SYNTHESIS OF ANTITUMOR AGENTS

描述：(首席调查者)四个人的合成， 自然产生的抗肿瘤药物被提出。许多已故的- 将对每个项目中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。 目的I.Gigantecin(I)是番荔枝属中稀有的一员。 含有不相邻的双四氢呋喃环的乙酰生素。这是一个 极强的体外肿瘤细胞生长抑制作用，据报道 S的GI50在10到负7和10到负9之间 微克/毫升对人肺癌和乳腺癌细胞株的抑制作用。 目的II.环芳环A(II)是C2对称的大碳环化合物 一种化合物，是唯一一种天然存在的化合物 (N.N)对环芳烃。它对KB和LoVo肿瘤细胞具有细胞毒作用。 目的Callipeltoside A(II)是最近报道的一种海洋天然产物 产品。稀有结构的大环内酯和氨基苷 从海洋生物中分离出的化合物的特征，以及一种独特的1- 二芳基-2-氯环丙烷是一种新的结构特征。这个 化合物对非小细胞肺癌N6细胞的细胞毒作用 和P388肿瘤细胞株。 目的IV.4-亚甲基-2-环己烯酮IVA和IVB对异构体 最近被分离出来，并在这里确定了它们的相对配置 在明尼苏达大学。第一种已经在前面描述过了， 在没有立体化学的情况下，在1996年罗纳-普伦克公司的一项专利中 公司。对微管蛋白聚合有抑制作用，GI50为1 ng/mL 对抗阿霉素耐药的P388/DOX细胞株。我们的样品 化合物还显示出显著的人体肿瘤细胞毒性。 在NCI组(例如，GI50的S的IVA低于100分钟和IVB的 大多数细胞株的总生长抑制率(TGI)小于1 nm 分别小于100 pM和3 nm，以对抗乳腺癌)。 新的综合方法论的发展是一个背景主题。新的 烯烃歧化反应和一种新的氧化不对称化合物 脱芳烃反应将在AIMS I的范围内进行研究 这些方法将普遍适用于该制剂 具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.