Diamine and PEGylated-diamine conjugates of triterpenic acids as potential anticancer agents

A set of 18 amide derivatives of oleanolic or maslinic acid has been semi-synthesised. Twelve were diamine conjugates at C-28 of these triterpenic acids and the other six were PEGylated-diamine derivatives. The cytotoxic effects of these 18 triterpenic derivatives in three cancer-cell lines (B16-F10, HT29, and Hep G2) have been assayed, and have been compared to three non-tumour cell lines of the same or a similar tissue (HPF, IEC-18, and WRL68). The cell viability percentages for the non-tumour HPF line for almost all diamine conjugates of the tested triterpenic acids ranged from 81% to 94%. The best cytotoxic results were achieved with the diamine conjugates of oleanolic or maslinic acid with the shortest and the longest diamine chain (IC₅₀ values from 0.76 μM to 1.76 μM), on the B16-F10 cell line, being between 140- and 20-fold more effective than their corresponding precursors. Four diamine conjugates of these triterpenic acids showed apoptotic effects on treated cells of the B16-F10 line, with total apoptosis rates, relative to control, of between 73% and 90%. The DNA-histogram analysis revealed that all compounds tested produced cell-cycle arrest in B16-F10 cells, increasing the number of these cells in the S phase. All the compounds analysed, except one, did not cause changes in mitochondrial-membrane potential during apoptosis of the B16-F10 cancer cells, suggesting an activation of the extrinsic apoptotic pathway for these compounds.