Nadysev Georgy Y, Tikhomirov Alexander S, Lin Ming-Hung, Yang Ya-Ting, Dezhenkova Lyubov G, Chen Huei-Yu, Kaluzhny Dmitry N, Schols Dominique, Shtil Alexander A, Shchekotikhin Andrey E, Chueh Pin Ju
Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia; Mendeleyev University of Chemical Technology, 9 Miusskaya Square, Moscow 125190, Russia.
Division of Urology, Department of Surgery, Tainan Municipal An-Nan Hospital-China Medical University, Tainan 70965, Taiwan; Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defence Medical Center, Taipei 11490, Taiwan.
Eur J Med Chem. 2018 Jan 1;143:1553-1562. doi: 10.1016/j.ejmech.2017.10.055. Epub 2017 Oct 19.
A series of 4-aminomethyl derivatives of heliomycin 1 was prepared using the Mannich reaction. The modification significantly improved aqueous solubility of the initially poorly soluble antibiotic. Testing the antiproliferative efficacy revealed a potent activity of heliomycin as well as its new derivatives on a panel of mammalian tumor cells including drug resistant variants. In contrast to 1 the new derivatives 7a, 7l, 7p generated a high level of ROS associated with induction of apoptosis in T24 bladder cancer cells. Introduction of 4-aminomethyl moiety increased the affinity to DNA and the ability to inhibit topoisomerase 1 making 7p the most promising candidate for further preclinical evaluation. Thus, aminomethylation is the first-in-class successful transformation of the antibiotic 1 resulting in an improved water solubility of derivatives and promising properties in search of novel anticancer drug candidates.
利用曼尼希反应制备了一系列海利霉素1的4-氨甲基衍生物。这种修饰显著提高了最初难溶性抗生素的水溶性。抗增殖功效测试表明，海利霉素及其新衍生物对包括耐药变体在内的一组哺乳动物肿瘤细胞具有强效活性。与1相比，新衍生物7a、7l、7p在T24膀胱癌细胞中产生了高水平的活性氧，与细胞凋亡的诱导有关。引入4-氨甲基部分增加了对DNA的亲和力和抑制拓扑异构酶1的能力，使7p成为进一步临床前评估最有前景的候选物。因此，氨甲基化是抗生素1的首例成功转化，提高了衍生物的水溶性，并在寻找新型抗癌药物候选物方面具有良好的性能。
