Begleiter Asher, Lin Denny, Larson Kimberly K, Lang Jennifer, Wu Xing, Cabral Teresa, Taylor Hallie, Guziec Lynn J, Kerr Paul D, Hasinoff Brian B, Guziec Frank S
Manitoba Institute of Cell Biology, CancerCare Manitoba, Departments of Internal Medicine, and Pharmacology and Therapeutics, University of Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba R3E 0V9, Canada.
Oncol Rep. 2006 Jun;15(6):1575-80.
Anthrapyrazoles have been investigated as cancer chemotherapeutic agents. The mechanism of action of these compounds is thought to involve inhibition of DNA topoisomerase II. A structure-activity study was carried out to determine the in vitro cytotoxic activity of nine novel anthrapyrazoles against human breast carcinoma, head and neck squamous cell carcinoma and leukemia cells, and against Chinese hamster ovary cells. The activity of these anthrapyrazole analogues was compared with that of two clinically tested anthrapyrazoles, losoxantrone and piroxantrone. Inhibition of topoisomerase II as a mechanism of action for the analogues was also investigated. The cytotoxic activity of the analogues was determined in vitro by MTT cell growth inhibition assay and inhibition of catalytic topoisomerase II activity by each compound was measured using a fluorometric DNA decatenation assay. All of the anthrapyrazole analogues inhibited the growth of the four cell lines with IC50 values that ranged from 0.1 to 45.2 microM. Losoxantrone was the most potent of the anthrapyrazole analogues studied. A tertiary amine in the basic side chain at N-2 increased the cytotoxic activity compared with a secondary amine in this side chain for many of the analogues, but not if there was a basic side chain at the C-5 position. A chlorine substituent on the basic side chain at N-2 did not have a consistent effect on activity. Moving the position of a chlorine substituent from C-5 to C-7 or introducing a basic side chain at C-5 did not have a consistent effect on cytotoxic activity. Anthrapyrazole analogues showed a broad range of activity for inhibiting topoisomerase II decatenation activity. Losoxantrone and piroxantrone were the most potent inhibitors of topoisomerase II activity. There was no significant correlation between the cytotoxic activity of the anthrapyrazole analogues and their ability to inhibit decatenation by topoisomerase II.
蒽吡唑类化合物已被作为癌症化疗药物进行研究。这些化合物的作用机制被认为涉及对DNA拓扑异构酶II的抑制。开展了一项构效关系研究，以确定9种新型蒽吡唑类化合物对人乳腺癌、头颈部鳞状细胞癌、白血病细胞以及中国仓鼠卵巢细胞的体外细胞毒性活性。将这些蒽吡唑类似物的活性与两种临床测试的蒽吡唑类药物洛索蒽醌和吡罗蒽醌的活性进行了比较。还研究了作为类似物作用机制的拓扑异构酶II抑制作用。通过MTT细胞生长抑制试验在体外测定类似物的细胞毒性活性，并使用荧光DNA解连环试验测量每种化合物对催化性拓扑异构酶II活性的抑制作用。所有蒽吡唑类似物均抑制这四种细胞系的生长，IC50值范围为0.1至45.2微摩尔。洛索蒽醌是所研究的蒽吡唑类似物中活性最强的。对于许多类似物而言，N-2位碱性侧链中的叔胺相比于该侧链中的仲胺可提高细胞毒性活性，但如果C-5位存在碱性侧链则不然。N-2位碱性侧链上的氯取代基对活性没有一致的影响。将氯取代基的位置从C-5移至C-7或在C-5位引入碱性侧链对细胞毒性活性没有一致的影响。蒽吡唑类似物在抑制拓扑异构酶II解连环活性方面表现出广泛的活性范围。洛索蒽醌和吡罗蒽醌是拓扑异构酶II活性的最强抑制剂。蒽吡唑类似物的细胞毒性活性与其抑制拓扑异构酶II解连环的能力之间没有显著相关性。
