RESUMO
The synthesis and biological evaluation of 9 dimeric compounds obtained by condensation of thiocolchicine and/or podophyllotoxin with 6 different dicarboxylic acids is described. In particular, tubulin assembly assay and immunofluorescence analysis results are reported. The biological data highlighted three compounds as being more active than the others, having a marked ability to inhibit the polymerization of tubulin in vitro and causing significant disruption to the microtubule network in vivo. The spacer unit was found to have a significant effect on biological activity, reinforcing the importance of the design of conjugate compounds to create new biologically active molecules in which the spacer could be useful to improve the solubility and to modulate the efficacy of well known anticancer drugs.
Assuntos
Colchicina/análogos & derivados , Podofilotoxina/química , Podofilotoxina/farmacologia , Animais , Bovinos , Linhagem Celular Tumoral , Colchicina/química , Colchicina/farmacologia , Imunofluorescência , Glutationa/metabolismo , Humanos , Concentração Inibidora 50 , Camundongos , Multimerização Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismoRESUMO
A series of novel hybrid compounds obtained by the attachment of anhydrovinblastine, vinorelbine, and vindoline to thiocolchicine, podophyllotoxin, and baccatin III are described. Two types of diacyl spacers are introduced. The influence of the hybrid compounds on tubulin polymerization is reported. The results highlight the importance of the length of the spacer. Immunofluorescence microscopy and flow cytometry measurements that compound with the best in vitro activity could disrupt microtubule networks in cell and prevent the formation of the proper spindle apparatus, thereby causing cell cycle arrest in the G2/M phase. The newly synthesized compounds were tested in the human lung cancer cell line A549.
Assuntos
Alcaloides/síntese química , Colchicina/análogos & derivados , Podofilotoxina/síntese química , Taxoides/síntese química , Moduladores de Tubulina/síntese química , Tubulina (Proteína)/metabolismo , Vimblastina/análogos & derivados , Vimblastina/síntese química , Alcaloides/toxicidade , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/toxicidade , Linhagem Celular Tumoral , Colchicina/síntese química , Colchicina/toxicidade , Técnicas de Química Combinatória , Dimerização , Desenho de Fármacos , Humanos , Podofilotoxina/toxicidade , Radiossensibilizantes/síntese química , Radiossensibilizantes/toxicidade , Suínos , Taxoides/toxicidade , Moduladores de Tubulina/toxicidade , Vimblastina/toxicidade , VinorelbinaRESUMO
A dynamic combinatorial library of thiocolchicine-podophyllotoxin derivatives based on the disulfide bond exchange reaction is described. The influence of a biological target on the composition of the reaction mixture has been demonstrated. Use of high-resolution ESI mass spectrometry to evaluate the composition of the mixture shows promise for the design of new large libraries. The biological evaluation demonstrates that formation of a divalent compound affords a new chemical entity whose biological activity is not merely the sum of the single ligands activities, thus reflecting a different interaction with the biological target.
