1. Mechanistic studies on the synthesis of bicalutamide
Nabil Asaad* and Shaun Fillery. Org. Biomol. Chem., 2009, 7, 678–686
Being a hydroxysulfone, bicalutamide (1) may be prepared directly from opening the appropriate epoxide with an aryl sulfinate, or in two steps with a thiolate to give a hydroxythioether which may be oxidised subsequently to the sulfone. Conceptually, these approaches differ only in whether oxidation of sulfur occurs prior to or after the epoxide-opening step, however the reduced nucleophilicity of the sulfinate relative to the thiolate clearly has practical implications. The aim of our studies was to demonstrate that the synthesis of bicalutamide (1)from the chlorohydrin (2) occurs via an intermediate epoxide (3)andthat the anionic sulfur nucleophiles 4-fluorobenzenethiolate (4)and 4-fluorobenzenesulfinate (5) react under the same conditions via the same mechanism. Whilst confirmation of the expected sequential pathway, as opposed to a direct SN2-displacement of chloride by the anionic sulfur nucleophiles, could be inferred from the presence and consumption of the intermediate epoxide in a “one-pot” reaction, we thought it prudent additionally to prepare and study the O-methyl analogue (8) of the chlorohydrin in order to verify that it did not form the O-methyl analogue of bicalutamide.
2. Development of an electrochemical method for the determination of bicalutamide at the SWCNT/CPE in pharmaceutical preparations and human biological fluids
Umar J. Pandit,* Imran Khan, Sneha Wankar, K. K. Raj and S. N. Limaye. Anal. Methods,2015,
Bicalutamide (BIC), N-(4-cyano-3-trifluoromethyl-phenyl)-3-(4-fluoro-phenylsulfonyl)-2-hydroxy-2-methyl-propionamide (Scheme 1), is an orally active potent, well-tolerated, nonsteroidal pure antiandrogen with negligible gastrointestinal intolerance. BIC binds to the androgen receptor (AR) which is essential for the development of male characters and is also a key factor for the development and progression of prostate cancer. BIC is one of the newest nonsteroidal antiandrogenic drugs traded as Caluran, Casodex, Bicaluran, etc.
3. Interaction mechanism exploration of R-bicalutamide/S-1 with WT/W741L AR using molecular dynamics simulations
Hongli Liu, Xiaoli An, Shuyan Li, Yuwei Wang, Jiazhong Li* and Huanxiang Liu. Mol. BioSyst., 2015, 11, 3347—3354
To investigate the mechanisms of drug resistance and to explore the reasons why subtle structural differences result in dramatic physiological action changes to aid new drug discovery and treat PCa, in this study, molecular dynamics (MD) simulations are employed to study the interaction modes of R-bicalutamide and S-1 with the WT and W741L AR respectively. Moreover, the binding free energy and energy decomposition are additionally calculated, which can provide further comprehension about the R-bicalutamide switch from an antagonist to an agonist due to W741L mutation, while the molecule S-1 remains agonistic.
4. Cocrystals of the antiandrogenic drug bicalutamide: screening, crystal structures, formation thermodynamics and lattice energies
Artem O. Surov, German L. Perlovich*. CrystEngChem.,2016, 18,4818–4829
Different strategies to improve the aqueous solubility and/or dissolution rate and thus the absorption of the drug have been described in the literature, such as solid dispersions, particle size reduction, development of various nanoparticulate delivery systems, and complexation with cyclodextrins. An alternative approach to overcome the solubility challenge without modification of the pharmacophore structure of an active pharmaceutical ingredient (API) is to develop new crystalline forms such as polymorphs, solvates, salts or cocrystals. Two polymorphic forms of bicalutamide have been reported and their crystal structures, physico-chemical properties and thermodynamic stability have been investigated. A solvate with dimethyl sulfoxide has been described by Perlovich et al. It should be stressed that bicalutamide represents a good example of an API for which salt formation is limited due to the lack of suitable ionizable groups. In this case, therefore, cocrystallization has great advantages since molecular cocrystals can be formed regardless of the API's ionisable status. To date, however, cocrystal formation for bicalutamide does not seem to have been systematically explored, and only two cocrystals of Bic with 4,4′-bipyridine and trans-1,2-bisIJ4-pyridyl)ethane are known. Unfortunately, these cocrystal formers may hardly be considered as pharmaceutically relevant. Thus, development of novel crystalline forms of bicalutamide with potentially enhanced key physicochemical properties is still of considerable interest.
