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1.
Toxicol In Vitro ; 28(5): 769-77, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24583196

ABSTRACT

Chalcones, naturally occurring open-chain flavonoids abundant in plants, have demonstrated anticancer activity in multiple tumor cells. In a previous work, the potential anticancer activity of three naphthylchalcones named R7, R13 and R15 was shown. In this study, the mechanism of actions of these chalcones was originally shown. The chalcones presented concentration and time-dependent cytotoxicity. To determine the type of cell death induced by chalcones, we assessed a series of assays including measurements of the caspase-8, -9 and -12 activities, expression of important apoptosis-related genes and proteins, changes in the cell calcium concentration and cytochrome c release. The activities of caspase-8, -9 and -12 increased after the treatment of L1210 cells with the three compounds. Chalcones R7 and R13 induced an increase of pro-apoptotic proteins Bax, Bid and Bak (only chalcone R13), as well as a decrease in anti-apoptotic Bcl-2 expression. These chalcones also induced an increase in Fas and a decrease in p21 and p53 expression. Chalcone R15 seems to act by a different mechanism to promote cell death, as it did not change the mitochondrion-related proteins, nor did it induce the cytochrome c release. All compounds induced an increase in cell calcium concentration and an increase in CHOP expression, which together with an increase in caspase-12 activity, suggest that chalcones could induce an endoplasmic reticulum (ER) stress. Taken together, these results suggest that chalcones induce apoptosis by different pathways, being an interesting strategy to suggest for cancer therapy.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Chalcones/pharmacology , Animals , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Calcium/metabolism , Cell Cycle/drug effects , Cell Death/drug effects , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cytochromes c/metabolism , Endoplasmic Reticulum Stress , Gene Expression , Leukemia/drug therapy , Leukemia/metabolism , Mice , NIH 3T3 Cells , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Vero Cells , fas Receptor/genetics , fas Receptor/metabolism
2.
Biochimie ; 95(4): 866-74, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23257665

ABSTRACT

Acute leukemia is a disorder of the hematopoietic system characterized by the expansion of a clonal population of cells blocked from differentiating into mature cells. Recent studies have shown that chalcones and their derivatives induce apoptosis in different cell lines. Since new compounds with biological activity are needed, the aim of this study was to evaluate the cytotoxic effect of three synthetic chalcones, derived from 1-naphthaldehyde and 2-naphthaldehyde, on human acute myeloid leukemia K562 cells and on human acute lymphoblastic leukemia Jurkat cells. Based on the results, the most cytotoxic compound (A1) was chosen for further analysis in six human acute leukemia cells and in a human colon adenocarcinoma cell line (HT-29). Chalcone A1 significantly reduced the cell viability of K562, Jurkat, Kasumi, U937, CEM and NB4 cells in a concentration and time-dependent manner when compared with the control group (IC50 values between ∼1.5 µM and 40 µM). It was also cytotoxic to HL-29 cells. To further examine its effect on normal cells, peripheral blood lymphocytes collected from healthy volunteers were incubated with the compound. It has also been incubated with human fibroblasts cultured from bone marrow (JMA). Chalcone A1 is non-cytotoxic to PBL cells and to JMA cells. A1 caused significant cell cycle arrest in all phases according to the cell line, and increased the proportion of cells in the sub G0/G1 phase. To evaluate whether this chalcone induced cell death via an apoptotic or necrotic pathway, cell morphology was examined using fluorescence microscopy. Cells treated with A1 at IC50 demonstrated the morphological characteristic of apoptosis, such as chromatin condensation and formation of apoptotic bodies. Apoptosis was confirmed by externalization of phosphatidylserine, which was detected by the Annexin V-FITC method, and by DNA fragmentation. The results suggest that chalcone A1 has potential as a new lead compound for cancer therapy.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Chalcones/chemical synthesis , Chalcones/pharmacology , Leukemia/pathology , Antineoplastic Agents/chemistry , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Chalcones/chemistry , Chemistry Techniques, Synthetic , Dose-Response Relationship, Drug , Humans , Time Factors
3.
Eur J Med Chem ; 48: 255-64, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22209415

