Tyloindicines: Chemistry and Biology

tyloindicines F-I是一种结构新颖、前景广阔的肿瘤选择性细胞毒性药物，目前正在研究中。它们的作用机制显然与目前已知的抗癌药物无关。因此，它们是开发潜在化疗药物的一个令人兴奋的先导。本提案描述了一项多学科合作的努力，旨在合成tyloindicals和相关类似物，阐明作用的分子机制，并表征化合物与分子靶点之间的相互作用。这种跨学科的方法涉及药物化学、分子生物学和生物化学方法。由于tyloindicals不容易从天然来源中获得，因此建议合成它们以及合成类似物以用作生物探针。tyloindicine受体的鉴定将通过受体的光标记、cdna -噬菌体展示技术、西药法和亲和柱纯化来检验。它们的细胞毒性和细胞机制也将被研究。此外，还提出了利用光亲和标记来表征tyloindicals与其生物靶点的相互作用。

The tyloindicines F-I, structurally novel promising tumor selective cytotoxic agents, are under study. They apparently act via mechanisms of action unrelated to currently known anticancer agents. Therefore, they are an exciting lead for development as potential chemotherapeutic agents. This proposal describes a multidisciplinary, collaborative effort towards the synthesis of the tyloindicines and related analogues, the elucidation of the molecular mechanism(s) of action, and the characterization of the interaction between the compounds and the molecular target(s). This interdisciplinary approach involves medicinal chemistry, molecular biology, and biochemistry approaches. Since the tyloindicines are not readily available from natural sources, their synthesis is proposed as well as the synthesis of analogues to be used as biological probes. The identification of the receptor for the tyloindicines will be examined by photolabeling of the receptor(s), by a cDNA-phage display technique, by the drug-western method, and affinity column purification. Their cytotoxicity and cellular mechanisms will be studied as well. In addition it is proposed to characterize the interaction of the tyloindicines with their biological targets with the help of photoaffinity labels.