- Title
- Potent short-chain fatty acid-based histone deacetylase inhibitors as anti-tumor agents
- Author
- Lu, Qiang
- Degree
- Doctor of Philosophy, Ohio State University,
Pharmacy, 2005.
- Advisor
- Ching-shih Chen
- Pages
- xix, 116 p. :ill (some col.)
- Abstract
- Inhibitors of histone deacetylases (HDACs) have emerged as potential therapeutic agents for the treatment of solid tumors and hematological malignancies. To date, several structurally distinct HDAC inhibitors have entered Phase I or II clinical trials, among which phenylbutyrate and similar short-chain fatty acids exhibit weak potency with IC50 in the mM range. This weak potency is, in part, attributable to their inability to access the zinc cation in the HDAC active-site pocket. Structural optimization of valproate, butyrate, phenylacetate, and phenylbutyrate by coupling them with Zn2+-chelating motifs through various aromatic -amino acid linkers has led to a novel class of Zn2+-chelating motif-tethered short-chain fatty acids that exhibited varying degree of HDAC inhibitory potency. N-hydroxy-4-(4-phenylbutyrylamino)-benzamide (HTPB) displayed nM potency in inhibiting HDAC activity. Exposure of several cancer cell lines to HTPB at sub-M showed reduced cell proliferation accompanied by histone hyperacetylation and elevated p21WAF/CIP1 expression. Structure-based optimization of HTPB was carried out by using the framework generated by the structure of histone deacetylase-like protein (HDLP)-trichostatin A (TSA) complexes. Docking of HTPB into the HDLP binding domain suggested that the hydrophobic microenvironment encompassed by Phe-198 and Phe-200 could be exploited for structural optimization. Two of the newly synthesized agents, N-Hydroxy-4-(3-methyl-2-phenyl-butyrylamino)-benzamide (HDAC-42) and 4-(2,2-Dimethyl-4-phenylbutyrylamino)-N-hydroxybenzamide (HDAC-44), displayed IC50s of 30 and 25 nM respectively. HDAC-42 and -44 exhibited optimal in vitro antiproliferative activity against a broad range of cancer cell lines with an average GI50 of 0.2 µM. Subsequent in vivo testing revealed that orally administered HDAC-42 and -44 at 50 and 100 mg/kg/day could effectively suppress PC-3 prostate tumor growth without demonstrable toxicity. Further examination of the activity of the optically active isomers of rac-HDAC-42 was carried out to investigate the effect of stereochemistry on ligand binding. The stereochemical preference of (S)-HDAC-42 over the (R)-counterpart in HDAC inhibition is noteworthy in that it is fivefold more potent. Molecular docking was carried out to shed light into this stereochemical discrimination. Modification of (S)-HDAC-42 was carried out in the aspect of increasing the stereo hindrance of the α-substituents and yielded several derivatives with comparable potency to that of (S)-HDAC-42.
- Subject Headings
- Chemistry, Pharmaceutical
Document number: osu1117541292.
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