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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.

Abstract
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.
AuthorsLalji K Gediya, Aashvini Belosay, Aakanksha Khandelwal, Puranik Purushottamachar, Vincent C O Njar
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 16 Issue 6 Pg. 3352-60 (Mar 15 2008) ISSN: 1464-3391 [Electronic] England
PMID18166465 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • 4-(1H-imidazol-1-yl)retinoic acid
  • Benzamides
  • Histone Deacetylase Inhibitors
  • Imidazoles
  • Phenylenediamines
  • Pyridines
  • entinostat
  • Tretinoin
  • tacedinaline
Topics
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (chemical synthesis, pharmacology)
  • Benzamides (chemical synthesis, pharmacology)
  • Cell Cycle (drug effects)
  • Cell Differentiation (drug effects)
  • Cell Line, Tumor
  • Drug Synergism
  • Histone Deacetylase Inhibitors
  • Humans
  • Imidazoles (chemical synthesis, pharmacology)
  • Male
  • Neoplasms, Experimental (drug therapy)
  • Phenylenediamines (chemical synthesis, pharmacology)
  • Prostatic Neoplasms (drug therapy, pathology)
  • Pyridines (chemical synthesis, pharmacology)
  • Transplantation, Heterologous
  • Tretinoin (agonists, analogs & derivatives, chemical synthesis, pharmacology)

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