title: 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.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201-1559, USA.
authors.forename: Lalji K
authors.initials: LK
authors.lastname: Gediya
authors.forename: Aashvini
authors.initials: A
authors.lastname: Belosay
authors.forename: Aakanksha
authors.initials: A
authors.lastname: Khandelwal
authors.forename: Puranik
authors.initials: P
authors.lastname: Purushottamachar
authors.forename: Vincent C O
authors.initials: VC
authors.lastname: Njar
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000138:chemical synthesis / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010655:Phenylenediamines / Q000138:chemical synthesis / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014212:Tretinoin / Q000819:agonists / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C496751:4-(1H-imidazol-1-yl)retinoic acid; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D007093:Imidazoles; D010655:Phenylenediamines; D011725:Pyridines; C118739:entinostat; D014212:Tretinoin; C081895:tacedinaline