Synthesis and characterization of tritylthioethanamine derivatives with potent KSP inhibitory activity

Abstract

Assembly of a bipolar mitotic spindle requires the action of class 5 kinesins, and inhibition or depletion of this motor results in mitotic arrest and apoptosis. S-trityl-L-cysteine is an allosteric inhibitor of vertebrate kinesin spindle protein (KSP) that has generated considerable interest due to its anticancer properties, however, poor pharmacological properties have limited the use of this compound. We have modified the triphenylmethyl and cysteine groups, guided by biochemical and cell-based assays, to yield new cysteinol and cysteamine derivatives with increased inhibitory activity, greater efficacy in model systems, and significantly enhanced potency against the NCI60 tumor panel. These results reveal a promising new class of conformationally-flexible small molecules as allosteric KSP inhibitors for use as research tools, with activities that provide impetus for further development as antitumor agents.

Clotrimazole as a Cancer Drug:A Short Review

“…Small molecules containing the triphenylmethyl motif has demonstrated potent anticancer properties [24,35-38]. All of these triphenylmethyl analogues induce cell cycle arrest in melanoma and other cancer cell lines by inhibiting cellular growth in G 1 - or M-phases [39].…”

“…All of these triphenylmethyl analogues induce cell cycle arrest in melanoma and other cancer cell lines by inhibiting cellular growth in G 1 - or M-phases [39]. Like S-trityl-L-cysteine, clotrimazole has no effect on tubulin polymerization which reduces the side effects observed compared with other classes of chemotherapeutic drugs [35]. Al-Qawasmeh et al produced a series of 27 clotrimazole analogs without the imidazole moiety.…”

Nitrogen-Containing Secondary Metabolites from a Deep-Sea Fungus Aspergillus unguis and Their Anti-Inflammatory Activity

“…Compounds 4 and 5 were synthesized according to the reported procedures with minor modifications [ 17 ]. Borane-tetrahydrofuran (Borane-THF, 4 mL, 4 mmol) was added dropwise to L - or D -cysteine (0.121 g, 1 mmol) in dry THF (5 mL) at 0°C under a nitrogen atmosphere, and stirred at ambient temperature for 7 h. The reaction mixture was quenched with dry dimethylfomamide (DMF, 1 mL) and stirred for 1 h. Farnesyl chloride (0.5 mmol) was added to the reaction mixture and stirred at room temperature for 3 h. The volatiles were removed in vacuo.…”

Structure‐Based Design of New KSP‐Eg5 Inhibitors Assisted by a Targeted Multicomponent Reaction

“…The IC 50 values obtained for the positive control compounds monastrol and STLC were 6.90 and 1.95 mm, respectively, consistently with previous studies. [25,26] Compounds 9, 12, 20, 21, 22 and 23 strongly inhibited microtubule-activated KSP activity (Table 2), the most potent compounds being 20 and 22, with IC 50 values of 1.49 and 1.37 mm, respectively; that is, four times more potent than monastrol and slightly more effective than STLC.…”