STABLE STEREOISOMER ANALOGS OF TOPO IIBETA INHIBITORS

sciitech开发有限责任公司通过新颖、合理的修饰来优化先导抗癌药物，提高药物在体内的性能。2-芳基乳酸显示出对实体肿瘤的高度选择性活性和对拓扑异构酶ii - β的新型特异性抑制。据报道，它们的立体化学会影响治疗指标和药物配置，这引起了科技公司的兴趣。在AACR-NCI-EORTC 1999上，一份海报显示啮齿动物、狗和灵长类动物迅速将NCI临床候选物的S立体异构体转化为R。在体外，骨髓中性粒细胞祖细胞对S异构体的耐受性优于R。因此，该SBIR的目标是：开发体内不易立体转化的2-芳香基乳酸的新型S异构体，从而更好地抗癌药物。提出了三种稳定2(S)-芳基乳酸抗癌剂的化学合成策略。第一阶段将通过人体代谢、人体骨髓安全性和实体肿瘤疗效的体外测试来论证可行性和评估原型结构。在II期，类似物将使用这些策略合成，需要通过体外测试和体内测试来稳定立体化学，并根据人类肿瘤异种移植模型的疗效优先考虑临床候选物。这项研究可能会导致有效的实体肿瘤药物，也会增强NCI正在开发的药物。建议的商业应用：2-芳基乳酸抗癌药物在临床前模型中对广泛的实体肿瘤具有高活性，包括具有高活性药物主要市场机会的肿瘤：乳腺癌、结肠癌、前列腺癌和胰腺癌。所提出的结构稳定了最活跃的立体异构体，并创造了该领域现有专利未涵盖的新化合物。

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.