一氧化氮供体型CDDO类似物的合成及抗肿瘤活性

Synthesis and antitumor activity of NO-donating CDDO analogues

摘要: 以齐墩果酸（OA）为起始原料，经5步反应合成了C环含有α,β-不饱和酮结构的CDDO类似物( 1 )；再以丁二酸为连接基团，将不同取代的呋咱氮氧化物与化合物 1 的C3-OH偶联，合成了一氧化氮（NO）供体型化合物( 4a ~ 4k )，其结构经IR、MS及¹H NMR确证。采用MTT法测定目标化合物对人肝癌细胞（HepG2和BEL-7402）、乳腺癌细胞MCF-7和结肠癌细胞Caco-2的增殖抑制活性。结果表明，化合物 4i 对4种肿瘤细胞均有显著的增殖抑制活性（IC₅₀=0.8~1.4 μmol/L），且与阳性对照药CDDO甲酯（CDDO-Me）相当，值得深入研究。

Abstract: The target compounds( 4a-4k ) were synthesized by building an α,β-unsaturated ketone moiety on C-ring of oleanolic acid (OA) via a five-step reaction sequence,yielding a CDDO analogue( 1 ),followed by coupling of C3-OH in Compound 1 with substituted furoxans using butanedioic acid as a linker.The structures of the target compounds were identified by IR,MS and ¹H NMR.The most active compound 4i displayed significant inhibitory effects(IC₅₀=0.8-1.4 μmol/L) against the proliferation of four human tumor cell lines(HepG2,BEL-7402,MCF-7 and Caco-2),and was as potent as the positive control 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester(CDDO-Me).Compound 4i is thus worthy of further studies.