Synthesis and structure-activity relationship studies on tryprostatin A, an inhibitor of breast cancer resistance protein
Synthesis and structure-activity relationship studies on tryprostatin A, an inhibitor of breast cancer resistance protein
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DOI：
10.1016/j.bmc.2008.02.050
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发表时间：
2008-04-15
影响因子：
3.5
通讯作者：
Cook, James M.
中科院分区：
文献类型：
--
作者：
Jain, Hiteshkumar D.;Zhang, Chunchun;Cook, James M.
Tryprostatin A是一种乳腺癌耐药蛋白的抑制剂，因此对Tryprostatin A类似物作为潜在的抗肿瘤抗有丝分裂剂的细胞周期抑制作用进行了一系列构效关系研究。测定这些类似物的生长抑制特性和扰乱tsFT 210细胞中细胞周期的能力。SAR研究鉴定了细胞毒性活性所需的基本结构特征。二酮哌嗪环中的绝对构型L-Tyr-L-pro与1的吲哚部分上的6-甲氧基取代基的存在一起沿着被证明对于拓扑异构酶II和微管蛋白聚合的双重抑制是必不可少的。生物学评价还表明1的吲哚支架上的2-异戊二烯基部分的存在对于有效抑制细胞增殖是必需的。用各种烷基或芳基取代1中的吲哚Na-H，将各种L-氨基酸掺入二酮哌嗪环中代替L-脯氨酸，以及用其它官能团取代1中的6-甲氧基，提供了活性类似物。吲哚Na-H或吲哚C-2位置上存在的取代基的性质影响这些类似物的作用机制。类似物68（IC 50 = 10 μ M）和67（IC 50 = 19 μ M）在抑制tsFT 210细胞生长方面分别比1（IC 50 = 68 μ M）强7倍和3.5倍。Tryprostatin B 8的非对映异构体-2对三种人癌细胞系H-520（IC_（50）= 11.9 μ M）、MCF-7（IC_（50）= 17.0 μ M）和PC-3（IC_（50）= 11.1 μ M）的生长具有有效的抑制作用，并且与临床上使用的抗癌剂依托泊苷（etoposide）等效。异硫氰酸酯类似物71和6-叠氮基类似物72在tsFT 210细胞增殖中与1一样有效，并且可能是标记BCRP的有用工具。(c)2008爱思唯尔有限公司保留所有权利。
Tryprostatin A is an inhibitor of breast cancer resistance protein, consequently a series of structure-activity studies on the cell cycle inhibitory effects of tryprostatin A analogues as potential antitumor antimitotic agents have been carried out. These analogues were assayed for their growth inhibition properties and their ability to perturb the cell cycle in tsFT210 cells. SAR studies resulted in the identification of the essential structural features required for cytotoxic activity. The absolute configuration L-Tyr-L-pro in the diketopiperazine ring along with the presence of the 6-methoxy substituent on the indole moiety of 1 was shown to be essential for dual inhibition of topoisomerase II and tubulin polymerization. Biological evaluation also indicated the presence of the 2-isoprenyl moiety on the indole scaffold of 1 was essential for potent inhibition of cell proliferation. Substitution of the indole Na-H in 1 with various alkyl or aryl groups, incorporation of various L-amino acids into the diketopiperazine ring in place of L- proline, and substitution of the 6-methoxy group in 1 with other functionality provided active analogues. The nature of the substituents present on the indole Na-H or the indole C-2 position influenced the mechanism of action of these analogues. Analogues 68 (IC50 = 10 mu M) and 67 ( IC50 = 19 mu M) were 7-fold and 3.5-fold more potent, respectively, than 1 ( IC50 = 68 mu M) in the inhibition of the growth of tsFT210 cells. Diastereomer-2 of tryprostatin B 8 was a potent inhibitor of the growth of three human carcinoma cell lines: H520 (IC50 = 11.9 mu M), MCF-7 (IC50 = 17.0 mu M) and PC-3 (IC50 = 11.1 mu M) and was equipotent with etoposide, a clinically used anticancer agent. Isothiocyanate analogue 71 and 6-azido analogue 72 were as potent as 1 in the tsFT210 cell proliferation and may be useful tools in labeling BCRP. (c) 2008 Elsevier Ltd. All rights reserved.