Synthesis of cytotoxic urs-12-ene- and 28-norurs-12-ene- type conjugates with amino- and mercapto-1,3,4-oxadiazoles and mercapto-1,2,4-triazoles

Abstract

A small library of 2-mercapto-1,3,4-oxadiazoles, 2-amino-1,3,4-oxadiazoles, and 3-mercapto-1,2,4-triazoles attached to the urs-12-ene- and 28-nor-urs-12-ene skeleton has been obtained. Ursolic acid derived hydrazides have been identified as useful starting materials for the developed synthesis. Ursolic acid hydrazide provided access to oxadiazoles attached directly to C-17 of the ursane core, but synthesis of structurally related 3-mercapto-1,2,4-triazoles was not possible in this way due to steric hindrance of the triterpenoid. Ester- and amide-linked hydrazides arising from ethoxycarbonylmethyl ursolate and ursolic acid amide with methyl β-alaninate served as key starting materials for the remotely connected mercapto-and amino-azoles. Antioxidant activities (DPPH method) of the newly obtained compounds are mediocre. However, excellent cytotoxicity and selectivity against MCF7 cell line were found for 28-nor-urs-12-ene 2-amino-1,3,4-oxadiazole conjugate. Also some other library members exceeded the cytotoxicity values of natural ursolic acid. The novel hybrid heterocycles with amino and mercapto substituents possess a great potential for further derivatization and are prospective scaffolds for the synthesis of triterpenoid analogs with chemopreventive and cytotoxic properties.

Keywords: 1,2,4-triazole; 1,3,4-oxadiazole; Anti-oxidant; Cytotoxicity tests; Molecular docking; Ursane conjugate.