A new series of bicalutamide, enzalutamide and enobosarm derivatives carrying pentafluorosulfanyl (SF5) and pentafluoroethyl (C2F5) substituents: Improved antiproliferative agents against prostate cancer

Abstract

A new series of bicalutamide, enzalutamide and enobosarm derivatives carrying pentafluorosulfanyl (SF5) and pentafluoroethyl (C2F5) substituents: improved antiproliferative agents against prostate cancer.

19F NMR as a tool in chemical biology

“…Notably, compounds with new fluorinated groups, for which there is no precedent in the literature, pose challenges for analy-sis of biotransformation products. For instance, the pentafluorosulfanyl (-SF 5 ) group is proposed as a replacement for trifluoromethyl (-CF 3 ) and has been incorporated into numerous biologically active compounds already [108,109]. Intuitively, investigating the biodegradation of these compounds in the absence of any reference compounds is complicated.…”

Studies of Halogen Bonding Induced by Pentafluorosulfanyl Aryl Iodides: A Potential Group of Halogen Bond Donors in a Rational Drug Design

“…Given the impressive physiochemical properties of the SF 5 unit, which include its high electronegativity (σ m = 0.61, σ p = 0.68; nearly equivalent to the NO 2 group: σ m = 0.73, σ p = 0.78) [30,31,32], high lipophilicity (π = 1.51; greater than that of the CF 3 group: π = 0.88 and the NO 2 group: π = −0.28) [32,33,34], and steric hindrance (nearly equivalent to that of the tert -butyl group) [34,35], the SF 5 -containing analogs of marketed drugs are attractive candidates in the future drug market (Figure 1b) [36,37,38,39,40,41]. More and more examples of biologically active SF 5 -containing drug candidates have been reported in recent years (Figure 1c) [35,38,39,40,41,42,43,44]. Extending our research to the design and synthesis of SF 5 -containing biologically attractive molecules [45,46,47,48,49,50,51,52,53,54,55,56,57] and a halogen bonding research program [58,59], we are interested in aryl iodides 1a – d consisting of SF 5 -group(s) in the benzene ring as potential drug fragments capable of halogen bonding, in particular, 3,5-bis-SF 5 -iodobenzene ( 1d , Figure 1d).…”

Recent Advances in the Synthesis and Medicinal Chemistry of SF5 and SF4Cl Compounds

“…Scheme 49 Synthesis and AR IC50s of 3-SF5 enzatulamide derivatives 43 Synthesis and anticancer activity studies on enzalutamide and enoborsam analogues carrying the SF5 group, were reported by Pertusati and co-workers. (Figure 3) 44 Figure 3 Enzalutamide, Enobosarm and SF5 analogues structures 44 Synthesis of SF5-substituted bicalutamide and enobosarm derivatives is shown in Scheme 50. Reaction of 3 or 4-SF5 aniline with methacryolyl chloride provided the corresponding methacrylamides, which were then converted into the corresponding epoxides by oxidation with a hydrogen peroxide/triluoroacetic anhydride mixture.…”

“…Scheme 51 Synthesis and AR IC50s of SF5 substituted enzalutamide analogues 44 Scheme 52 Synthesis and AR IC50s of SF5 substituted enzalutamide analogues. 44 Key: iPAC = isopropyl acetate Shibata et al reported unsymmetrical ortho-SF5 phenylaryl-λ 3iodonium salts as potential antitumor agents that were tested against human lymphoma U937 cells. 45 Ortho-SF5-substituted diaryliodonium salts were designed with different aryl groups (e.g.…”