ABSTRACT
Diesel exhaust (DE) emissions from a parking garage located in the basement of a school were characterized during spring and winter using direct reading devices and integrated sampling methods. Concentrations of CO and NO2 were evaluated using electrochemical sensors and passive colorimetric tubes, respectively. Elemental and total carbon concentrations were measured using the NIOSH 5040 method. Particle number concentrations (PNCs), respirable particulate matter (PMresp) mass concentrations, and size distributions were evaluated using direct reading devices. Indoor concentrations of elemental carbon, PNC, CO, and NO2 showed significant seasonal variation; concentrations were much higher during winter (p < 0.01). Concentrations of the PMresp and total carbon did not show significant seasonal variation. Pearson correlation coefficients were 0.9 (p < 0.01) and 0.94 (p < 0.01) between the parking garage and ground floor average daily PNCs, and between the parking garage and first floor average daily PNCs, respectively. Since DE is the main identified source of fine and ultrafine particles in the school, these results suggest that DE emissions migrate from the parking garage into the school. Our results highlight the relevance of direct reading instruments in identifying migration of contaminants and suggest that monitoring PNC is a more specific way of assessing exposure to DE than monitoring the common PMresp fraction.
Subject(s)
Air Pollutants/analysis , Vehicle Emissions/analysis , Carbon/analysis , SchoolsABSTRACT
Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.
Subject(s)
Benzamides/pharmacology , Enzyme Inhibitors/pharmacology , Pyrimidines/pharmacology , Animals , Antineoplastic Agents/pharmacology , Benzamides/chemical synthesis , Cell Line, Tumor , Cell Proliferation , Chemistry, Pharmaceutical/methods , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Drug Design , Enzyme Inhibitors/chemistry , Histone Deacetylase Inhibitors , Humans , Inhibitory Concentration 50 , Mice , Neoplasm Transplantation , Pyrimidines/chemical synthesis , Structure-Activity RelationshipABSTRACT
The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.
Subject(s)
Benzamides/pharmacology , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Pyrimidines/pharmacology , Administration, Oral , Animals , Benzamides/administration & dosage , Benzamides/chemistry , Dogs , Drug Screening Assays, Antitumor , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Humans , Male , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted.
Subject(s)
Apoptosis/drug effects , Benzamides/pharmacology , Cell Proliferation/drug effects , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Lung Neoplasms/drug therapy , Pyrimidines/pharmacology , Acetylation , Animals , Benzamides/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Female , Histone Deacetylase 1 , Histone Deacetylase 2 , Histone Deacetylases/metabolism , Humans , Hydroxamic Acids/pharmacology , In Vitro Techniques , Isoenzymes , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Mice , Mice, Nude , Pyrimidines/pharmacokinetics , Repressor Proteins/antagonists & inhibitors , Repressor Proteins/metabolism , Tumor Cells, Cultured , Vorinostat , Xenograft Model Antitumor AssaysABSTRACT
The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs is described. Some of these compounds were shown to inhibit HDAC1 with IC(50) values below the micromolar range, induce hyperacetylation of histones, upregulate expression of the tumor suppressor p21(WAF1/Cip1), and inhibit proliferation of human cancer cells. In addition, certain compounds of this class were active in several human tumor xenograft models in vivo.
Subject(s)
Aniline Compounds/chemical synthesis , Aniline Compounds/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Aniline Compounds/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzamides/chemistry , Breast/cytology , Breast/drug effects , Cell Line , Cyclin-Dependent Kinase Inhibitor p21/biosynthesis , Enzyme Inhibitors/chemistry , Epithelial Cells/cytology , Epithelial Cells/drug effects , HCT116 Cells , Histone Deacetylase 1 , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Structure-Activity RelationshipABSTRACT
Inhibition of histone deacetylases (HDAC) is emerging as a new strategy in human cancer therapy. The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides is presented herein. From the different series bearing a six-membered heteroaromatic ring studied, the s-triazine series showed the best HDAC1 enzyme and in vitro anti-proliferative activities with IC(50) values below micromolar range. Some of these compounds can also significantly reduce tumor growth in human tumor xenograft models in mice.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Pyrimidines/pharmacology , Triazines/chemical synthesis , Triazines/pharmacology , Animals , Antineoplastic Agents/chemistry , Benzamides/chemistry , Disease Models, Animal , Drug Design , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Mice , Structure-Activity Relationship , Triazines/chemistryABSTRACT
A variety of N-(2-amino-phenyl)-4-(heteroarylmethyl)-benzamides were designed and synthesized. These compounds were shown to inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induced hyperacetylation of histones, induced the expression of the tumor suppressor protein p21(WAF1/Cip1), and inhibited cellular proliferation. Certain compounds of this class also showed in vivo activity in various human tumor xenograft models in mice.
