Part IV. 环丙沙星C-3羧基衍生物均三唑并噻二嗪及吡唑并均三唑的合成和抗肿瘤活性研究

基于抗菌氟喹诺酮的作用机制, 一个有效的转化其抗菌活性到抗肿瘤活性的修饰途径被进一步发展。用稠杂环均三唑并噻二嗪作为环丙沙星 (CFX) 羧基的生物电子等排体, 设计合成了1-环丙基-6-氟-7-哌嗪-1-基- 3-(6-取代苯基-7H-[1, 2, 4]三唑并[3, 4-b][1, 3, 4]噻二嗪-3-基)-喹啉-4(1H)-酮 (5a～5e) 及相应的N-乙酰稠杂环化合物 (6a～6e)。同时发现, 均三唑并噻二嗪在热醋酐中可发生噻二嗪环的缩环挤出硫反应到相应的三乙酰化吡唑并均三唑新稠环体系 (7a～7e)。用MTT法评价了新稠杂环化合物对L1210、CHO和HL60 3种癌细胞株的体外生长抑制活性。结果表明, 15个供试化合物的活性 (IC₅₀ < 25 μmol·L⁻¹) 均显著高于母体化合物CFX的活性(IC₅₀ > 150 μmol·L⁻¹), 而且活性按7a～7e > 5a～5e > 6a～6e顺序递减。

Part IV. Synthesis and antitumor evaluation of s-triazolothiadiazines and pyrazolo s-triazoles derived from ciproxacin

An efficient modified route based on the targeting mechanism of antibacterial fluoroquinolones for the shift from the antibacterial activity to the antitumor one was further developed.  Using a fused heterocyclic ring, s-triazolothiadiazine as a carboxyl bioisostere of ciprofloxacin, the title compounds, 1-cyclopropyl-6-fluoro- 7-piperazin-1-yl-3-(6-substituted-phenyl-7H-[1, 2, 4]triazolo[3, 4-b][1, 3, 4]thiadiazin-3-yl)-quinolin-4(1H)-ones (5a−5e) and their corresponding N-acetyl products (6a−6e), were designed and synthesized, separately.  Meaningfully, a ring-contraction of fused six-membered thiadiazine occurred by a sulfur extrusion reaction gave new tri-acetylated fused heterocycles related to pyrazolo[5, 1-c][1, 2, 4] triazoles (7a−7e).  The in vitro antitumor activity against L1210, CHO and HL60 cell lines was also evaluated for the synthesized fifteen heterocycles compared to parent ciprofloxacin by methylthiazole trazolium (MTT) assay.  Interestingly, the  results displayed that fifteen fused heterocyclic compounds showed more significant growth inhibitory activity (IC₅₀ < 25.0 μmol·L⁻¹) than that of parent ciprofloxacin (IC₅₀ > 150.0 μmol·L⁻¹), and the active order decreased from 7a−7e to 5a−5e to 6a−6e, respective.