Goniotriol衍生物的合成及体外抑制肿瘤细胞活性

Syntheses and anticancer activities in vitro of derivatives of Goniotriol

目的 :研究 goniotriol抗肿瘤作用的构效关系。方法 :以 α- D-葡庚糖酸 - δ-内酯为原料经 9步反应合成了 6个新的 goniotriol的衍生物。化合物 1在浓硫酸和无水硫酸镁的作用下与丙酮缩合 ,再被 60 %的醋酸水解 ,经 Na IO4氧化得醛 2 ,总产率 71.3 % ;然后醛 2与 C6 H4Mg Br发生格氏反应 ,生成混合物 3 ;混合物 3被 Na IO4氧化后 ,直接与Ph3P=CHCO2 Et反应得混合物 4;4在催化量的 DBU作用下环合 ,得化合物 5和化合物 6;将化合物 6与不同的酰氯反应得化合物 7a～ c;7a～ c再经 75 %的醋酸水溶液水解得 goniotriol衍生物 8a～ c。化合物的结构均经 IR、1 H- NMR、MS和元素分析证实。经 MTT法筛选了对 A 2 780、HCT- 8、Bel 742 0、KB瘤株的抑制活性。结果 :化合物 7a、7c、8a、8c体外对多种瘤株抑制强度与 8- O-肉桂酰基 - goniotriol类似 ,7b、8b则无活性。结论 :邻位溴取代的苯甲酰基

Objective: To study the relationship of structure and activities of goniotriol. Methods: The derivatives of goniotriol have been synthesized in nine steps from α-D-glucoheptonic-δ-lactone(1). Compound 1 reacted with acetone in the presence of cat. H_2SO_4 and anhydrous MgSO_4, and then was hydrolysed with 60% aq. HOAc, finally was oxidized by NaIO_4 into aldehyde 2 in a yield of 71.3%. The aldehyde 2 reacted immediately with PhMgBr giving the mixture 3. The mixture 3 was oxidized by NaIO_4, reacted with Ph_3P=CHCO_2Et giving compounds 4, and then induced by cat. DBU in THF provided the compounds 5 and 6. The esterfication of 6 with acid chloride in DMAP, Et_3N gave the esters 7a^c. Acid hydrolysis of the acetone protecting group of 7a^c in 75% aq. HOAc gave compounds 8a^c. Their structures were confirmed by IR, 1H-NMR, MS, element analyses. The anticancer activities of the compounds were screened by MTT methods (A2780, HCT-8, Be1 74200KB). Results: Six derivatives of goniotriol are new compounds. Pharmacological test show that anticancer activities of goniotriol(7a, 7c, 8a, 8c) are similar to 8-O- cinnamyl -goniotriol in vitro. Conclusion: The anticancer activities of derivatives of 8-O-(o-BrC_6H_4CO)-goniotriol are very low.