ABSTRACT

Gliomas are the most common and devastating tumors of the central nervous system (CNS). Many pieces of evidence point out the relevance of natural compounds for cancer therapy and prevention, including chalcones. In the present study, eight synthetic quinoxaline-derived chalcones, structurally based on the selective PI3Kγ inhibitor AS605240, were evaluated for anti-proliferative activity and viability inhibition using glioma cell lines from human and rat origin (U-138 MG and C6, respectively), at different time-periods of incubation and concentrations. The results revealed that four chalcones (compounds 1, 6, 7 and 8), which present methoxy groups at A-ring, displayed higher efficacies and potencies, being able to inhibit either cell proliferation or viability, in a time- and concentration-dependent manner, with an efficacy that was greater than that seen for the positive control compound AS605240. Flow cytometry analysis demonstrated that incubation of C6 cells with compound 6 led to G1 phase arrest, likely indicating an interference with apoptosis. Furthermore, compound 6 was able to visibly inhibit AKT activation, allied to the stimulation of ERK MAP-kinase. The chalcones tested herein, especially those displaying a methoxy substituent, might well represent promising molecules for the adjuvant treatment of glioma progression.


Subject(s)
Antineoplastic Agents/chemical synthesis , Brain Neoplasms/drug therapy , Chalcones/chemical synthesis , Chalcones/pharmacology , Glioma/drug therapy , Quinoxalines/chemical synthesis , Quinoxalines/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Brain Neoplasms/pathology , Cell Cycle Checkpoints/physiology , Cell Growth Processes/drug effects , Cell Line, Tumor , Chalcones/chemistry , Glioma/pathology , Humans , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Molecular Structure , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism , Quinoxalines/chemistry , Rats , Spectrophotometry, Infrared , Structure-Activity Relationship
4.
J Med Chem ; 55(1): 390-402, 2012 Jan 12.
Article in English | MEDLINE | ID: mdl-22136336

ABSTRACT

Tuberculosis (TB) is a major infectious disease caused by Mycobacterium tuberculosis (Mtb). According to the World Health Organization (WHO), about 1.8 million people die from TB and 10 million new cases are recorded each year. Recently, a new series of naphthylchalcones has been identified as inhibitors of Mtb protein tyrosine phosphatases (PTPs). In this work, 100 chalcones were designed, synthesized, and investigated for their inhibitory properties against MtbPtps. Structure-activity relationships (SAR) were developed, leading to the discovery of new potent inhibitors with IC(50) values in the low-micromolar range. Kinetic studies revealed competitive inhibition and high selectivity toward the Mtb enzymes. Molecular modeling investigations were carried out with the aim of revealing the most relevant structural requirements underlying the binding affinity and selectivity of this series of inhibitors as potential anti-TB drugs.


Subject(s)
Antitubercular Agents/chemical synthesis , Bacterial Proteins/antagonists & inhibitors , Chalcones/chemical synthesis , Models, Molecular , Mycobacterium tuberculosis/enzymology , Protein Tyrosine Phosphatases/antagonists & inhibitors , Amino Acid Sequence , Antitubercular Agents/chemistry , Bacterial Proteins/chemistry , Benzene Derivatives/chemical synthesis , Benzene Derivatives/chemistry , Chalcones/chemistry , Humans , Kinetics , Molecular Sequence Data , Naphthalenes/chemical synthesis , Naphthalenes/chemistry , Protein Binding , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Protein Tyrosine Phosphatase, Non-Receptor Type 1/chemistry , Protein Tyrosine Phosphatases/chemistry , Sequence Alignment , Structure-Activity Relationship
5.
Bioorg Med Chem ; 19(16): 5046-52, 2011 Aug 15.
Article in English | MEDLINE | ID: mdl-21757358

