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

• Published in: European journal of medicinal chemistry Vol. 148; pp. 325 - 336
• Main Authors: Medina-O’Donnell, Marta, Rivas, Francisco, Reyes-Zurita, Fernando J., Martinez, Antonio, Lupiañez, Jose A., Parra, Andres
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 25.03.2018; Elsevier
• Subjects: Apoptosis; Chemistry, Medicinal; Cytotoxicity; Diamine conjugate; Life Sciences & Biomedicine; Maslinic acid; Oleanolic acid; Pharmacology & Pharmacy; Science & Technology; Triterpene; Cytotoxicity; Maslinic acid; Diamine conjugate; Triterpene; Oleanolic acid; Apoptosis; CANCER-CHEMOTHERAPY; NATURAL-PRODUCTS; PREVENTION; C-28; OLEANANE TRITERPENOIDS; PENTACYCLIC TRITERPENOIDS; ANTIPROLIFERATIVE EVALUATION; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.02.044

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. [Display omitted] •18 diamine conjugates of OA or MA were tested for cytotoxicity in three cancer-cell lines.•The percentages of non-tumour HPF live cells were quite high for almost all the diamine conjugates.•The propane-1,3-diamine conjugate of OA showed the best result total apoptosis (93.7% in B16-F10 cells).•All tested compounds resulted in cell cycle arrest in the S phase in the B16-F10 cell line.