New C-19-modified geldanamycin derivatives: synthesis, antitumor activities, and physical properties study
New C-19-modified geldanamycin derivatives: synthesis, antitumor activities, and physical properties study
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新型C-19修饰格尔德霉素衍生物：合成、抗肿瘤活性和物理性质研究
DOI：
10.1080/10286020.2016.1160896
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发表时间：
2016
影响因子：
1.7
通讯作者：
Zhao
中科院分区：
文献类型：
--
作者：
Yufa Liu;Jingjing Zhong;Ling Lin;Juanjuan Liu;Yi;Weiqing He;Zhao
摘要 从发酵后期的吸水链霉菌 17997 中鉴定出噻嗪格尔德霉素 (2)。 pH值首次被提出作为其生物合成的重要因素。经证实，2是由格尔德霉素（1，GDM）与半胱氨酸或氨基乙硫醇盐酸盐在体外pH>7时直接化学反应产生的。还讨论了化合物 2 的拟议合成途径。合成了 11 种新的 C-19 修饰的 GDM 衍生物，包括 5 种稳定的对苯二酚形式的衍生物，其中大多数表现出理想的特性，例如较低的细胞毒性、增加的水溶性和有效的抗肿瘤活性。特别是，化合物 5 和 8 在 pH 7.0 磷酸盐缓冲液中对 HepG2 细胞表现出抗肿瘤活性，IC50 值为 2.97-6.61 μM，细胞毒性较低，且水溶性比 1 至少高 15 倍。
Abstract Thiazinogeldanamycin (2) was identified from Streptomyces hygroscopicus 17997 at the late stage of the fermentation. The pH was firstly proposed as an important factor in the biosynthesis of it. It was verified that 2 was produced by direct chemical reactions between geldanamycin (1, GDM) and cysteine or aminoethanethiol hydrochloride at pH > 7 in vitro. The proposed synthesis pathway for compound 2 was also discussed. Eleven new C-19-modified GDM derivatives, including five stable hydroquinone form derivatives, were synthesized, most of which exhibited desirable properties such as lower cytotoxicity, increased water solubility, and potent antitumor activity. Especially, compounds 5 and 8 showed antitumor activities against HepG2 cell with IC50 values of 2.97–6.61 μM, lower cytotoxicity and at least 15-fold higher water solubility compared with 1 in pH 7.0 phosphate buffer.
影响因子：
8.4
作者：
Kummar, Shivaani;Gutierrez, Martin E.;Gardner, Erin R.;Chen, Xiaohong;Figg, William D.;Zajac-Kaye, Maria;Chen, Min;Steinberg, Seth M.;Muir, Christine A.;Yancey, Mary Ann;Horneffer, Yvonne R.;Juwara, Lamin;Melillo, Giovanni;Ivy, S. Percy;Merino, Maria;Neckers, Len;Steeg, Patricia S.;Conley, Barbara A.;Giaccone, Giuseppe;Doroshow, James H.;Murgo, Anthony J.
通讯作者：
Murgo, Anthony J.