ABSTRACT

In this work we described the synthesis, the antileishmanial activity and the molecular modeling and structure-activity relationship (SAR) evaluations of a series of chalcone derivatives. Among these compounds, the methoxychalcones 2h, 2i, 2j, 2k and 2l showed significant antileishmanial activity (IC(50)<10 µM). Interestingly 2i (IC(50)=2.7 µM), 2j (IC(50)=3.9 µM) and 2k (IC(50)=4.6 µM) derivatives presented better antileishmanial activity than the control drug pentamidine (IC(50)=6.0 µM). Our SAR study showed the importance of methoxy di-ortho substitution at phenyl ring A and the relationship between the frontier orbital HOMO coefficients distribution of these molecules and their activity. The most active compounds 2h, 2i, 2j, 2k, and 2l fulfilled the Lipinski rule-of-five which theoretically is important for good drug absorption and permeation through biological membranes. The potential profile of 2j (IC(50)=3.9 µM and CC(50)=216 µM) pointed this chalcone derivative as a hit compound to be further explored in antileishmanial drug design.


Subject(s)
Antiprotozoal Agents/pharmacology , Chalcone/pharmacology , Leishmania braziliensis/growth & development , Antiprotozoal Agents/chemistry , Chalcone/analogs & derivatives , Chalcone/chemistry , Leishmania braziliensis/drug effects , Models, Molecular , Structure-Activity Relationship
6.
Bioorg Med Chem ; 18(22): 8026-34, 2010 Nov 15.
Article in English | MEDLINE | ID: mdl-20952199

ABSTRACT

In this study, we investigated the effects of 24 chalcone derivatives from 2-naphthylacetophenone toward a lymphoblastic leukemia cell line (L1210). Three compounds, called R7, R13, and R15, presented concentration- and time-dependent cytotoxicity and induced cellular death by apoptosis via mitochondrial injury and oxidative stress. The effects of these compounds appear to occur through different mechanisms because R13 and R7 induced a greater disturbance of mitochondrial potential, and all compounds induced disturbances of cellular ATP content and increased caspase-3 activity before cellular death. These compounds also interfered with antioxidant enzymes activities and GSH content through different mechanisms.


Subject(s)
Antineoplastic Agents/chemistry , Apoptosis , Caspase 3/metabolism , Chalcone/analogs & derivatives , Chalcones/chemistry , Leukemia/drug therapy , Mitochondria/drug effects , Oxidative Stress , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Cell Line, Tumor , Chalcone/therapeutic use , Chalcone/toxicity , Chalcones/therapeutic use , Chalcones/toxicity , Humans , Reactive Oxygen Species/metabolism
7.
J Pharm Pharmacol ; 62(9): 1128-36, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20796191

