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1.
Chem Res Toxicol ; 36(12): 1973-1979, 2023 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-37963190

RESUMO

As a potential means for smoking cessation and consequently prevention of smoking-related diseases and mortality, in this study, our goal was to investigate the inhibition of nicotine metabolism by P450 2A6. Smoking is the main cause of many diseases and disabilities and harms nearly every organ of the body. As reported by the Centers for Disease Control and Prevention (CDC), more than 16 million Americans are living with diseases caused by smoking. On average, the life expectancy of a smoker is about 10 years less than a nonsmoker. Smoking cessation can substantially reduce the incidence of smoking-related diseases, including cancer. At least, 70 of the more than 7000 cigarette smoke components, including polycyclic aromatic hydrocarbons, N-nitrosamines, and aromatic amines, are known carcinogens. Nicotine is the compound responsible for the addictive and psychopharmacological effects of tobacco. Cytochrome P450 enzymes are responsible for the phase I metabolism of many tobacco components, including nicotine. Nicotine is mainly metabolized by cytochrome P450s 2A6 and 2A13 to cotinine. This metabolism decreases the amount of available nicotine in the bloodstream, leading to increased smoking behavior and thus exposure to tobacco toxicants and carcinogens. Here, we report the syntheses and P450 2A6 inhibitory activities of a number of new flavone-based esters and acids. Three of the flavone derivatives studied were found to be potent competitive inhibitors of the enzyme. Docking studies were used to determine the possible mechanisms of the activity of these inhibitors.


Assuntos
Flavonas , Nicotina , Humanos , Nicotina/farmacologia , Nicotina/metabolismo , Citocromo P-450 CYP2A6/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Carcinógenos/metabolismo , Flavonas/farmacologia
2.
J Oncol Res Ther ; 8(2)2023.
Artigo em Inglês | MEDLINE | ID: mdl-37538786

RESUMO

Background: Many current anti-cancer drugs used to treat breast cancer mediate tumor cell death through the induction of apoptosis. Cancer cells, however, often acquire multidrug-resistance following prolonged exposure to chemotherapeutics. Consequently, molecular pathways involved in tumor cell proliferation have become potential targets for pharmacological intervention. Ceramides are tumor suppressor lipids naturally found in the cell membrane, and are central molecules in the sphingolipid signalling pathway. Methods: Our lab has targeted the ceramide signaling pathway for potential pharmacological intervention in the treatment of breast cancer. Previously, we have shown that certain ceramide analogs have therapeutic potential in the treatment of chemo-sensitive and multidrug-resistant breast cancers. Using the most active analog from our previous studies as the lead compound, new analogs containing a flavone moiety were designed and synthesized. In general, flavone derivatives often show interesting pharmacological properties, and compounds based on these molecules have been found useful in many different therapeutic areas including anti-tumor, anti-coagulants, and anti-HIV therapy. Results: Synthesis and biological evaluation of five new flavonoid ceramide analogs are reported here. These compounds were also shown to be self-fluorescent, which can be useful when investigating their distribution and action in cancer cells. Conclusion: Four out of the five flavone ceramide analogs in this study showed significant anti-proliferation activities in the three cell lines studied, MDA-MB-232, MCF-7, and MCF-7TN-R; some showing varying degrees of selectivity. The mechanisms involved in cell proliferation inhibition are complicated and further studies are needed.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34722929

RESUMO

AIM: In this study, our goal was to study the inhibition of nicotine metabolism by P450 2A6, as a means for reduction in tobacco use and consequently the prevention of smoking-related cancers. Nicotine, a phytochemical, is an addictive stimulant, responsible for the tobacco-dependence in smokers. Many of the other phytochemicals in tobacco, including polycyclic aromatic hydrocarbons, N-nitrosamines, and aromatic amines, are potent systemic carcinogens. Tobacco smoking causes about one of every five deaths in the United States annually. Nicotine plasma concentration is maintained by the smokers' smoking behavior within a small range. Nicotine is metabolized by cytochrome P450s 2A6 and 2A13 to cotinine. This metabolism causes a decrease in nicotine plasma levels, which in turn leads to increased tobacco smoking, and increased exposure to the tobacco carcinogens. METHODS: Using the phytochemical nicotine as a lead structure, and taking its interactions with the P450 2A6 binding pocket into consideration, new pyridine derivatives were designed and synthesized as potential selective mechanism-based inhibitors for this enzyme. RESULTS: The design and synthesis of two series of novel pyridine-based compounds, with varying substituents and substitution locations on the pyridine ring, as well as their inhibitory activities on cytochrome P450 2A6 and their interactions with its active site are discussed here. Substitutions at position 3 of the pyridine ring with an imidazole or propargyl ether containing group showed the most optimal interactions with the P4502A6 active site. CONCLUSION: The pyridine compounds with an imidazole or propargyl ether containing substituent on position 3 were found to be promising lead compounds for further development. Hydrogen-bonding interactions were determined to be crucial for effective binding of these molecules within the P450 2A6 active site.

