ABSTRACT
A series of N-substituted amino caproic hydroxamic acid histone deacetylase inhibitors derivatives was designed in good-toexcellent yields and evaluated for their antiproliferative activity in a panel of human cancer cell lines, showing half maximum effective concentration varying from 700 nM to > 100 µM. Interestingly, the replacement of a furyl group by a thienyl one impacted very significantly the cap role on this antiproliferative activity and on histone acetylation induced by these drugs in cell-based but also in cell-free enzyme assays, suggesting an important role of the electronic density attached to the oxygen or sulfur atoms.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Aminocaproates/chemistry , Aminocaproates/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , HumansABSTRACT
A series of SAHA cap derivatives was designed and prepared in good-to-excellent yields that varied from 49% to 95%. These derivatives were evaluated for their antiproliferative activity in several human cancer cell lines. Antiproliferative activity was observed for concentrations varying from 0.12 to >100 microM, and a molecular modeling approach of selected SAHA derivatives, based on available structural information of human HDAC8 in complex with SAHA, was performed. Strikingly, two compounds displayed up to 10-fold improved antileukemic activity with respect to SAHA; however, these compounds displayed antiproliferative activity similar to SAHA when assayed against solid tumor-derived cell lines. A 10-fold improvement in the leukemic vs peripheral blood mononuclear cell therapeutic ratio, with no evident in vivo toxicity toward blood cells, was also observed. The herein-described compounds and method of synthesis will provide invaluable tools to investigate the molecular mechanism responsible for the reported selectively improved antileukemic activity.
Subject(s)
Antineoplastic Agents/chemical synthesis , Histone Deacetylase Inhibitors/chemical synthesis , Hydroxamic Acids/chemical synthesis , Leukemia/drug therapy , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Blood Cell Count , Cell Line, Tumor , Drug Screening Assays, Antitumor , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/chemistry , Humans , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Mice , Models, Molecular , Repressor Proteins/antagonists & inhibitors , Repressor Proteins/chemistry , Structure-Activity Relationship , Toxicity Tests, Chronic , VorinostatABSTRACT
The interaction of squalamine (SQ) with eukaryotic and prokaryotic membranes was studied and compared with the interaction of two other cationic amphipathic antimicrobials (CAAs), i.e. the antibiotic polymyxin B (PMB) and the detergent hexadecyltrimethylammonium bromide (CTAB). Whole cell experiments showed that the three CAA have in common the ability to interact with lipopolysaccharide-containing membranes through a divalent cation sensitive process. Differences were found regarding their kinetics of membrane permeabilisation and their selectivity for bacteria, with a preferential permeabilisation of bacteria by PMB>SQ and no selectivity for CTAB. Experiments with lipid monolayers and bilayers showed that this selectivity did not correlate with a preferential interaction of the CAAs with lipids but rather relies on differences in their ability to penetrate lipid bilayers and to cause electrically active lesions. Incidentally, our results also suggest that the distribution coefficient of CAAs could be used to predict their selectivity for bacteria.
