Design, semisynthesis and cytotoxic activity of novel ester derivatives of betulinic acid-1,2,4 oxadiazoles

Abstract

Taking into consideration of the biological activity of betulinic acid derivatives containing a oxadiazole ring, the semisynthetic betulinic acid-1,2,4-oxadiazole esters (14-25) were synthesized starting from betulinic acid (1) and 5-(bromomethyl)-3-aryl-1,2,4-oxadiazoles (2-13) and final compounds were tested for cytotoxic activity on three human cancer cell lines in vitro. All tested compounds showed good cytotoxic activity. The structures of synthesized compounds are established based on infrared (IR), nuclear magnetic resonance (NMR), and mass spectrometry.

Novel 3′-Substituted-1′,2′,4′-Oxadiazole Derivatives of 18βH-Glycyrrhetinic Acid and Their O-Acylated Amidoximes: Synthesis and Evaluation of Antitumor and Anti-Inflammatory Potential In Vitro and In Vivo

“…According to previous studies, the introduction of heterocyclic moieties to triterpenoids is a promising approach that could improve their biological effects [68]. For instance, it was shown that the addition of oxadiazole-containing moieties to triterpenoids markedly increased their cytotoxicity against tumor cells [24,25], enhanced selectivity for leukemia cells [69], and reinforced anti-inflammatory properties [70,71].…”

Novel 1,2,4-Oxadiazole Derivatives in Drug Discovery

“…In a study reported by Challa K., Krishna C. and coworkers C28-modified Betulinic Acid (Figure 7) bearing 1,2,4-oxadiazole ring connected via ester or amide linker have been synthesized and evaluated against human colon carcinoma (Colo 205), human liver cancer (Hep G2) and HeLa cell lines [57,58]. Performed screening revealed moderate potential of all obtained derivatives with the highest biological activities for analogs 4a-4d (Table 2) (the IC 50 values in a range of 26.1-34.3 µM).…”

“…Interestingly, flow cytometry assay revealed that the above-mentioned compounds are potent inducers of apoptosis in MCF-7, MDA-MB-231 and MEL-8 cell lines and are acting in a dose-dependent manner. [55] [ 57,58] O…”

Synthesis and Cytotoxic Activity of Triterpenoid Thiazoles Derived from Allobetulin, Methyl Betulonate, Methyl Oleanonate, and Oleanonic Acid

“…To gather more information about the influence of the terpenic part of the molecule on the cytotoxic activity, we prepared four analogous sets of N‐substituted aminothiazoles from four different commercially available triterpenes, allobetulone ( 2 a ), methyl betulonate ( 3 a ), methyl oleanonate ( 4 a ), and oleanonic acid ( 5 a ). Compounds 2 a , 3 a , 4 a , and 5 a are derivatives of triterpenes betulinic acid, oleanolic acid, and 18α‐oleanane; such derivatives are commonly studied for their high cytotoxic activities . Comparing activities in derivatives prepared from methyl oleanonate ( 4 a ) and from free oleanonic acid ( 5 a ) would allow us to estimate, if methyl esters are less active than free acids, as it is usual in triterpenoids …”

“…Compounds 2a, 3a, 4a,a nd 5a are derivatives of triterpenes betulinic acid, oleanolic acid, and 18a-oleanane;s uch derivatives are commonly studied for their high cytotoxic activities. [34][35][36][37] Comparing activities in derivatives prepared from methyl oleanonate (4a)a nd from free oleanonic acid (5a) would allow us to estimate, if methyl esters are lessa ctive than free acids, as it is usual in triterpenoids. [20,27,38] The classical Hantzsch synthesis of aminothiazoles does not give good yields in the case of triterpenoids and steroids because of harsh reactionc onditions [39,40] and the reaction does not allow to simply obtain N-substituted compounds.…”