RESUMO
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 ß-tubulin residues CYS 241 and ALA 250, and its thiosulfonate bridge made a hydrogen bond with ß-tubulin residue ASN 258. Compound 2 g had hydrophobic interactions with ß-tubulin residues ALA 250, CYS 241 and ALA 254, but there was no significant interaction of the disulfide bridge with tubulin.
Assuntos
Bibenzilas/química , Proliferação de Células/efeitos dos fármacos , Dissulfetos/síntese química , Dissulfetos/farmacologia , Ácidos Tiossulfônicos/síntese química , Ácidos Tiossulfônicos/farmacologia , Moduladores de Tubulina/farmacologia , Linhagem Celular Tumoral , Dissulfetos/química , Humanos , Modelos Moleculares , Relação Estrutura-Atividade , Ácidos Tiossulfônicos/químicaRESUMO
Insect pests have caused economic losses valued at billions of dollars in agricultural production. Anagasta kuehniella (Zeller), the Mediterranean flour moth, is of major economic importance as a flour and grain feeder and is often a severe pest in flourmills. This study provides a suitable route for the direct preparation of thiosulfonates 2 and 3 from thiols, under mild conditions, with good yields; these thiosulfonates were tested for their regulatory effect on insect growth. The chronic ingestion of thiosulfonates resulted in a significant reduction in larval survival and weight. In addition, the tryptic activity of larvae was sensitive to these thiosulfonates. Results suggest that thiosulfonates 2 and 3 have a potential antimetabolic effect when ingested by A. kuehniella. The use of AgNO(3)/BF(3)·OEt(2) and Al(H(2)PO(4))(3)/HNO(3) provides a suitable route for the direct preparation of thiosulfonates from thiols under mild conditions with good yields. These thiosulfonates were toxic for A. kuehniella larvae, suggesting their potential as biotechnological tools.