ABSTRACT

OBJECTIVES: New compounds with biological targets and less cytotoxicity to normal cells are necessary for cancer therapy. In this work ten synthetic chalcones derived from 2-naphtaldehyde were evaluated for their cytotoxic effect in murine acute lymphoblastic leukemia cells L-1210. METHODS: A series of ten chalcones derived from 2-naphtaldehyde and corresponding acetophenones were prepared by aldolic condensation, using methanol as solvent under basic conditions, at room temperature for 24 h. The cell viability was determined by MTT colorimeter method. The cell cycle phase analysis was carried out by flow cytometry after propidium iodide staining. The apoptosis induction was assessed by exposure to phosphatidylserine (ANNEXIN V-FITC). Cytometric analysis was performed to evaluate the expression of p53, Bcl-2 and Bax protein. The caspase-3 expression was studied by immunoblotting analysis. KEY FINDINGS: A preliminary screening of a series of ten chalcones derived from 2-naphtaldehyde showed that chalcone 8, (2E)-3-(2-naphtyl)-1-(3'-methoxy-4'-hydroxy-phenyl)-2-propen-1-one, had the highest cytotoxic effect (IC50 of 54 microM), but not in normal human lymphocytes. To better understand the cytotoxic mechanism of chalcone 8, its effect on cell cycle and apoptosis was assessed. Our results showed that chalcone 8 caused cell cycle arrest in the G2/M phase and a significant increase in the proportion of cells in the subG0/G1 phase. Our results also demonstrated that chalcone 8 promoted a modification in Bax:Bcl-2 ratio and increased p53 expression and caspase-3 activation. CONCLUSIONS: The studied chalcone 8 has cytotoxic effect against L-1210 lymphoblastic leukaemic cells, and this effect is associated with increase of p-53 and Bax expression.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Chalcones/pharmacology , Leukemia/drug therapy , Plant Extracts/pharmacology , Acetophenones/chemical synthesis , Aldehydes/pharmacology , Aldehydes/therapeutic use , Animals , Antineoplastic Agents/therapeutic use , Caspase 3/metabolism , Cell Line, Tumor , Chalcones/chemical synthesis , Chalcones/therapeutic use , Leukemia/metabolism , Leukemia L1210 , Lymphocytes/drug effects , Mice , Naphthalenes/pharmacology , Naphthalenes/therapeutic use , Plant Extracts/therapeutic use , Proto-Oncogene Proteins c-bcl-2/metabolism , Tumor Suppressor Protein p53/metabolism , bcl-2-Associated X Protein/metabolism
8.
Bioorg Med Chem ; 18(11): 3783-9, 2010 Jun 01.
Article in English | MEDLINE | ID: mdl-20462762

ABSTRACT

Tuberculosis (TB) is a major cause of morbidity and mortality throughout the world, and it is estimated that one-third of the world's population is infected with Mycobacterium tuberculosis. Among a series of tested compounds, we have recently identified five synthetic chalcones which inhibit the activity of M. tuberculosis protein tyrosine phosphatase A (PtpA), an enzyme associated with M. tuberculosis infectivity. Kinetic studies demonstrated that these compounds are reversible competitive inhibitors. In this work we also carried out the analysis of the molecular recognition of these inhibitors on their macromolecular target, PtpA, through molecular modeling. We observed that the predominant determinants responsible for the inhibitory activity of the chalcones are the positions of the two methoxyl groups at the A-ring, that establish hydrogen bonds with the amino acid residues Arg17, His49, and Thr12 in the active site of PtpA, and the substitution of the phenyl ring for a 2-naphthyl group as B-ring, that undergoes pi stacking hydrophobic interaction with the Trp48 residue from PtpA. Interestingly, reduction of mycobacterial survival in human macrophages upon inhibitor treatment suggests their potential use as novel therapeutics. The biological activity, synthetic versatility, and low cost are clear advantages of this new class of potential tuberculostatic agents.


Subject(s)
Antitubercular Agents/chemistry , Chalcones/pharmacology , Mycobacterium tuberculosis/drug effects , Protein Tyrosine Phosphatases/antagonists & inhibitors , Chalcones/chemical synthesis , Chalcones/chemistry , Kinetics , Models, Molecular , Mycobacterium tuberculosis/enzymology , Mycobacterium tuberculosis/growth & development , Structure-Activity Relationship
9.
Eur J Med Chem ; 45(4): 1332-7, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20061067

ABSTRACT

The purpose of the present work was to investigate, following previous works, naphthylchalcones as antihyperglycemic agent in glucose loaded animal model, insulin secretion as well as the action of these compounds on glucose uptake in a target tissue of insulin. The naphthylchalcones were found to have an acute serum glucose-lowering effect in hyperglycemic normal rats. In addition, chalcones 2 and 4 stimulated significantly the insulin secretion induced by glucose. These results suggest that the presence of nitro group and their position in the phenyl rings are responsible for the antihyperglycemic activity of chalcones. Additionally, the effect of chalcones on serum glucose-lowering seems to be a consequence of insulin secretion and these chalcones represent potential compounds with strong antihyperglycemic properties.


