Synthesis and cytotoxicity studies of substituted ester-, amide- and urea-type ursane hybrids containing a 1,2,3-triazole linker.

A synthesis of hybrids based on esters, amides of the ursane series, and 28-norursane ureas containing terminal alkyne or azide groups was performed via copper-catalyzed azide-alkyne cycloaddition (CuAAC). Derivatives of modified gallic acid, methyl azidobenzoates, 4-(azidomethyl)-3-methyl-1,2,5-oxadiazole-2-oxide, and dimethyl but-2-indiate were used as cyclization partners. The cytotoxicity of the resulting hybrids was evaluated on a panel of human cancer cell lines (MCF-7, HepG2, HeLa, U87MG, A549). Most of the ester and amide derivatives demonstrated weak antiproliferative activity and low selectivity. At the same time, urea conjugates 14a, 17a, 19, 19a showed pronounced cytotoxicity against MCF-7 and HeLa cells. The most active compound 19a effectively inhibited the growth of MCF-7 (IC₅₀ = 6.50 ± 0.49 μM) and HeLa (IC₅₀ = 7.87 ± 1.86 μM), while maintaining low toxicity for normal fibroblasts. The selectivity profile of 19a (SI = 10-12) significantly exceeds that of the reference drug doxorubicin (SI = 0.8-5.6). Hybrids based on 2-azidoethylurea were more active than propargylurea-derived congeners. The deprotection of OH groups of the polyphenol fragment increased cytotoxicity and selectivity. Molecular docking results indicate that urea hybrids with a 1,2,3-triazole linker may have a higher affinity for the ATP-binding site of Akt1 kinase compared to ester and amide analogs. This study substantiates a strategy for the development of selective antitumor agents based on triterpenoid ureas with polar substituents, which are promising for further preclinical optimization.