Improved synthesis of histone deacetylase inhibitors (HDIs) (MS-275 and CI-994) and inhibitory effects of HDIs alone or in combination with RAMBAs or retinoids on growth of human LNCaP prostate cancer cells and tumor xenografts
Improved synthesis of histone deacetylase inhibitors (HDIs) (MS-275 and CI-994) and inhibitory effects of HDIs alone or in combination with RAMBAs or retinoids on growth of human LNCaP prostate cancer cells and tumor xenografts
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DOI：
10.1016/j.bmc.2007.12.007
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发表时间：
2008-03-15
影响因子：
3.5
通讯作者：
Njar, Vincent C. O.
中科院分区：
文献类型：
--
作者：
Gediya, Lalji K.;Belosay, Aashvini;Njar, Vincent C. O.
我们已经开发了新的，简单的，和有效的方法来合成两个有前途的组蛋白去乙酰化酶抑制剂（HDIs），CI-994，（N-（2-氨基苯基）-4-乙酰氨基苯甲酰胺），MS-275（N-（2-氨基苯基）4-[N-（吡啶-3-基-甲氧羰基）氨基甲基]苯甲酰胺）从市售的乙酰氨基苯甲酸和3-（羟甲基）吡啶，分别。该方法分别以80%和72%的总产率提供CI-994和MS-275。我们发现四种HDIs（CI-994、MS-275、SAHA和TSA）与类维生素A全反式维甲酸（ATRA）或13-顺式维甲酸（13-CRA）或我们的非典型维甲酸代谢阻断剂（RAMBA）1（VN/14-1）或2（VN/66-1）的组合对人LNCaP前列腺癌细胞产生协同抗肿瘤活性。2和SAHA的组合诱导LNCaP细胞的G1和G2/M细胞周期阻滞和S期减少。2 + SAHA处理有效下调细胞周期蛋白D1和cdk 4，上调促分化标志物细胞角蛋白8/18和促凋亡Bad和Bax。皮下给药后，与对照相比，2、SAHA或2 + SAHA耐受性良好，并引起肿瘤生长的显著抑制/消退。这些结果表明，化合物2及其与SAHA的组合是潜在有用的药剂，其保证了用于治疗前列腺癌的进一步临床前开发。(C)2007爱思唯尔有限公司保留所有权利。
We have developed new, simple, and efficient procedures for the synthesis of two promising histone deacetylase inhibitors (HDIs), CI-994, (N-(2-aminophenyl)-4-acetylaminobenzamide), and MS-275 (N-(2-aminophenyl)4-[N-(pyridine-3-yl-methoxycarbonyl)aminomethyl]benzamide) from commercially available acetamidobenzoic acid and 3-(hydroxymethyl)pyridine, respectively. The procedures provide CI-994 and MS-275 in 80% and 72% overall yields, respectively. We found that the combination of four HDIs (CI-994, MS-275, SAHA, and TSA) with retinoids all-trans-retinoic acid (ATRA) or 13-cis-retinoic acid (13-CRA) or our atypical retinoic acid metabolism blocking agents (RAMBAs) 1 (VN/14-1) or 2 (VN/66-1) produced synergistic anti-neoplastic activity on human LNCaP prostate cancer cells. The combination of 2 and SAHA induced G1 and G2/M cell cycle arrest and a decrease in the S phase in LNCaP cells. 2 + SAHA treatment effectively down-regulated cyclin D1 and cdk4, and up-regulated pro-differentiation markers cytokeratins 8/18 and pro-apoptotic Bad and Bax. Following subcutaneous administration, 2, SAHA or 2 + SAHA were well tolerated and caused significant suppression/regression of tumor growth compared with control. These results demonstrate that compound 2 and its combination with SAHA are potentially useful agents that warrant further preclinical development for treatment of prostate cancer. (C) 2007 Elsevier Ltd. All rights reserved.