Design, Synthesis, and Cytotoxicity Evaluation of Novel Griseofulvin Analogues with Improved Water Solubility.

International Journal of Medicinal Chemistry Pub Date : 2017-01-01 Epub Date: 2017-12-07 DOI:10.1155/2017/7386125
Ahmed K Hamdy, Mahmoud M Sheha, Atef A Abdel-Hafez, Samia A Shouman
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引用次数: 5

Abstract

Griseofulvin 1 is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Study of SAR of some griseofulvin analogues has led to the identification of 2'-benzyloxy griseofulvin 3, a more potent analogue which retards tumor growth through inhibition of centrosomal clustering. However, similar to griseofulvin 1, compound 3 exhibited poor aqueous solubility. In order to improve the poor water solubility, six new griseofulvin analogues 5-10 were synthesized and tested for their antiproliferative activity and water solubility. The semicarbazone 9 and aminoguanidine 10 analogues were the most potent against HCT116 and MCF-7 cell lines. In combination studies, compound 9 was found to exert synergistic effects with tamoxifen and 5-fluorouracil against MCF-7 and HCT116 cells proliferation, respectively. The flow cytometric analysis of effect of 9 on cell cycle progression revealed G2/M arrest in HCT116. In addition, compound 9 induced apoptosis in MCF-7 cells. Finally, all synthesized analogues revealed higher water solubility than griseofulvin 1 and benzyloxy analogue 3 in pH 1.2 and 6.8 buffer solutions.

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新型水溶性灰黄霉素类似物的设计、合成及细胞毒性评价。
灰黄霉素1是一种重要的抗真菌药物,近年来因其对哺乳动物癌细胞的抗增殖作用而受到关注。一些灰黄霉素类似物的SAR研究导致鉴定出2'-苯氧基灰黄霉素3,这是一种更有效的类似物,通过抑制中心体聚集来延缓肿瘤生长。然而,与灰黄霉素1类似,化合物3表现出较差的水溶性。为了改善灰黄霉素水溶性差的问题,合成了6个新的灰黄霉素类似物5-10,并对其抗增殖活性和水溶性进行了测试。缩氨基脲9和氨基胍10类似物对HCT116和MCF-7细胞系最有效。在联合研究中发现,化合物9与他莫昔芬和5-氟尿嘧啶分别对MCF-7和HCT116细胞增殖具有协同作用。流式细胞术分析9对细胞周期进程的影响显示HCT116中G2/M阻滞。此外,化合物9可诱导MCF-7细胞凋亡。最后,所有合成的类似物在pH为1.2和6.8的缓冲溶液中的水溶性均高于灰黄霉素1和苯氧基类似物3。
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期刊介绍: International Journal of Medicinal Chemistry is a peer-reviewed, Open Access journal that publishes original research articles as well as review articles in all areas of chemistry associated with drug discovery, design, and synthesis. International Journal of Medicinal Chemistry is a peer-reviewed, Open Access journal that publishes original research articles as well as review articles in all areas of chemistry associated with drug discovery, design, and synthesis.
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