p-甲基-哥纳三醇衍生物的合成及体外抑制肿瘤细胞活性

SYNTHESES AND ANTITUMOR ACTIVITIES OF THE DERIVATIVES OF P-METHYL GONIOTRIOL IN VITRO

目的 寻找高效低毒的哥纳三醇类抗肿瘤化合物。方法 以α D 葡庚糖酸 δ 内酯为原料经 9步反应 ,合成了 18个 8 位取代的p 甲基 哥纳三醇衍生物 ,他们的结构经IR ,1 HNMR ,MS和元素分析证实。经MTT法筛选了对A2 780 ,HCT 8,Bel74 2 ,KB瘤株的抗肿瘤活性。结果 15个化合物 (7,8b～h ,9b～h)为新化合物。结论 体外对多种瘤株 (A2 780 ,HCT 8,Bel74 2 ,KB)均显示了不同强度的抑制活性。

AIM To find derivatives of p methyl goniotriol with more potent antitumor activities and lacking undesirable effects. METHODS Eighty derivatives of p methyl goniotriol have been synthesized in nine steps from α D glucoheptonic δ lactone (2). Compound 2 reacted with acetone in the catalyzer, H 2SO 4 and anhydrous MgSO 4, and then reacted with 60% aqua HOAc, finally was oxidized by NaIO 4 at room temperature into aldehyde 3 in a yield of 71 3%. The aldehyde 3 reacted immediately with P CH 3 PhMgBr giving mixture 4. The mixture 4 was oxidized by NaIO 4, reacted with Ph 3P CHCO 2Et and then induced by catalyzer. 1,8 Diazabicylclo[5,4,0]undec 7 ene in THF providing the compounds 6 and 7. The esterfication of 6 with cinnamyl chloride et al in 4 dimethylaminopyridine, Et 3N gave the esters 8a～h. Acid hydrolysis of the acetone protecting group of 8a～h in 75% aqua HOAc gave compounds 9a～h. Their chemical structures were confirmed by IR, 1HNMR , MS and element analysis. The antitumor activities of the compounds were screened by MTT methods. RESULTS Fifteen derivatives of p methyl goniotriol (7, 8b～h, 9b～h) are new compounds. CONCLUSION Pharmacological tests indicate that these compounds showed antitumor activities toward tumor cells (A2780, HCT 8, Bel742, KB) in vitro . The antitumor activities of 8b, 8d, 8g and 9h were more potent than howiinol A.