Synthesis of New Fluorinated Tubastatin A Derivatives Based on Cyclopentane/Cyclohexane with Good Anti‐tumor Activity in Vitro

Abstract Two series of novel fluorinated Tubastatin A derivatives based on cyclopentane or cyclohexane substitution were first time synthesized by 5 steps at high yield. The influence of the cycloalkanes substituted N ‐methylpiperidine and/or fluorinated group on the cap group of Tubastatin A for the in vitro anti‐tumor activity of seven different tumor cell lines (human hepatoma cells Bel7402 and HepG2, human nasopharyngeal carcinoma cells CNE2 and SUNE1, human breast cancer cells MDA‐MB‐231 and MCF‐7, and human pancreatic cancer cells SW1990) was investigated. Compared with Tubastatin A, these novel derivatives with fluorinated groups on the benzene ring of the cap group enhance activity, and modification of the N ‐methylpiperidine to cycloalkanes of the cap group improves solubility. The most promising compound trifluoromethyl and cyclohexane substituted derivative, N ‐hydroxy‐4‐((6‐(trifluoromethyl)‐1,2,3,4‐tetrahydro‐9 H ‐carbazol‐9‐yl)methyl) benza‐mide ( 6 h ), had a wide range of anti‐tumor cell range, the IC 50 value for human pancreatic cancer cell line SW1990 was 1.17 μM. Hence, fluorinated groups and cyclohexane result in a wide range of anti‐tumor cell range and good anti‐cancer activity.