以酯键链接的甾体羟肟酸化合物的合成及体外抗肿瘤活性OA

In this study,cholesterol,dehydroepiandrosterone,and pregnenolone were used as starting materials to design and synthesize a series of novel steroidal-hydroxamic acid conjugates linked via ester bonds.Structural modification of the steroidal core was achieved through condensation and hydrolysis reactions,followed by conjugation with hydroxamic acid fragments.A stepwise synthetic strategy was employed to construct the steroidal and hydroxamic acid fragments,which were subsequently conjugated using a molecular hybridization approach.Multiple steroid-hydroxamic acid conjugates with ester linkages were successfully prepared,and the reaction conditions were systematically optimized.For in vitro antitumor activity screening,the MTT assay was performed with SAHA as a positive control.The results indicated that compounds Methyl N-(tritylamino)-4-oxobutanoate(4a)and Methyl N-(tritylamino)-4-oxopentanoate(4b)exhibited superior antiproliferative activity against SKOV-3 tumor cells compared to other tested cell lines.Compound 4a showed moderate inhibitory activity against several tumor cell lines,with an IC50 value of 9.23 μmol/L against T47D cells,whereas compound 4b demonstrated enhanced potency against the HeLa cell line,achieving an IC50 value as low as 8.58 μmol/L.Molecular docking studies were conducted to further explore the mechanism of action.Compound 4a displayed superior binding affinity through diverse hydrophobic interactions,while 4b exhibited greater potential in catalytic inhibition by coordinating with zinc ions.This research provides a new strategy and direction for the future development of highly effective antitumor drug precursor compounds.