Mukherjee Chatterjee Sayantani, Jain Chetan Kumar, Singha Soumen, Das Piyal, Roychoudhury Susanta, Majumder Hemanta Kumar, Das Saurabh
Department of Chemistry (Inorganic Section) and Department of Physics, Jadavpur University, Kolkata 700032, India.
Cancer Biology & Inflammatory Disorder Division and Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Kolkata 700032, India.
ACS Omega. 2018 Aug 30;3(8):10255-10266. doi: 10.1021/acsomega.8b00706. eCollection 2018 Aug 31.
Quinalizarin (THAQ), a hydroxy-9,10-anthraquinone analogue of the family of anthracycline anticancer drugs and an inhibitor of protein kinase, was observed for its anticancer activity. Because apart from showing anticancer activity, anthracyclines and their analogues also show cardiotoxic side effects, believed to be addressed through metal complex formation; an effort was made to realize this by preparing a Co complex of THAQ. The aim of this study was to find out if complex formation leads to a decrease in the generation of intermediates that are responsible for toxic side effects. However, because this also meant that efficacy on cancer cells would be compromised, studies were undertaken on two cancer cell lines, namely, acute lymphoblastic leukemia (ALL) MOLT-4 and HCT116 cells. The complex decreases the flow of electrons from NADH to molecular oxygen (O) in the presence of NADH dehydrogenase forming less semiquinone than THAQ. It showed increased affinity toward DNA with binding constant values remaining constant over the physiological pH range unlike THAQ (for which decrease in binding constant values with increase in pH was observed). The complex is probably a human DNA topoisomerase I and human DNA topoisomerase II poison acting by stabilizing the covalent topoisomerase-cleaved DNA adduct, a phenomenon not observed for THAQ. Activity of the compounds on cancer cells suggests that THAQ was more effective on ALL MOLT-4 cells, whereas the complex performed better on HCT116 cells. Results suggest that the formation of semiquinone probably dominates the action because of THAQ, whereas the performance of the complex is attributed to increased DNA binding, inhibition of topoisomerase, and so forth. Inspite of a decrease in the generation of superoxide by the complex, it did not hamper efficacy on either cell line, probably compensated by improved DNA binding and inhibition of topoisomerase enzymes which are positive attributes of complex formation. A decrease in superoxide formation suggests that the complex could be less cardiotoxic, thus increasing its therapeutic index.
醌茜（THAQ）是蒽环类抗癌药物家族的一种羟基 - 9,10 - 蒽醌类似物，也是一种蛋白激酶抑制剂，人们对其抗癌活性进行了观察。由于除了具有抗癌活性外，蒽环类药物及其类似物还表现出心脏毒性副作用，据信可通过形成金属配合物来解决这一问题；因此人们尝试通过制备THAQ的钴配合物来实现这一点。本研究的目的是探究配合物的形成是否会导致产生有毒副作用的中间体数量减少。然而，由于这也意味着对癌细胞的疗效会受到影响，因此对两种癌细胞系进行了研究，即急性淋巴细胞白血病（ALL）MOLT - 4细胞和HCT116细胞。在存在NADH脱氢酶的情况下，该配合物会减少电子从NADH流向分子氧（O），形成的半醌比THAQ少。与THAQ不同（THAQ的结合常数随pH升高而降低），该配合物对DNA表现出更高的亲和力，其结合常数在生理pH范围内保持恒定。该配合物可能是一种人类DNA拓扑异构酶I和人类DNA拓扑异构酶II毒药，其作用方式是稳定拓扑异构酶切割DNA后的共价加合物，而THAQ未观察到这种现象。这些化合物对癌细胞的活性表明，THAQ对ALL MOLT - 4细胞更有效，而该配合物在HCT116细胞上表现更好。结果表明，由于THAQ，半醌的形成可能在其作用中占主导地位，而该配合物的性能归因于DNA结合增加、拓扑异构酶抑制等。尽管该配合物产生的超氧化物减少，但它并未妨碍对任何一种细胞系的疗效，这可能是由于DNA结合改善和拓扑异构酶抑制得到了补偿，而这些都是配合物形成的积极特性。超氧化物形成的减少表明该配合物可能心脏毒性较小，从而提高了其治疗指数。
