SYNTHESIS OF ANTITUMOR AGENTS

描述：（主要研究者的）四个合成， 提出了天然存在的抗肿瘤剂。 很多已故的- 将对每个项目的阶段合成中间体进行检查 明尼苏达大学的抗肿瘤活性 （合作）和国家癌症研究所。 艾姆岛Gigantecin（I）是番荔枝科（Annonaceous）植物中罕见的一种， 含有不相邻的双四氢呋喃环的乙酸配基。 这是一 据报道，它是体外肿瘤细胞生长的极其有效的抑制剂， GI 50大约是10的负7次方和10的负9次方 μ g/mL对人肺癌和乳腺癌细胞系的作用。 Aim II. 羟基环蕃A（II）是C2-对称大碳环化合物， 一种化合物，是唯一一种天然存在的 （n.n）paracyclophanes.它对KB和LoVo肿瘤细胞具有细胞毒性。 Aim III. 海桐花甙A（II）是一种新发现的海洋天然产物 产品 大环内酯和氨基糖苷，结构罕见 从海洋生物中分离的化合物的特征，以及独特的1- 二烯炔基-2-氯环丙烷是新的结构特征。 的 化合物对NSCLC-N6（非小细胞肺癌）具有细胞毒性 和P388肿瘤细胞系。 目标四。 异构体对4-亚甲基-2-环己烯酮IVA和IVB 是最近分离出来的，它们的相对构型是在这里确定的。 在明尼苏达大学。 第一种是以前描述过的， 在1996年Rhone-Poulenc Rönner的专利中， 公司 抑制微管蛋白聚合，GI_（50）为1 ng/mL 针对阿霉素耐药的P388/DOX细胞系。 我们的样品 化合物还显示出显著水平的人肿瘤细胞毒性 在NCI面板中（例如，IVA小于100 pM和IVB小于100 pM的GI 50 对于大多数细胞系小于1 nM， 分别小于100 pM和3 nM）。 新的合成方法学的发展是一个背景主题。 新 烯烃复分解反应和一种新的氧化不对称 脱芳构化反应将在目标I的范围内进行研究 和IV. 这些方法将普遍适用于制备 有药用价值的化合物

DESCRIPTION: (Principal Investigator's) The synthesis of four, naturally occurring, antitumor agents is proposed. Many of the late- stage synthetic intermediates in each of the projects will be examined for antitumor activity both here at the University of Minnesota (collaboratively) and at the National Cancer Institute. Aim I. Gigantecin (I) is a member of the rare class of Annonaceous acetogenins containing non-adjacent, bis-tetrahyfuran rings. It is an extremely potent inhibitor of in vitro tumor cell growth, reportedly having GI50's of around ten to the minus 7 and ten to the minus nine microg/mL toward human lung and breast carcinoma cell lines. Aim II. Cylindrocylophane A(II) is a C2-symmetric macrocarbocyclic compound that is a member of the only family of naturally occurring (n.n)paracyclophanes. It is cytotoxic against KB and LoVo tumor cells. Aim III. Callipeltoside A(II) is a recently reported marine natural product. The macrocyclic lactone and amino-glycoside, rare structural features for compounds isolated from marine organisms, and a unique 1- dienynyl-2-chlorocyclopropane are the novel structural features. The compound is cytotoxic toward NSCLC-N6 (non-small-cell lung carcinoma) and P388 tumor cell lines. Aim IV. The pair of isomeric 4-methylene-2-cyclohexenones IVA and IVB was recently isolated and their relative configurations determined here at the University of Minnesota. The first was previously described, without stereochemistry, in a 1996 patent from the Rhone-Poulenc Rorer company. It inhibited tubulin polymerization and had a GI50 of 1ng/mL against the doxorubicin-resistant, P388/DOX cell line. Samples of our compounds also showed remarkable levels of human tumor cell cytotoxicity in the NCI panel (e.g., GI50's for IVA of less than 100pM and IVB of less than 1nM for most cell lines and total growth inhibition (TGI) of less than 100pM and 3nM, respectively, against a breast cancer). The development of new synthetic methodology is a background theme. New aspects of the alkene metathesis reaction and a new oxidative asymmetric dearomatization reaction will be studied within the context of Aims I and IV. These methods will be generally applicable to the preparation of compounds of pharmaceutical interest.