Subject(s)
Benzamides/chemistry , Benzamides/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Amination , Animals , Binding Sites , Cell Line , Histone Deacetylases/chemistry , Histone Deacetylases/metabolism , Humans , Methylation , Mice , Models, Molecular , Molecular Structure , Niacin/pharmacology , Structure-Activity Relationship , Urea/chemistry , Vasodilation/drug effects , ortho-Aminobenzoates/chemistryABSTRACT
Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzamides/chemical synthesis , Histone Deacetylase Inhibitors , NADH, NADPH Oxidoreductases/antagonists & inhibitors , Antineoplastic Agents/chemistry , Benzamides/chemistry , Benzamides/pharmacology , Catalytic Domain , Cell Line , Histone Deacetylase 1 , Histone Deacetylases/chemistry , Histone Deacetylases/metabolism , Humans , Models, Molecular , NADH, NADPH Oxidoreductases/chemistry , NADH, NADPH Oxidoreductases/metabolism , Structure-Activity RelationshipABSTRACT
Inhibition of histone deacetylases (HDACs) is emerging as a new strategy in human cancer therapy. Novel 2-aminophenyl benzamides and acrylamides, that can inhibit human HDAC enzymes and induce hyperacetylation of histones in human cancer cells, have been designed and synthesized. These compounds selectively inhibit proliferation and cause cell cycle arrest in various human cancer cells but not in normal cells. The growth inhibition of 2-aminophenyl benzamides and acrylamides against human cancer cells in vitro is reversible and is dependent on the induction of histone acetylation. Compounds of this class can significantly reduce tumor growth in human tumor xenograft models.
Subject(s)
Acrylamides/pharmacology , Benzamides/pharmacology , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Acrylamides/chemistry , Benzamides/chemistry , Cell Line, Tumor , Enzyme Inhibitors/chemistry , Humans , Structure-Activity RelationshipABSTRACT
A variety of omega-substituted alkanoic acid (2-amino-phenyl)-amides were designed and synthesized. These compounds were shown to inhibit recombinant human histone deacetylases (HDACs) with IC(50) values in the low micromolar range and induce hyperacetylation of histones in whole cells. They induced expression of p21WAF1/Cip1 and caused cell-cycle arrest in human cancer cells. Compounds in this class showed efficacy in human tumor xenograft models.
Subject(s)
Amides/chemistry , Amides/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Cell Cycle/drug effects , Cell Cycle/physiology , Cell Line, Tumor , Histone Deacetylases/metabolism , HumansABSTRACT
A series of sulfonamide hydroxamic acids and anilides have been synthesized and studied as histone deacetylase (HDAC) inhibitors that can induce hyperacetylation of histones in human cancer cells. The inhibition of HDAC activity represents a novel approach for intervening in cell cycle regulation. The lead candidates were screened in a panel of human tumor and normal cell lines. They selectively inhibit proliferation, cause cell cycle blocks, and induce apoptosis in human cancer cells but not in normal cells. The structure-activity relationships, the antiproliferative activity, and the in vivo efficacy are described.
Subject(s)
Antineoplastic Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors , Hydroxamic Acids/chemical synthesis , Sulfonamides/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Cycle/drug effects , Cell Line , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Mice , Mice, Nude , Neoplasm Transplantation , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Transplantation, HeterologousABSTRACT
Inhibition of histone deacetylases (HDACs) is emerging as a new strategy in human cancer therapy. We have designed and synthesized novel nonhydroxamate sulfonamide anilides that can inhibit human HDAC enzymes and can induce hyperacetylation of histones in human cancer cells. These compounds selectively inhibit proliferation and cause cell cycle blocks in various human cancer cells but not in normal cells. The growth inhibitory activity of sulfonamide anilides against human cancer cells in vitro is reversible and is dependent on the induction of histone acetylation. One of these compounds (Compound 2) can significantly reduce tumor growth of implanted human colon tumors in nude mice. Unlike another anilide-based HDAC inhibitor, MS-275, which decreases both red and white blood counts and reduces spleen weights in mice, Compound 2 does not exhibit noticeable toxicity. By using cDNA array analysis, we have identified downstream genes whose expression is altered by Compound 2 in human cancer cells. In correlation with its antitumor activity both in vitro and in vivo, Compound 2 induces expression of p21(WAF1/Cip1), gelsolin, and keratin 19, while down-regulating expression of cyclin A and cyclin B1 in human cancer cells in a dose-dependent manner. Our results suggest that sulfonamide anilides are novel HDAC inhibitors and may be useful as antiproliferative agents in cancer chemotherapy.
Subject(s)
Anilides/pharmacology , Antineoplastic Agents/pharmacology , Histone Deacetylase Inhibitors , Sulfonamides/pharmacology , Acetylation/drug effects , Anilides/toxicity , Animals , Antineoplastic Agents/toxicity , Benzamides/pharmacology , Benzamides/toxicity , Colonic Neoplasms/drug therapy , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Cyclin A/biosynthesis , Cyclin B/biosynthesis , Cyclin B1 , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/biosynthesis , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/toxicity , Female , G2 Phase/drug effects , Histones/metabolism , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Mitosis/drug effects , Pyridines/pharmacology , Pyridines/toxicity , Sulfonamides/toxicity , Xenograft Model Antitumor AssaysABSTRACT
A series of new, structurally simple trichostatin A (TSA)-like straight chain hydroxamates were prepared and evaluated for their ability to inhibit partially purified human histone deacetylase 1 (HDAC-1). Some of these compounds such as 8m, 8n, 12, and 15b exhibited potent HDAC inhibitory activity with low nanomolar IC(50) values, comparable to natural TSA. These compounds induce hyperacetylation of histones in T24 human cancer cells and significantly inhibit proliferation in various human cancer cells. They also induce expression of p21 and cause cell cycle blocks in human cancer cells. In this paper, we describe the synthesis of these new compounds as well as structure-activity relationship results from enzyme inhibition and alterations in cellular function.