Subject(s)
Chalcones/pharmacology , Hypoglycemic Agents/pharmacology , Animals , Blood Glucose/analysis , Enzyme-Linked Immunosorbent Assay , Insulin/blood , Insulin/metabolism , Insulin Secretion , Male , Rats , Rats, Wistar
10.
Biochimie ; 91(11-12): 1493-8, 2009.
Article in English | MEDLINE | ID: mdl-19747522

ABSTRACT

In this study, the in vivo and in vitro anti-hyperglycemic activity of chalcone derivatives of 3,4-methylenedioxy, with a substituent electron-acceptor nitro group in the A or B ring, was investigated. As expected, the second generation sulfonylurea glipizide stimulated insulin secretion and reduced glycemia over the study period. Also, it was demonstrated for the first time that chalcones are able to increase insulin secretion and this event was coincident with serum glucose-lowering in the oral glucose tolerance test. Additionally, the chalcones studied had a similar effect on insulin secretion and serum glucose-lowering as glipizide. The effect of chalcones in terms of inducing insulin secretion was greater than that of glipizide after 30 min. Moreover, chalcones were not able to stimulate glucose uptake in soleus muscle, either in the presence of insulin or in the absence of this hormone. In addition, the oral treatment with chalcones did not alter glycemia in diabetic rats. These reports indicate that the effect of chalcones on serum glucose-lowering in hyperglycemic-normal rats is mainly a consequence of insulin secretion, highlighting these chalcones as novel compounds with strong anti-hyperglycemic properties.


Subject(s)
Blood Glucose/drug effects , Chalcone/pharmacology , Glipizide/pharmacology , Hypoglycemic Agents/pharmacology , Insulin/metabolism , Administration, Oral , Animals , Chalcone/administration & dosage , Diabetes Mellitus, Experimental/blood , Glipizide/administration & dosage , Glucose/analysis , Glucose Tolerance Test , Insulin Secretion , Male , Rats , Rats, Wistar
11.
Eur J Med Chem ; 44(4): 1630-7, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19211173

ABSTRACT

Searching for leading compounds of new drugs for cancer therapy, we studied the toxicity of 13 hydroxychalcones never tested before toward melanoma cell line (B16-F10). The compounds were obtained by aldolic condensation between aldehydes and hydroxylated acetophenones, in alkaline conditions. Three of them showed cytotoxicity to the cell line. Two of them induced mitochondrial GSH and ATP depletion and promoted cell death through apoptosis in melanoma cells. One of the compounds induced cell death through necrosis but did not significantly decrease the intracellular mitochondrial GSH and ATP levels in melanoma cells. The results suggest that the predominant factor for the activity is the molecule shape, and secondarily the number of hydroxyl groups.


Subject(s)
Adenosine Triphosphate/metabolism , Apoptosis/drug effects , Chalcone/chemistry , Chalcone/pharmacology , Glutathione/metabolism , Melanoma/metabolism , Melanoma/pathology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , DNA Fragmentation/drug effects , Dose-Response Relationship, Drug , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Magnetic Resonance Spectroscopy , Melanoma/drug therapy , Melanoma/genetics , Mice , Mitochondria/drug effects , Mitochondria/metabolism , Spectrophotometry, Infrared
12.
Bioorg Med Chem Lett ; 18(23): 6227-30, 2008 Dec 01.
Article in English | MEDLINE | ID: mdl-18930396

ABSTRACT

In the search for lead compounds for new drugs for tuberculosis, the activity of 38 synthetic chalcones were assayed for their potential inhibitory action towards a protein tyrosine phosphatase from Mycobacterium tuberculosis--PtpA. The compounds were obtained by aldolic condensation between aldehydes and acetophenones, under basic conditions. Five compounds presented moderate or good activity. The structure-activity analysis reveals that the predominant factor for the activity is the molecule planarity/hydrophobicity and the nature of the substituents.


