepatically impaired. We now demonstrate a rather short synthesis of (R)-bicalutamide, starting with a naturally occurring, chiral precursor.
- James, Kenneth D,Ekwuribe, Nnochiri N
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p. 5905 - 5908
(2007/10/03)
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