Study On Design, Synthesis Of Antitumor Component From Uvaria Genus-Zeylenone Analogues

Uvaria plants, which are belonged to Annonaceae Trib. Uvariease, contain mainly polyoxygenated cyclohexenes, annonaceous acetogenins and flavones. Some studies showed that polyoxygenated cyclohexenes, especially cyclohexenones, had strong anti- tumor activities. Among of them, Zeylenone was potent against human colon, breast and liver tumor cells, and had same potency to tumor cells with multidrug resistance as sentivity cells, and had strong inhibition to adenosine and uridine transport of tumor cells. Some natural products with structures of cyclohexenone may have anti-tumor activities.Current studies about polyoxygenated cyclohexenes are focused on separation and purification from plants. Because of more than one substituent in the structures of polyoxygenated cyclohexenes, the varietis of their type, configuration, and location may lead to different potency to tumor cells. Studies on the structure-activity relationship of polyoxygenated cyclohexenes maybe find lead compounds with anti-tumor activity. Therefore, this paper studies on modification of Zeylenone structure. Based onα,β-cyclohexenone, two kinds of polyoxygenated cyclohexones were designed and synthesized with bionics principle. The first synthetic route started from shikimic acid, by esterification with methanol, protection of hydroxyl with isopropylidine group and TBDMS respectively, reduction ofα,β-unsaturated ester, esterification with benzoyl chloride, deprotection of isopropylidine group and TBDMS, selective protection of trans diol with 2, 3 butandione, oxidation of ally alcohol and deprotection of 2, 3-butandione, in overall yield of 5.3%. The second synthetic route started from intermediate of the fifth step reaction in the first route, then dihydroxylation, protection of cis-diol, deprotection from TBDMS, esterification with p-toluenesulfonylchloride, elimination, deprotection of isopropylidine group and finally selective oxidation of ally alcohol. The total yield of the former eleven steps was 1.3%. We obtained fifteen novel compounds(LT-2, LT-3, LT-4, LT-5, LT-6, LT-7, LT-8, LT-9, LF-6a, LF-6b, LF-7, LF-8, LF-9, LF-10, LF-11) and eleven target compounds, among of which two were polyoxygenated cyclohexenones(LT-8, LT-9) and nine were cyclohexenes(LT-1, LT-2, LT-3, LT-4, LT-5, LT-6, LT-7, LF-10, LF-11). Their structures were identified by 1HNMR, IR and HR-MS. Many efforts had been made to synthesize target compounds and the intermediates.The anti-tumor activities of target compounds are in process using CKK-8 method.