Evaluation of Novel Sansalvamide A Derivatives as Potential Anti-Cancer Agents

摘要 山醋柳胺A（SanA）支架是一种用于开发新型癌症的有前途的结构 治疗学我们已经使用San A支架生产了7种对胰腺和胰腺癌细胞有细胞毒性的化合物， 结肠癌细胞系中的浓度。San A衍生品特别令人感兴趣，因为 它们与其它种类的市售癌症治疗剂不具有结构同源性， 在一个新的位点抑制一个既定的靶点（Hsp 90），它们比药物更有效 目前可用于治疗结肠癌和胰腺癌。已知的Hsp 90抑制剂与 N-末端结构域，而我们的化合物的独特之处在于它们靶向C-末端结构域并阻断C-末端结构域。 肌醇六磷酸激酶2（IP 6 K2）的结合。本项目的总体目标是开发一部小说 在一些实施方案中，本发明涉及基于San A支架的化疗剂。我们的假设是，甚至具有 更大的效力和选择性可以通过修改关键结构特征，确定在我们的合成 初步研究。具体目标是：a）进行San A衍生物的结构-活性研究， 选择先导候选化合物，B）鉴定关键的细胞靶标并确定其机制， San A类似物杀死肿瘤细胞，和c）确定先导San A衍生物在结肠中的功效和毒性 和胰腺异种移植模型。

ABSTRACT The sansalvamide A (San A) scaffold is a promising structure for the development of novel cancer therapeutics. We have used the San A scaffold to produce 7 compounds that are cytotoxic to pancreatic and colon cancer cell lines at nanomolar concentrations. The San A derivatives are of particular interest because they do not share structural homology with other classes of marketed cancer therapeutics, they appear to inhibit an established target (Hsp90) at a novel site, and they are significantly more potent than the drugs currently available for the treatment of colon and pancreatic cancer. Known Hsp90 inhibitors interact with the N-terminal domain whereas our compounds are unique in that they target the C-terminal domain and block the binding of inositol hexakisphosphate kinase 2 (IP6K2). It is the overall goal of this project to develop a novel chemotherapeutic agent based on the San A scaffold. It is our hypothesis that analogs of San A with even greater potency and selectively can be synthesized by modifying key structural features identified in our preliminary studies. The specific aims are to: a) Conduct structure-activity studies of San A derivatives and select a lead candidate compound, b) Identify the key cellular targets and determine the mechanism by which San A analogs kill tumor cells, and c) Determine the efficacy and toxicity of a lead San A derivative in colon and pancreatic xenograft models.