Moreau P, Anizon F, Sancelme M, Prudhomme M, Sevère D, Riou J F, Goossens J F, Hénichart J P, Bailly C, Labourier E, Tazzi J, Fabbro D, Meyer T, Aubertin A M
Synthèse, Electrosynthèse et Etude de Systèmes à Intérêt Biologique, Université Blaise Pascal, UMR 6504, 63177 Aubière, France.
J Med Chem. 1999 May 20;42(10):1816-22. doi: 10.1021/jm980702n.
Bromo analogues of the natural metabolite rebeccamycin with and without a methyl substituent on the imide nitrogen were synthesized. The effects of the drugs on protein kinase C, the binding to DNA, and the effect on topoisomerase I were determined. The drugs' uptake and their antiproliferative activities against P388 leukemia cells sensitive and resistant to camptothecin, their antimicrobial activity against a Gram-positive bacterium (B. cereus), and their anti-HIV-1 activity were measured and compared to those of the chlorinated and dechlorinated analogues. Dibrominated imide 5 shows a remarkable activity against topoisomerase I, affecting both the kinase and DNA cleavage activity of the enzyme. The marked cytotoxic potency of this compound depends essentially on its capacity to inhibit topoisomerase I.
合成了天然代谢产物瑞贝克霉素的溴代类似物，其酰亚胺氮上有或没有甲基取代基。测定了这些药物对蛋白激酶C的作用、与DNA的结合以及对拓扑异构酶I的作用。测量了这些药物的摄取及其对喜树碱敏感和耐药的P388白血病细胞的抗增殖活性、对革兰氏阳性菌（蜡样芽孢杆菌）的抗菌活性以及抗HIV-1活性，并与氯化和脱氯类似物进行了比较。二溴代酰亚胺5对拓扑异构酶I显示出显著活性，影响该酶的激酶和DNA切割活性。该化合物显著的细胞毒性效力主要取决于其抑制拓扑异构酶I的能力。
