Molecular design and synthesis of histone deacetylase inhibitors as antineoplastic agents

Abstract

In this study, five series of (E)-6-(4-(amino-substituted)phenyl)-4-oxohex-5- enoic acids IIb-f (E), (E)-3-(4-(amino-substituted)phenyl)acrylic acids IIIa-g (E), 4-(4-(amino-substituted) phenylamino)-4-oxobutanoic acids VIa,b,e, 5-(4-(aminosubstituted) phenylamino)-5-oxo-pentanoic acids VIIa,f and 2-((4-(aminosubstituted) phenyl)carbamoyl)benzoic acids VIIIa,e were designed and synthesized. Selected compounds IIb-f (E), IIIf (E), VIb, VIIf were screened in vitro for their antiproliferative effect on 60 human NCI tumor cell lines. Compound IIf (E) displayed significant inhibitory activity against NCI Non-Small Cell Lung A549/ATCC Cancer cell line (68% inhibition) and NCI-H460 Cancer cell line (66% inhibition). Compound IIIf (E) displayed significant inhibitory activity against Breast cancer MDA-MB-468 cell line (57.34% inhibition). Moreover, the target compounds IIb-f (E), IIIa-g (E), VIa,b,e and VIIa,f VIIIa,e were evaluated in vitro for their antiproliferative activity on HepG2 Cancer cell line in which histone deacetylase (HDAC) is overexpressed. Compounds IIc (E), IIf (E), IIIb (E), and IIIg (E) exhibited the highest antiproliferative activity against HepG2 human cancer cell lines with IC50 ranging from 2.27-10.71 μM. In addition, selected compounds IIb,c,f (E), IIIb,f,g (E), VIa, VIIa and VIIIa were tested against (HDAC1) at 10 μM, where none of the tested compounds showed inhibition activity at this concentration. Furthermore, selected compounds IIf (E), IIIf (E) and VIIa were tested against (HDAC2-11) at 50 μM, where surprisingly newly synthesized compound IIf (E) showed remarkable increase in HDAC activity against different HDAC isoforms instead of the expected inhibitory activity against class I HDACs and compound IIIf (E) showed potential enzyme inhibitory activity against different HDAC isoforms (27% inhibition against HDAC6, 25% inhibition against HDAC8, 20% inhibition against HDAC5).