4.
ACS Omega ; 4(6): 10610-10619, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31460159

RESUMO

Human epidermal growth factor receptor 2 (HER2) is overexpressed in nearly 20-30% of breast cancers and is associated with metastasis resulting in poor patient survival and high recurrence. The dual EGFR/HER2 kinase inhibitor lapatinib has shown promising clinical results, but its limitations have also led to the resistance and activation of tumor survival pathways. Following our previous investigation of quinones as HER2 kinase inhibitors, we synthesized several naphthoquinone derivatives that significantly inhibited breast tumor cells expressing HER2 and trastuzumab-resistant HER2 oncogenic isoform, HER2Δ16. Two of these compounds were shown to be more effective than lapatinib at the inhibition of HER2 autophosphorylation of Y1248. Compounds 7 (5,8-dihydroxy-2-methylnaphthalene-1,4-dione) and 9 (2-(bromomethyl)-5,8-dihydroxynaphthalene-1,4-dione) inhibited HER2-expressing MCF-7 cells (IC50 0.29 and 1.76 µM, respectively) and HER2Δ16-expressing MCF-7 cells (IC50 0.51 and 1.76 µM, respectively). Compound 7 was also shown to promote cell death in multiple refractory breast cancer cell lines with IC50 values ranging from 0.12 to 2.92 µM. These compounds can function as lead compounds for the design of a new series of nonquinonoid structural compounds that can maintain a similar inhibition profile.

5.
J Undergrad Chem Res ; 17(4): 102-104, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-31363349

RESUMO

Cytochrome P450 enzymes are a superfamily of hemoproteins involved in the metabolism and detoxification of endogenous and exogenous compounds. P450s are involved in the bioactivation of certain procarcinogens leading to the production of carcinogenic species. This has resulted in P450s' popularity as targets in cancer research. Developing selective and potent mechanism-based inhibitors for these enzymes is expected to be the key to understanding their mechanisms of action, as well as, developing potential anticancer agents. Our group has shown that certain aryl and aryl-alkyl acetylenes act as inhibitors of these enzymes. In an attempt to increase the number of selective P450 inhibitors available for enzymatic studies, five novel dibenzofuran ethers and esters have been designed and synthesized successfully.

6.
Molecules ; 22(7)2017 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-28698457

RESUMO

The cytochrome P450 (CYP) family 1A enzymes, CYP1A1 and CYP1A2, are two of the most important enzymes implicated in the metabolism of endogenous and exogenous compounds through oxidation. These enzymes are also known to metabolize environmental procarcinogens into carcinogenic species, leading to the advent of several types of cancer. The development of selective inhibitors for these P450 enzymes, mitigating procarcinogenic oxidative effects, has been the focus of many studies in recent years. CYP1A1 is mainly found in extrahepatic tissues while CYP1A2 is the major CYP enzyme in human liver. Many molecules have been found to be metabolized by both of these enzymes, with varying rates and/or positions of oxidation. A complete understanding of the factors that govern the specificity and potency for the two CYP 1A enzymes is critical to the development of effective inhibitors. Computational molecular modeling tools have been used by several research groups to decipher the specificity and potency factors of the CYP1A1 and CYP1A2 substrates. In this review, we perform a thorough analysis of the computational studies that are ligand-based and protein-ligand complex-based to catalog the various factors that govern the specificity/potency toward these two enzymes.


