Tokyo Chemical Industry Co. Ltd.

Kinesin spindle protein (KSP) represents a promising target for cancer therapy with a mechanism of action distinct from conventional microtubule agents. We previously identified S-trityl-_L-cysteine (STLC) derivatives as potent and selective KSP inhibitors. In this study, we designed STLC derivatives with diverse physicochemical properties for further structural optimization using in silico analyses. rac-1-C and 2-C were synthesized via a key allylation reaction of ethylene-bridged triarylmethanol mediated by XtalFluor-E. Compound 2-C (HCT116 half growth inhibition (GI₅₀): 1.2 nM) was identified as the minimal pharmacophore for KSP inhibition. Additionally, we explored the feasibility of using these inhibitors as linker-payloads in antibody-drug conjugates (ADCs). Guided by structure-activity relationships, we synthesized enzyme-cleavable valine-citrulline-p-aminobenzyloxycarbonyl linker STLC derivatives (VC-linker-STLCs) capable of cathepsin B-mediated payload release. Slight structural differences in the payload affected the cleavage reaction rate. These results suggest that VC-linker-STLCs have potential uses as linker-payloads for ADCs.

A new type of oxidation-reduction condensation of alcs. with sulfur, nitrogen, and oxygen nucleophiles by the combined use of Ph diphenylphosphinite (PhOPPh₂) and oxidants such as azides or di-Et azodicarboxylate (DEAD) are described.In these reactions, chiral secondary and tertiary alcs. are converted into the corresponding chiral sulfides, azides, esters and ethers under mild and neutral conditions with almost complete inversion of stereochem. configuration.