Hydrothiolation of benzyl mercaptan to arylacetylene: application to the synthesis of (E) and (Z)-isomers of ON 01910·Na (Rigosertib®), a phase III clinical stage anti-cancer agent

Abstract

A stereoselective and efficient method for free radical addition of benzyl thiol to aryl acetylene in the presence of Et3B-hexane has been developed for the synthesis of (Z) and (E)-styryl benzyl sulfides where base catalyzed hydrothiolations have failed. The scope of this reaction was successfully extended for the synthesis of (E)-ON 01910·Na, a phase III clinical stage anti-cancer agent and its inactive geometrical isomer (Z)-ON 01910·Na. It is interesting to note that all the E-isomers synthesized have shown better cytotoxicity profile on cancer cells compared to the Z-isomers.

Rigosertib as a selective anti-tumor agent can ameliorate multiple dysregulated signaling transduction pathways in high-grade myelodysplastic syndrome

“…Rigosertib is a member of a broader class of unsaturated sulfone kinase inhibitors that allosterically inhibit substrate binding 13 22 . Rigosertib has received increasing focus due to its promising anti-tumor activity in a wide variety of cancer cells without affecting the proliferation and survival of normal cells.…”

Synthesis and antitumor effects of novel benzyl naphthyl sulfoxide/sulfone derivatives derived from Rigosertib

“…21 Compounds 12a-12e were prepared by nitro reduction of 11a-11d and 10a, while 12a-12d were further esteried, salied and followed by hydrolysis reactions to give compounds 13a-13c, 14a-14b and 15a-15b. 28 All the synthesized compounds were puried by recrystallization or silica gel column chromatography, and all of the target compounds were characterized by 1 H-NMR, 13 C-NMR and HR-MS spectra analyses.…”

Hydroelementation of Unsaturated C–C Bonds Catalyzed by Metal Scorpionate Complexes

“…Many advances have been made in metal‐free nucleophilic and radical over the years, however the highly reactive nature of sulfur nucleophiles and radicals makes chemoselectivity difficult to achieve. Radical alkyne hydrothiolation has been successfully applied to the synthesis of ON 01910 (Rigosertib), while transition‐metal‐catalyzed alkyne hydrothiolation has been successfully applied to the total synthesis of K777, a cysteine protease inhibitor (Figure )…”