Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, USA.
J Med Chem. 2010 Feb 11;53(3):1347-56. doi: 10.1021/jm901667k.
Our triazole-based histone deacetylase inhibitor (HDACI), octanedioic acid hydroxyamide[3-(1-phenyl-1H-[1,2,3]triazol-4-yl)phenyl]amide (4a), suppresses pancreatic cancer cell growth in vitro with the lowest IC(50) value of 20 nM against MiaPaca-2 cell. In this study, we continued our efforts to develop triazol-4-ylphenyl bearing hydroxamate analogues by embellishing the terminal phenyl ring of 4a with different substituents. The isoform inhibitory profile of these hydroxamate analogues was similar to those of 4a. All of these triazol-4-ylphenyl bearing hydroxamates are pan-HDACIs like SAHA. Moreover, compounds 4h and 11a were found to be very effective inhibitors of cancer cell growth in the HupT3 (IC(50) = 50 nM) and MiaPaca-2 (IC(50) = 40 nM) cancer cell lines, respectively. Compound 4a was found to reactivate the expression of CDK inhibitor proteins and to suppress pancreatic cancer cell growth in vivo. Taken together, these data further support the value of the triazol-4-ylphenyl bearing hydroxamates in identifying potential pancreatic cancer therapies.
我们的三唑类组蛋白去乙酰化酶抑制剂（HDACI），辛二酸羟酰胺[3-(1-苯基-1H-[1,2,3]三唑-4-基)苯基]酰胺（4a），在体外抑制胰腺癌细胞生长的最低 IC（50）值为 20 nM，对 MiaPaca-2 细胞具有最低的抑制作用。在这项研究中，我们继续努力开发三唑-4-基苯并羟肟酸类似物，通过在 4a 的末端苯环上用不同的取代基修饰。这些羟肟酸类似物的同工酶抑制谱与 4a 的相似。所有这些三唑-4-基苯并羟肟酸都是 pan-HDACIs，与 SAHA 相似。此外，化合物 4h 和 11a 被发现对 HupT3（IC（50）= 50 nM）和 MiaPaca-2（IC（50）= 40 nM）癌细胞系的癌细胞生长具有非常有效的抑制作用。化合物 4a 被发现能重新激活 CDK 抑制剂蛋白的表达，并能抑制体内胰腺癌细胞的生长。总之，这些数据进一步支持了三唑-4-基苯并羟肟酸在鉴定潜在的胰腺癌治疗方法方面的价值。
