Agensys Inc., an affiliate of Astellas Pharma Inc. , 1800 Stewart Street, Santa Monica, California 90404, United States.
J Nat Prod. 2017 Sep 22;80(9):2484-2491. doi: 10.1021/acs.jnatprod.7b00359. Epub 2017 Sep 8.
Synthetic analogues of the natural occurring dolastatin 10 are of great interest in cancer due to their potent in vitro activity and their uses as payloads in antibody drug conjugates (ADCs). Modification of the dolastatin 10 core scaffold has mainly focused on modifications of the P1, N-terminus, and P5, C-terminus, with minimal attention to the P2 subunit. In this paper we discuss the introduction of heteroatoms to the P2 side chain, which results in potent activity in vitro. The most active compounds contained azides in the P2 unit and required a phenylalanine-derived P5 subunit.
由于其在体外的强大活性及其作为抗体药物偶联物 (ADC) 的有效载荷的应用，天然存在的 dolastatin 10 的合成类似物在癌症治疗方面引起了极大的关注。对 dolastatin 10 核心支架的修饰主要集中在 P1、N 末端和 P5、C 末端的修饰上，而对 P2 亚基的关注较少。在本文中，我们讨论了在 P2 侧链中引入杂原子，这导致了体外的强大活性。最有效的化合物在 P2 单元中含有叠氮化物，并且需要一个衍生自苯丙氨酸的 P5 单元。
