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

Bioorg Med Chem. 2008 Mar 15;16(6):3352-60. doi: 10.1016/j.bmc.2007.12.007. 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / chemical synthesis
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Benzamides / chemical synthesis
  • Benzamides / pharmacology
  • Cell Cycle / drug effects*
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Drug Synergism
  • Histone Deacetylase Inhibitors*
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / pharmacology
  • Male
  • Neoplasms, Experimental / drug therapy
  • Phenylenediamines / chemical synthesis
  • Phenylenediamines / pharmacology
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Pyridines / chemical synthesis
  • Pyridines / pharmacology
  • Transplantation, Heterologous
  • Tretinoin / agonists
  • Tretinoin / analogs & derivatives
  • Tretinoin / chemical synthesis
  • Tretinoin / pharmacology*


  • 4-(1H-imidazol-1-yl)retinoic acid
  • Benzamides
  • Histone Deacetylase Inhibitors
  • Imidazoles
  • Phenylenediamines
  • Pyridines
  • entinostat
  • Tretinoin
  • tacedinaline