Subject(s)
Chalcones/chemical synthesis , Chalcones/pharmacology , Mycobacterium tuberculosis/enzymology , Protein Tyrosine Phosphatases/antagonists & inhibitors , Bacterial Proteins , Chalcones/chemistry , Combinatorial Chemistry Techniques , Drug Resistance, Bacterial/drug effects , Molecular Structure , Protein Tyrosine Phosphatases/genetics , Structure-Activity Relationship , Tuberculosis/drug therapy
13.
Chem Biol Interact ; 171(3): 355-62, 2008 Feb 15.
Article in English | MEDLINE | ID: mdl-18164698

ABSTRACT

A series of chalcone derivatives from 3,4-methylenedioxybenzaldehyde and substituted acetophenones have been synthesized and investigated as antihyperglycemic agents in a glucose loaded animal model. Chalcones with biological activity were compared with lispro, regular insulin and tolbutamide effects on serum glucose levels. Compound 01, without substituent in the A-ring was not able to change glycemic levels. On the other hand, compounds 03, 04, 05, 09 and 10 with substitutions at position 3' and/or 4' in the A-ring caused significant reduction in serum glucose levels. Concerning the antihyperglycemic effect, compounds 03 and 05 (methoxy substituent) inhibited the hyperglycemia induced by glucose around 96% similar to that demonstrated for lispro insulin and tolbutamide at 60 min. A rapid and lasting antihyperglycemic effect was found with compound 09 and 10 (nitro substituent). In conclusion, besides the nature of the functional groups electron-donor substituent, as methoxy and hydroxyl or electron-acceptor, as nitro groups, the position of the group may be mandatory for biological activity.


Subject(s)
Blood Glucose/drug effects , Chalcone/analogs & derivatives , Chalcone/administration & dosage , Hyperglycemia/drug therapy , Hypoglycemic Agents/administration & dosage , Administration, Oral , Animals , Blood Glucose/analysis , Chalcone/chemical synthesis , Chalcone/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Glucose/administration & dosage , Hyperglycemia/blood , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Insulin/administration & dosage , Male , Molecular Structure , Rats , Rats, Wistar , Stereoisomerism , Time Factors , Tolbutamide/administration & dosage
14.
Bioorg Med Chem ; 16(2): 658-67, 2008 Jan 15.
Article in English | MEDLINE | ID: mdl-17988874

ABSTRACT

Inhibition of nitric oxide (NO) production by altering the expression of induced enzymes involved is potentially an important strategy for obtaining antiinflammatory agents. In the search for hits to obtain lead compounds for new drugs of this class, 14 synthetic chalcones derived from 2,4,6-trimethoxyacetophenone were evaluated in terms of their inhibitory action, in vitro, in relation to NO production in murine macrophages of the line RAW 264.7 induced by bacterial lipopolysaccharides (LPS). All the compounds were obtained by aldolic condensation between the acetophenone and corresponding aldehydes, under basic conditions. The mean IC(50) values, calculated through dose versus inhibitory effect curves, in four independent experiments, varied between 1.34 and 27.60microM, and were compared with the positive control, compound 1400W (IC(50)=3.78microM), a highly selective inhibitor of iNOS (induced nitric oxide synthase). Eight chalcones gave mean IC(50) values less than or equal to those obtained for 1400W, which suggests that these molecules may act as inhibitors of inflammatory process. The QSAR study reveals that electron-withdrawing groups in the B-ring seem to increase the inhibition of nitrite production, mainly when in position 2. A substitution in the ortho position of the A-ring seems to be necessary for the activity.


Subject(s)
Acetophenones/chemistry , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Chalcones/chemical synthesis , Chalcones/pharmacology , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Animals , Anti-Inflammatory Agents/chemistry , Chalcones/chemistry , Inhibitory Concentration 50 , Mice , Molecular Structure , Nitric Oxide/antagonists & inhibitors , Nitric Oxide/biosynthesis , Nitric Oxide Synthase Type II/biosynthesis , Nitric Oxide Synthase Type II/drug effects , Quantitative Structure-Activity Relationship
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