Purushottamachar Puranik - 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 xenograf...

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      Publication Details (including relevant citation   information):

      Bioorg Med Chem. 2008   Mar 15;16(6):3352-60. Epub 2007 Dec 8.


      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.


      Address (URL): http://www.ncbi.nlm.nih.gov/pubmed/18166465