Synthesis and Cytotoxicity of Complex Betulinic Acid Amides

The main objective of this investigation was focused on the structure modification of betulinic acid to design novel cytotoxic compounds. The cytotoxicity of the amides of betulinic acid with several diamines was compared with that of the compounds bearing an additional amide bond formed by means of 4-methoxybenzoic acid. It was prepared by a green biotechnological approach from trans-anethole isolated from anise (Pimpinella anisum L.) seeds. Cisplatin and doxorubicin, the pharmacologically used anticancer agents, were used as the positive references. One of the target compounds (9) showed cytotoxicity in HeLa (IC50 = 5.4 ± 0.8 μM; SI > 9.3) and MCF7 (IC50 = 7.0 ± 1.1 μM; SI > 7.2) cancer cell lines while being nontoxic in normal human foreskin fibroblasts (IC50 > 50 μM), and it showed a better cytotoxicity profile than structurally related compounds 8 and 10. The aromatic substituent and the C(3)-OAc group in 9 were also advantageous for the cytotoxicity profile of 9 in comparison with its intermediate compound 8. Several intermediates and target compounds showed a better cytotoxicity profile than cisplatin.