Analogue Based Design, Synthesis, Biological Evaluation, and Molecular Docking of Some Thalidomide Metabolites as Selective Cytotoxic and Antiangiogenic Agents against Multiple Myeloma.

The synthesis and evaluation of some bioisosteres of thalidomide metabolites for antiangiogenic and anticancer activity on multiple myeloma are described in this article. Four compounds, diethyl 2-(thiophene-2-sulfonamido) pentanedioate, N1,N5-diethyl-2-(thiophene-2-sulfonamido) pentanediamide, N1,N5-dihexyl-2-(thiophene-2-sulfonamido) pentanediamide, and N-(1,5-dioxo-1,5-bis(2-phenylhydrazinyl)pentan-2-yl)thiophene-2-sulfonamide exhibit cytotoxic effect on human multiple myeloma cell line (RPMI8226) with IC50 (in μM) values 3.33, 0.75, 1.23, and 3.28, respectively. The in vitro studies on human umbilical vein endothelial cells (HUVEC) and normal African green monkey kidney epithelial cells (Vero cell line) concluded that these compounds bear antiangiogenic properties and are selectively cytotoxic to cancer cells. Except for N-(1,5-dioxo-1,5-bis(2-phenylhydrazinyl)pentan-2-yl)Thiophene-2-sulfonamide, it was found to be toxic to normal epithelial cells. The "trypan blue" dye exclusion method was used to conduct an antiproliferative assay of the active compounds on HUVECs. The phosphorylation inhibition assay on Vascular Endothelial Growth Factor Receptor-2 Tyr-1175 (VEGFR-2 Tyr-1175) revealed that N1,N5-diethyl-2-(thiophene-2-sulfonamido) pentanediamide and N1,N5-dihexyl-2-(thiophene-2-sulfonamido) pentanediamide are active, indicating that the molecules have antiangiogenic activity by targeting VEGFR-2 Tyr-1175, a key autophosphorylation site that regulates pro-angiogenic responses. On CDOCKER, a molecular docking study of the most active compound N1,N5-diethyl-2-(thiophene-2-sulfonamido) pentanediamide with VEGFR-2 revealed that they might interact with the essential amino acid residues, with a binding energy of –105.304 kcal/mol. [ABSTRACT FROM AUTHOR]