TY - JOUR

T1 - Synthesis and cytotoxicity studies of substituted ester-, amide- and urea-type ursane hybrids containing a 1,2,3-triazole linker

AU - Popov, Sergey A

AU - Shults, Elvira E

AU - Marenina, Mariya K

AU - Meshkova, Yulia V

AU - Tolstikova, Tatyana G

AU - Baev, Dmitry S

AU - Nefyodov, Andrey A

N1 - Sergey A. Popov, Elvira E. Shults, Mariya K. Marenina, Yulia V. Meshkova, Tatyana G. Tolstikova, Dmitry S. Baev, Andrey A. Nefyodov, Synthesis and cytotoxicity studies of substituted ester-, amide- and urea-type ursane hybrids containing a 1,2,3-triazole linker, Steroids, Volumes 235–236, 2026, 109848, ISSN 0039-128X, https://doi.org/10.1016/j.steroids.2026.109848. This work was supported from the Russian Science Foundation, Grant Number: 23-73-00077.

PY - 2026/8/21

Y1 - 2026/8/21

N2 - 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.

AB - 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.

KW - гибриды мочевины урсана

KW - CuAAC-связывание

KW - исследование цитотоксичности

KW - молекулярный докинг

KW - Ursane urea hybrids

KW - CuAAC coupling

KW - Cytotoxicity study

KW - Molecular docking

UR - https://www.scopus.com/pages/publications/105048515981

U2 - 10.1016/j.steroids.2026.109848

DO - 10.1016/j.steroids.2026.109848

M3 - Article

C2 - 42628614

VL - 235-236

SP - 109848

JO - Steroids

JF - Steroids

SN - 0039-128X

ER -