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.
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Authors | Lalji K Gediya, Aashvini Belosay, Aakanksha Khandelwal, Puranik Purushottamachar, Vincent C O Njar |
Journal | Bioorganic & medicinal chemistry
(Bioorg Med Chem)
Vol. 16
Issue 6
Pg. 3352-60
(Mar 15 2008)
ISSN: 1464-3391 [Electronic] England |
PMID | 18166465
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- 4-(1H-imidazol-1-yl)retinoic acid
- Benzamides
- Histone Deacetylase Inhibitors
- Imidazoles
- Phenylenediamines
- Pyridines
- entinostat
- Tretinoin
- tacedinaline
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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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