Assuntos
Citocromo P-450 CYP1A1/química , Inibidores do Citocromo P-450 CYP1A2/química , Citocromo P-450 CYP1A2/química , Inativação Metabólica , Citocromo P-450 CYP1A1/antagonistas & inibidores , Humanos , Ligantes , Fígado/enzimologia , Fígado/metabolismo , Modelos Moleculares , Estresse Oxidativo/genética , Especificidade por Substrato
7.
Phytomedicine ; 27: 39-51, 2017 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-28314478

RESUMO

BACKGROUND: While current therapies for osteoporosis focus on reducing bone resorption, the development of therapies to regenerate bone may also be beneficial. Promising anabolic therapy candidates include phytoestrogens, such as daidzein, which effectively induce osteogenesis of adipose-derived stromal cells (ASCs) and bone marrow stromal cells (BMSCs). PURPOSE: To investigate the effects of glyceollins, structural derivatives of daidzein, on osteogenesis of ASCs and BMSCs. STUDY DESIGN: Herein, the osteoinductive effects of glyceollin I and glyceollin II were assessed and compared to estradiol in ASCs and BMSCs. The mechanism by which glyceollin II induces osteogenesis was further examined. METHODS: The ability of glyceollins to promote osteogenesis of ASCs and BMSCs was evaluated in adherent and scaffold cultures. Relative deposition of calcium was analyzed using Alizarin Red staining, Bichinchoninic acid Protein Assay, and Alamar Blue Assay. To further explore the mechanism by which glyceollin II exerts its osteoinductive effects, docking studies of glyceollin II, RNA isolation, cDNA synthesis, and quantitative RT-PCR (qPCR) were performed. RESULTS: In adherent cultures, ASCs and BMSCs treated with estradiol, glyceollin I, or glyceollin II demonstrated increased calcium deposition relative to vehicle-treated cells. During evaluation on PLGA scaffolds seeded with ASCs and BMSCs, glyceollin II was the most efficacious in inducing ASC and BMSC osteogenesis compared to estradiol and glyceollin I. Dose-response analysis in ASCs and BMSCs revealed that glyceollin II has the highest potency at 10nM in adherent cultures and 1µM in tissue scaffold cultures. At all doses, osteoinductive effects were attenuated by fulvestrant, suggesting that glyceollin II acts at least in part through estrogen receptor-mediated pathways to induce osteogenesis. Analysis of gene expression demonstrated that, similar to estradiol, glyceollin II induces upregulation of genes involved in osteogenic differentiation. CONCLUSION: The ability of glyceollin II to induce osteogenic differentiation in ASCs and BMSCs indicates that glyceollins hold the potential for the development of pharmacological interventions to improve clinical outcomes of patients with osteoporosis.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Estradiol/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Pterocarpanos/farmacologia , Células-Tronco/efeitos dos fármacos , Adulto , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Feminino , Humanos , Pessoa de Meia-Idade , Fitoestrógenos/farmacologia , Glycine max/química , Estados Unidos
8.
Molecules ; 22(1)2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28067791

RESUMO

Liver X receptors (LXRs) have been increasingly recognized as a potential therapeutic target to treat pathological conditions ranging from vascular and metabolic diseases, neurological degeneration, to cancers that are driven by lipid metabolism. Amidst intensifying efforts to discover ligands that act through LXRs to achieve the sought-after pharmacological outcomes, several lead compounds are already being tested in clinical trials for a variety of disease interventions. While more potent and selective LXR ligands continue to emerge from screening of small molecule libraries, rational design, and empirical medicinal chemistry approaches, challenges remain in minimizing undesirable effects of LXR activation on lipid metabolism. This review provides a summary of known endogenous, naturally occurring, and synthetic ligands. The review also offers considerations from a molecular modeling perspective with which to design more specific LXRß ligands based on the interaction energies of ligands and the important amino acid residues in the LXRß ligand binding domain.


Assuntos
Desenho de Fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Receptores X do Fígado/agonistas , Ativação Enzimática/efeitos dos fármacos , Humanos , Ligantes , Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Doenças Metabólicas/tratamento farmacológico , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso/tratamento farmacológico , Oxisteróis/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Doenças Vasculares/tratamento farmacológico
9.
Drug Metab Lett ; 10(4): 270-277, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28000546

