Novel Vitamin B6 based prodrugs of gemcitabine

描述（由申请人提供）：本提案的长期目标是开发更有效的癌症治疗方法，特别是胰腺癌。本提案的具体重点 是为了提高药物吉西他滨的抗癌活性。这将通过合成新的吉胞他滨缀合物来实现，所述吉胞他滨缀合物的形式使得能够增加摄取到癌细胞中的途径和一旦进入细胞内就快速激活的额外途径。吉西他滨需要在细胞内活化才能证明其抗癌活性。新的化合物将包含一种已经预活化的吉胞他滨。本项目的具体目标是：（1）合成5种新型吉胞他滨化合物，并评估其在血浆和实验室条件下的稳定性;（2）完成这些新型化合物在许多癌细胞系中的活性表征。这将包括定量化合物对细胞杀伤、集落形成能力和细胞迁移能力的影响。此外，我们将定量在暴露于药物和新化合物后的不同时间在细胞内发现的最具活性形式的吉胞他滨的形成速率。为了研究细胞摄取机制，将在存在和不存在Gem使用的标准核苷转运蛋白抑制剂的情况下评估活性和生物分析终点。这项拟议研究的积极结果将为MBC Pharma的商业化努力提供多种资产。一种新的治疗胰腺癌的先导化合物将为许可证提供资产。此外，来自新药平台的先导化合物的展示将使针对不同适应症的多种化合物的潜在开发成为可能。预计该技术最终将产生显著改善癌症患者结局的治疗剂。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to develop more effective therapies for cancer, specifically pancreatic cancer. The specific focus of this proposal is to improve upon the anti-cancer activity of the drug gemcytabine. This will be accomplished by synthesizing novel conjugates of gemcytabine in a form that enables increased pathways for uptake into cancer cells and additional paths to rapid activation once inside cells. Gemcytabine requires activation within a cell before it can demonstrate its anti-cancer activity. The novel compounds will incorporate a form of gemcytabine already preactivated. The specific aims of this project are: (1) To synthesize 5 novel gemcytabine based compounds and assess their stability in plasma and laboratory conditions; and (2), complete characterization of these novel compound's activities in a number of cancer cell lines. This will include quantitation of the compounds effects on cell killing, colony formation ability and cell migration ability. In addition we will quantitate the rate of formation of the most active forms of gemcytabine found within the cells at various times after exposure to the drug and novel compounds. To investigate the mechanism of cellular uptake, activity and bioanalytical endpoints will be assessed in the presence and absence of inhibitors of the standard nucleoside transporters used by Gem. Positive results from this proposed research will provide multiple assets to MBC Pharma's commercialization efforts. A new lead compound for treating pancreatic cancer will provide assets for licensing. In addition, the demonstration of a lead compound from novel drug platform will enable the potential development of multiple compounds for different indications. It is anticipated that this technology will ultimately result in therapeutic agents that will significanty improve the outcomes of cancer patients.