Design,Synthesis And Biological Evaluation Of Topoisomerase Ⅰ/Cyclooxygenase-2 Dual Inhibitors As Potential Anti-colon Cancer Agents

Colon cancer is a malignant tumor which is featured by significant morbidity and mortality.However,due to the current therapy drugs suffer from severe toxicity,limited efficiency and drug resistance,there is an urgent need for discovering new agents with high and broad efficiency as well as low toxicity.Topoisomerase I（Topo I）and Cyclooxygenases-2（COX-2）are overexpressed in colon cancer tissues,both of them play important roles in the development of colon cancer.Drug combination strategy of Topo I inhibitor and COX-2 inhibitor revealed advantages of high efficiency and decreasing toxicity which demonstrate that Topo I/COX-2 dual inhibitors have great potential in colon cancer therapy.In the previous work,our group has developed compound I-1 as a Topo I/COX-2 inhibitor which demonstrates moderate anticancer activities.However it suffers from the poor inhibitory activities and water solubility,which prevent it to be an ideal anti-colon cancer agent.In order to discovery the novel dual inhibitors with better efficiency,this work introduces a series of polar groups to the skeleton of I-1 to improve the Topo I/COX-2 inhibition and water solubility.In the first part of this work,we design and synthesize 19 compounds,and perform systematic structural characterization.The anti-colon cancer activities and therapeutic effect of colitis are evaluated in the second part.Topo I and COX-2inhibition experiments reveal that the introduction of ethylene glycol derivatives as polar groups at 4-position in A ring can improve the dual inhibition.The piperazine ring substituted compound W10 which is the Topo I toxic agent causing DNA damage,shows the best dual inhibition:IC₅₀=0.90±0.17μM for Topo I and IC₅₀=2.31±0.07μM for COX-2.Compared with I-1,the dual inhibition is improved by 10 times.What’s more,compared with I-1（<0.5μg/m L）,the water solubility of W10（32.33μg/m L）also increase observably.W10 also demonstrate broad and good anti-proliferation activities to tested colon cancer,especially to HT29 and RKO.In the experiments in vitro,W10 arrests cell cycle at G1/G0 phase,induces apoptosis through mitochondrial pathway,and suppresses abnormal activation of NF-κB in colon cancer cells.The experiments in vivo reveal that W10 possesses appropriate pharmacokinetic parameters.W10 inhibits tumor growth in the subcutaneously implanted tumor model in nude mouse and inhibits angiogenesis in tumor tissue（TGI=57.86%）.In DSS induced colitis model,the high-dose and medium-dose W10demonstrate moderate efficiency in colitis.As an efficient Topo I/COX-2 dual inhibitor,W10 is expected to be an ideal drug molecule for the treatment of colon cancer.