Tyloindicines: Chemistry and Biology

拟南芥素F-I是一种结构新颖、有前途的肿瘤选择性细胞毒性药物，目前正在研究中。 它们显然通过与目前已知的抗癌剂无关的作用机制发挥作用。 因此，他们是一个令人兴奋的领导发展作为潜在的化疗药物。该提案描述了一个多学科的，合作努力，以合成的藜芦碱和相关的类似物，阐明的分子机制（S）的行动，和表征的化合物和分子之间的相互作用的目标（S）。 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。由于不容易从天然来源获得的藜芦碱，它们的合成以及合成类似物被用作生物探针。将通过受体的光标记、cDNA-噬菌体展示技术、药物-蛋白质免疫法和亲和柱纯化来检查野靛碱受体的鉴定。 它们的细胞毒性和细胞机制也将被研究。 此外，它提出了表征与它们的生物靶标的相互作用的光亲和标记的帮助下，野扁豆碱。

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.