Novel Vitamin B6 based prodrugs of gemcitabine

描述(申请人提供)：这项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。这项提案的具体重点是 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西他滨结合物来实现，这种形式能够增加癌细胞摄取的途径，以及一旦进入细胞就能快速激活的额外途径。吉西他滨需要在细胞内激活，才能证明其抗癌活性。这些新化合物将包含一种已经预活化的吉西他滨。该项目的具体目标是：(1)合成5个新的基于吉西他滨的化合物，并评估它们在血浆和实验室条件下的稳定性；以及(2)完整地表征这些新化合物在一些癌细胞系中的活性。这将包括量化化合物对细胞杀伤、克隆形成能力和细胞迁移能力的影响。此外，我们将量化在药物和新化合物暴露后不同时间在细胞内发现的最活跃形式的吉西他滨的形成速度。为了研究细胞摄取的机制，将在存在和不存在Gem使用的标准核苷转运体的抑制剂的情况下对活性和生物分析终点进行评估。这项拟议研究的积极结果将为MBC制药公司的商业化努力提供多种资产。用于治疗胰腺癌的一种新的先导化合物将为许可提供资金。此外，来自新型药物平台的先导化合物的展示将使多种化合物针对不同的适应症进行潜在的开发。预计这项技术最终将产生显著改善癌症患者预后的治疗剂。

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.