Widespread secondary plant metabolites (betulinic, ursolic and oleanolic acids) are promising scaffolds for the discovery of new drugs. Among the many semi-synthetic derivatives of lupane triterpenoids known today, the anticancer agent, C-28 ester of betulinic acid with tris(hydroxymethyl)aminomethane (NVX-207), has been actively studied. This betulinic acid derivative, which has shown significant antitumor activity in vitro and in vivo against various malignant tumors, is a candidate drug. It is known that modification of the structure of the triterpenoid skeleton can lead to significant changes in biological properties. In this regard, we have synthesized C-28 esters of ursolic, oleanolic acids and C20-29 hydrogenated betulinic acid bearing tris(hydroxymethyl)aminomethane (TRIS), and transformed them into guanidinium salts by guanylation of the primary amino group in a branched ester fragment under the action of 1H-pyrazole-1-carboxamidine hydrochloride. The obtained compounds were tested in vitro experiments on five human cancer cell lines. The presence of TRIS-fragment in the triterpenoid conjugates markedly enhanced the cytotoxic action as compared to the parent compounds, dihydrobetulinic, ursolic and oleanolic acids, (IC50 values 2.8-7.6 mkM for Jurkat cells and 1.8-6.8 mkM for U937 cells), while the correlation between the cytotoxic activity and the chemical structure of the triterpenoid skeleton was not observed. Extended biological testing of these triterpenoids by using flow cytometry analysis showed that antitumor activity of compounds is caused by apoptotic processes and induction of cell cycle arrest in the S-phase. New triterpenoids were also tested for their antimicrobial activity against the growth of four bacterial strains (Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Staphylococcus aureus (MRSA)) and two fungal strains (Candida albicans and Cryptococcus neoforman). The TRIS-dihydrobetulinic acid conjugate and its guanidinium derivative did not exhibit antimicrobial properties. The corresponding ursane and oleane-skeleton pentacyclic tritrerpenoids showed good bacteriostatic activity against methicillin-resistant S. aureus (MICs 4 and 32 mkg / mL) and excellent antifungal effect against Cryptococcus neoformans and Candida albicans (MICs 4 and 0.25 mkg / mL).
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C-28 esters of triterpenoid acids bearing tris(hydroxymethyl)aminomethane: Synthesis, anticancer and antimicrobial activity.
Published: 14 November 2019 by MDPI in The 23rd International Electronic Conference on Synthetic Organic Chemistry session Bioorganic, Medicinal and Natural Products Chemistry
Keywords: pentacyclic triterpene, betulinic acid, ursolic acid, oleanolic acid, amine- and guanidine derivatives, NVX-207, cytotoxicity, antimicrobial activity