STABLE STEREOISOMER ANALOGS OF TOPO IIBETA INHIBITORS

Science Tech Development LLC通过新颖、合理的修饰来优化领先的抗癌药物，以增强体内的药物性能。2-芳基-乳酸表现出对实体瘤的高度选择性活性和对拓扑异构酶II-β的新型、特异的抑制作用。据报道，它们的立体化学影响治疗指数和药物处置，引起了科学技术公司的兴趣。在AACR-NCI-EORTC 1999上，一张海报展示了啮齿动物、狗和灵长类动物在体外将一名NCI临床候选者的S立体异构体快速转化为R，骨髓中性粒细胞前体细胞对S异构体的耐受性好于R。因此，这项SBIR的目标是：开发体内对立体转化不耐受的新型2-芳基-乳酸S异构体，从而获得更好的抗癌药物。为稳定2(S)-芳基-乳酸抗癌剂，科创提出了三种化学合成策略。第一阶段将论证可行性，并使用人体新陈代谢、人类骨髓安全性和实体肿瘤疗效的体外测试来评估原型结构。在第二阶段，将使用这些策略合成类似物，这些策略需要通过稳定立体化学的体外测试和体内测试，并根据人体肿瘤异种移植模型的疗效优先考虑临床候选药物。这项研究可能会导致有效的固体肿瘤药物，并加强国家癌症研究所正在开发的药物。拟议的商业应用：2-芳基-乳酸抗癌剂在临床前模型中对广泛的实体肿瘤具有高度活性，包括代表高活性药物的主要市场机会的肿瘤：乳腺癌、结肠癌、前列腺癌和胰腺癌。建议的结构稳定了最活跃的立体异构体，并创造了这一领域现有专利没有涵盖的新化合物。

SciTech Development LLC optimizes lead anticancer agents via novel, rational modifications that enhance drug performance in vivo. 2-Aryl- lactic acids show highly selective activity against solid tumors and novel, specific inhibition of topoisomerase II-beta. Their stereochemistry reportedly affects therapeutic index and drug disposition, attracting SciTech's interest. At AACR-NCI-EORTC 1999, a poster showed rodents, dogs, and primates rapidly converting the S stereoisomer of a NCI clinical candidate into R In vitro, bone marrow neutrophil progenitors tolerated the S isomer better than R. Hence, the goal of this SBIR: development of novel S isomers of 2-aryl-lactic acids refractory to stereoinversion in vivo and thereby better anticancer agents. SciTech proposes three chemical synthetic strategies for stabilizing 2(S)-aryl-lactic acid anticancer agents. Phase I will demonstrate feasibility and assess prototype structures using in vitro tests for human metabolism, human bone marrow safety, and solid tumor efficacy. In Phase II, analogs will be synthesized using these strategies, required to pass this in vitro testing and in vivo testing for stabilized stereochemistry, and clinical candidates prioritized by efficacy in human tumor xenograft models. This research could lead to effective solid tumor agents and also enhance the drug being developed by the NCI. PROPOSED COMMERCIAL APPLICATIONS: 2-Aryl-lactic acid anticancer agents are highly active against a broad panel of solid tumors in preclinical models including tumors that represent major market opportunities for highly active drugs: cancers of the breast, colon, prostate, and pancreas. The proposed structures stabilize the most active stereoisomers and create novel compounds not covered by existing patents in this area.