Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China; School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Bioorg Med Chem Lett. 2021 May 15;40:127954. doi: 10.1016/j.bmcl.2021.127954. Epub 2021 Mar 17.
Natural products (NPs) have played a crucial role in the discovery and development of antitumor drugs. However, the high structural complexity of NPs generally results in unfavorable physicochemical profiles and poor drug-likeness. A powerful strategy to tackle this obstacle is the structural simplification of NPs by truncating nonessential structures. Herein, a series of tetrahydro-β-carboline derivatives were designed by elimination of the D ring of NP evodiamine. Structure-activity relationship studies led to the discovery of compound 45, which displayed highly potent antitumor activity against all the tested cancer cell lines and excellent in vivo antitumor activity in the HCT116 xenograft model with low toxicity. Further mechanistic research indicated that compound 45 acted by dual Top1/2 inhibition and induced caspase-dependent cell apoptosis coupled with G/M cell cycle arrest. This proof-of-concept study validated the effectiveness of structural simplification in NP-based drug development, discovered compound 45 as a potent antitumor lead compound and enriched the structure-activity relationships of evodiamine.
天然产物（NPs）在抗肿瘤药物的发现和开发中发挥了至关重要的作用。然而，NPs 的结构高度复杂，通常导致不理想的理化性质和较差的类药性。解决这一障碍的一个有力策略是通过截断非必需结构来简化 NPs 的结构。在此，通过消除 NP 吴茱萸碱的 D 环，设计了一系列四氢-β-咔啉衍生物。构效关系研究发现，化合物 45 对所有测试的癌细胞系均表现出高度有效的抗肿瘤活性，并且在 HCT116 异种移植模型中具有优异的体内抗肿瘤活性和低毒性。进一步的机制研究表明，化合物 45 通过双重 Top1/2 抑制作用诱导 caspase 依赖性细胞凋亡，并伴有 G/M 细胞周期阻滞。这项概念验证研究验证了结构简化在基于 NP 的药物开发中的有效性，发现化合物 45 是一种有效的抗肿瘤先导化合物，并丰富了吴茱萸碱的构效关系。
