4,5-二取代苯并(氧化)呋咱类衍生物的合成及体外抗肿瘤活性

Synthesis and Antitumor Activities in vivo of 4,5-Disubstituted Benzofuroza and Benzofuroxan Derivatives

为探索抗肿瘤活性更优的新结构类型化合物,以2-硝基-4-氯苯胺为原料,经重氮化、叠氮取代、成环、硝化、亲核取代反应,合成4,5-二取代苯并氧化呋咱类衍生物4a—4e;中间体2经还原、硝化、亲核取代反应,得到4,5-二取代苯并呋咱类衍生物7a—7e,新化合物的结构均经~1H-NMR及ESI-MS确证。以5-氟尿嘧啶为阳性对照药,人非小细胞肺癌细胞NCI H460、乳腺癌细胞MCF-7和结肠癌细胞HCT-116为试验瘤株,采用SRB法评价目标化合物的体外抗肿瘤活性。以XI-006为阳性对照药,测定4a—4e对MCF-7和HCT-116的IC50值。结果表明,浓度为5μmol/L时,苯并氧化呋咱化合物较苯并呋咱化合物的抗肿瘤作用强。其中,4a—4e对MCF-7及HCT-116的IC_(50)值均优于先导化合物XI-006,值得进一步深入研究。

In order to explore novel structural compounds with better anti-tumor activity,the 4,5-disubstituted benzofuroxan derivatives 4a-4e are synthesized from 4-chloro-2-nitroaniline through diazo-reaction,azide substitution,ring formation,nitration,and substitution,and the 4,5-disubstituted benzofuroza derivatives 7a-7e are prepared from 4a-4e by reduction,nitrification and substitution.The structures of novel compounds are confirmed by 1H-NMR and ESI-MS.Using 5-fluorouracil as the positive control drug,the antitumor activities in vitro of the target compounds against NCI H460,MCF-7 and HCT-116 are tested by SRB assay.The IC 50 values of compounds 4a-4e against MCF-7 and HCT-116 are determined with XI-006 as the positive control drug.The results show that the anti-tumor activity of benzofuroxan compounds are stronger than benzofuroza compounds at the concentration of 5μmol/L.The IC 50 values indicate that 4a-4e exhibit higher activity against MCF-7 and HCT-116 than the lead compound XI-006,which is worthy of further study.