Synthesis and Biological Evaluation of Squamostolide, Rollicosin and Their Related Analogs

• Main Authors: Cheng-Lin Lee, 李政霖
• Other Authors: Ming-Jung Wu
• Format: Others
• Language: zh-TW
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/00800387469769047938

博士 === 高雄醫學大學 === 藥學研究所博士班 === 94 === Squamostolide 50 and Rollicosin 51 were isolated from annonaceous plants, Annona squamosa and Rollina mucosa, respectively. These two compounds possessed potent cytotoxicities against the growth of several cancer lines and special features with two lactone moieties on both sides of an aliphatic chain. Syntheses of compounds 50 and 51 were based on a convergent palladium catalyzed coupling reaction. Synthesis of 50 was completed by a Pd(II) catalyzed coupling reaction of terminal acetylene 52a and vinyliodide 53. Compound 52a was prepared starting from 5-hexyn-1-ol in six steps, including protection of terminal acetylene, oxidation of the alcohol, Grignard reagent addition to the aldehyde, Claisen-Johnson rearrangement, Sharpless AD reaction and finally desilylation. Vinyliodide 53 was synthesized by alkylation of diiodide 69 with lactone 63 in 75% yield. Diiodide 69 was prepared using 1-hexyne as the strating material in six steps in 24% overall yield. Synthesis of 63 was started from D-glutamic acid in five steps and in 16% overall yield. Coupling of 52a and 53 gave the enyne 70 in 86% yield. Hydrogenation of the enyne 70 followed by oxidation of the sulfide and thermal elimination gave squamostolide. Synthesis of 51 was carried out by a Pd(II) catalyzed coupling of iodoacetylene 117 and terminal acetylene 118. Preparation of 117 was started from 1-heptyne in eight steps and in 14% overall yield. Synthesis of 127 was carried out in two different pathways. Alkylation of lactone 63 with allyl iodide gave 126. Asymmmetric dihydroxylation of 126 produced a diol intermediate, followed by Sharpless one pot epoxidation gave 127 in 55% yield. The other pathway was achieved by alkylation of (S)-epichlorohydrin with lactone 63 afforded epoxide 127 in 50% yield. Oxidation of the sulfide of 127 followed by thermal elimination gave 128 in 95% yield. Reaction of 127 with trimethylacetylene lithium salt produced alcohol 129 in 85% yield. Desiylation of 128 gave 118 in 75% yield. Coupling of 117 and 118 afforded diyne 130 in 53% yield. Finally, hydrogenation of 130 using rhodium as a catalyst produced rollicosin in 80% yield. A series of squamostolide and rollicosin analogs were also synthesized by the aboved mentioned methods. The biological activities of these molecules have been evaluated. Squamostolide showed anticancer activity against the growth of WiDr, A-549 and MCF-7 with IC50 values in 38.7, 33.1 and 41.1µM, respectively. The squamostolide analog 72b exhibited the best cytotoxicity against the growth of HCCT-2998 with IC50 value in 2.26 µM. Rollicosin and its analog 137 showed specific inhibition of the growth of WiDr with IC50 values in 24.0 and 10.2 µM, respectively.