Mahanine: Chemical Inspiration for Leukemia Treatment

描述（由申请人提供）：自20世纪40年代以来，超过一半的抗癌药物是天然产物或受天然产物的启发而开发的。传统上，抗癌药物是从对多种癌细胞系具有广泛效力的化合物中开发出来的，但对特定类型的癌症具有选择性的分子提供了相当大的希望。这些选择性化合物将使个性化的癌症治疗能够减少或消除与当前一代癌症治疗相关的副作用。Mahanine是一种天然存在的化合物，对白血病细胞系具有高度的选择性活性。本提案描述了利用1)n -芳基化和氧化联芳基偶联以及2)Crombie铬合成来合成mahanine和新的类似物。通过高效、可扩展和灵活的机械路线，将合成一个小型的类似物库来构建详细的结构活动关系。这一信息将有助于发现具有更高活性和选择性的化合物。这些更活跃的类似物将为潜在的治疗用途提供候选物。此外，将在白血病细胞中进行详细的机制研究，以精确确定其作用方式和细胞靶点。总的来说，这项研究将推进白血病的研究和这种致命疾病的治疗。

DESCRIPTION (provided by applicant): Since the 1940s, over half of the anticancer drugs developed are natural products or inspired by natural products. Anticancer drugs have traditionally been developed from compounds with broad potency against multiple cancer cell lines, but molecules that are selective for a particular type of cancer offer considerable promise. These selective compounds will enable a personalized cancer treatment that could reduce or eliminate the side effects associated with current generation cancer treatments. Mahanine is a naturally occurring compound that has demonstrated highly selective activity against leukemia cell lines. This proposal describes the synthesis of mahanine and novel analogues utilizing a 1) N-arylation and oxidative biaryl coupling and 2) Crombie chromene synthesis. With an efficient, scalable, and flexible route to mahanine, a small library of analogues will be synthesized to construct a detailed structure activity relationship. This information will facilitate the discovery of compounds with improved activity and selectivity. These more active analogues will provide a candidate for potential therapeutic use. In addition, detailed mechanistic studies will be performed in leukemia cells to precisely determine the mode of action and cellular target. Overall, this research will advance the study of leukemia and treatments for this deadly disease.