Diaryl disulfides and thiosulfonates as combretastatin A-4 analogues: Synthesis, cytotoxicity and antitubulin activity.

ABSTRACT: Diaryl disulfides and diaryl thiosulfonates were synthesized with the two phenyl rings of all compounds bearing identical halide substituents. Because of structural similarity to the potent antimitotic natural product combretastatin A-4 (CA-4), the compounds were examined for inhibition of tubulin polymerization, and the thiosulfonates were more active than the disulfides. The nine thiosulfonates had IC₅₀ values ranging from 1.2 to 9.1 µM, as compared with 1.3 µM obtained with CA-4. The compounds thus ranged from equipotent with CA-4 to 7-fold less active. The nine disulfides had IC₅₀ values ranging from 1.2 to 5.1 µM, as compared with 0.54 µM obtained with CA-4. The compounds thus ranged from less than half as active as CA-4 to over 9-fold less active. The most active members of each group, 2 g and 3c, in the assembly assay were modeled into the colchicine site. Compound 3c had significant hydrophobic interactions with β-tubulin residues CYS 241 and ALA 250, and its thiosulfonate bridge made a hydrogen bond with β-tubulin residue ASN 258. Compound 2 g had hydrophobic interactions with β-tubulin residues ALA 250, CYS 241 and ALA 254, but there was no significant interaction of the disulfide bridge with tubulin.

SUBMITTER: Khodyuk RGD 

PROVIDER: S-EPMC9348037 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature