Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
J Med Chem. 2021 Dec 23;64(24):17572-17600. doi: 10.1021/acs.jmedchem.1c01491. Epub 2021 Dec 8.
The discovery that certain indenoisoquinolines inhibit the religation reaction of DNA in the topoisomerase I-DNA-indenoisoquinoline ternary complex led to a structure-based drug design research program which resulted in three representatives that entered Phase I clinical trials in cancer patients at the National Cancer Institute. This has stimulated a great deal of interest in the design and execution of new synthetic pathways for indenoisoquinoline production. More recently, modulation of the substitution pattern and chemical nature of substituents on the indenoisoquinoline scaffold has resulted in a widening scope of additional biological targets, including RXR, PARP-1, MYC promoter G-quadruplex, topoisomerase II, estrogen receptor, VEGFR-2, HIF-1α, and tyrosyl DNA phosphodiesterases 1 and 2. Furthermore, convincing evidence has been advanced supporting the potential use of indenoisoquinolines for the treatment of diseases other than cancer. The rapidly expanding indenoisoquinoline knowledge base has provided a firm foundation for further advancements in indenoisoquinoline chemistry, pharmacology, and therapeutics.
某些吲[并]喹啉抑制拓扑异构酶 I-DNA-吲[并]喹啉三元复合物的连接反应的发现，导致了基于结构的药物设计研究计划，该计划的结果是三种代表物在国家癌症研究所的癌症患者中进入了 I 期临床试验。这激发了人们对吲[并]喹啉生产新合成途径的设计和实施产生了极大的兴趣。最近，吲[并]喹啉支架上取代基的取代模式和化学性质的调节，导致了更多额外生物学靶标的范围扩大，包括 RXR、PARP-1、MYC 启动子 G-四链体、拓扑异构酶 II、雌激素受体、VEGFR-2、HIF-1α 和酪氨酰 DNA 磷酸二酯酶 1 和 2。此外，有令人信服的证据表明，吲[并]喹啉有可能用于治疗除癌症以外的疾病。吲[并]喹啉知识基础的迅速扩大，为吲[并]喹啉化学、药理学和治疗学的进一步发展提供了坚实的基础。
