Design, synthesis, and biological evaluation of phenylsulfonylfuroxan-β-carboline-hydroxamic acid ternary hybrids for cancer

Abstract

A total of 21 novel ternary hybrids containing phenylsulfonylfuroxan, β-carboline, and hydroxamic acid moieties were designed and synthesized. Their antitumor activities and underlying mechanisms of action were systematically evaluated. In vitro studies demonstrated that most of the target compounds exhibited moderate to potent antiproliferative activity. Among them, compound 23a showed the most promising activity against triple-negative breast cancer (TNBC) MDA-MB-231 cells, with a significant antiproliferative effect (IC₅₀ = 0.29 μM) and favorable selectivity. Further investigations revealed that 23a significantly inhibited cell invasion and migration in MDA-MB-231 cells. Mechanistically, 23a exerted its antitumor effects through simultaneous targeting of HDAC6, DNA, and the release of high levels of nitric oxide (NO). Additionally, 23a induced apoptosis and caused G2/M phase cell cycle arrest. Pharmacokinetic parameters indicate that 23a possesses good absorption and rapid clearance in rat plasma, suggesting that it has suitable pharmacokinetic properties for antitumor activity in vivo. In vivo antitumor studies demonstrated that 23a achieved a superior tumor growth inhibition (54.49 %) compared to SAHA (34.16 %). In a Lewis lung carcinoma (LLC) metastatic mouse model, 23a significantly inhibited pulmonary metastasis formation. Moreover, 23a exhibited good safety profiles in ICR mice. These results collectively demonstrate that compound 23a represents a promising multi-target anticancer and anti-metastatic drug candidate with favorable development potential.