RESUMO

BACKGROUND: Members of the cytochrome P450 1A family metabolize many procarcinogens such as polycyclicaromatic hydrocarbons and heterocyclic amines. Inactivation of these enzymes is a prerequisite for cancer prevention and treatment in certain cases. Mechanism-based inhibition (time and co-factor dependent) is an effective method for the inactivation of these enzymes. Our recent study on emodin analogs revealed an anthraquinone with ortho-methylarylamine moiety that exhibited timedependent inhibition of P450 enzymes 1A1 and 1A2. METHODS: To determine whether the amino group or the methyl group or both were responsible for the time-dependent inhibition of these enzymes, a set of eleven compounds containing the orthomethylarylamine moiety were identified through a database search, and studied for the inhibition of the P450 enzymes 1A1, 1A2, 2A6 and 2B1. Our earlier studies on carbazole derivatives provided us with highly selective P450 1A2 inhibitors. Glycine scanning studies were performed on the docked proteinligand complexes of compounds 1-20 in order to understand the contribution of different protein residues towards the ligand binding. RESULTS: Four compounds were found to cause selective time-dependent inhibition of P450 1A1 with KI values ranging from 0.24 to 8.25 mM. These compounds exhibited only direct inhibition of P450 1A2. Molecular modeling studies of these molecules indicated that the shapes of the molecules, their binding modes, and the methyl substituent in close proximity (4.5-5.7 Å) to the heme-Fe all contributed to their selective time-dependent inhibition activity on P450 1A1. Glycine scanning studies for P450 1A1 indicated that ligand interaction with Phe123 was the strongest binding contributor and similar studies for P450 1A2 indicated that ligand interactions with the phenylalanine residues 226 and 260 were the largest binding contributors. CONCLUSION: Four compounds have been identified that exhibit selective time-dependent inhibition of P450 1A1. Modeling studies have indicated that the proximity of the aromatic methyl group to the heme-Fe could be the main contributor for time-dependent inhibition. Future studies will focus on the confirmation of the involvement of the aromatic methyl group in enzyme inactivation.


Assuntos
Antraquinonas/farmacologia , Citocromo P-450 CYP1A1/metabolismo , Inibidores do Citocromo P-450 CYP1A2/farmacologia , Citocromo P-450 CYP1A2/metabolismo , Ensaios Enzimáticos , Humanos , Concentração Inibidora 50 , Ligantes , Simulação de Acoplamento Molecular , Fenilalanina/metabolismo , Ligação Proteica , Fatores de Tempo
10.
Bioorg Med Chem Lett ; 26(13): 3187-3191, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27173800

RESUMO

PIM1 is a proto-oncogene encoding the serine/threonine PIM1 kinase. PIM1 kinase plays important roles in regulating aspects of cell cycle progression, apoptosis resistance, and has been implicated in the development of such malignancies as prostate cancer and acute myeloid leukemia among others. Knockout of PIM1 kinase in mice has been shown to be non-lethal without any obvious phenotypic changes, making it an attractive therapeutic target. Our investigation of anthraquinones as kinase inhibitors revealed a series of quinone analogs showing high selectivity for inhibition of the PIM kinases. Molecular modeling studies were used to identify key interactions and binding poses of these compounds within the PIM1 binding pocket. Compounds 1, 4, 7 and 9 inhibited the growth of DU-145 prostate cancer cell lines with a potency of 8.21µM, 4.06µM, 3.21µM and 2.02µM.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Quinonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Estrutura Molecular , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Quinonas/síntese química , Quinonas/química , Relação Estrutura-Atividade
11.
Expert Opin Ther Pat ; 26(1): 139-47, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26514241

RESUMO

Cytochrome P450's (CYP's) constitute a diverse group of over 500 monooxygenase hemoproteins, catalyzing transformations that involve xenobiotic metabolism, steroidogenesis and other metabolic processes. Over-production of the steroid hormone cortisol is implicated in the progression of diseases such as diabetes, heart failure and hypertension, stroke, Cushing's syndrome, obesity and renal failure, among others. The biosynthesis of cortisol involves a cascade of cholesterol metabolizing reactions regulated through three major CYP proteins: 17α-hydroxylase-C17/20-lyase (CYP17), 21-hydroxylase (CYP21), and 11ß-hydroxylase (CYP11B1). Excess activities of these enzymes are linked to the progression of malignancies including prostate, breast, ovarian, and uterine cancers. A series of novel functionalized dioxane analogs have been developed and recently patented as CYP17, CYP21, and CYP11B1 inhibitors, which lead to the modulation of cortisol production as a method for treating, delaying, slowing, and inhibiting the implicated diseases. The findings disclosed in this patent have been analyzed and compared with the literature data on inhibitors of CYP17, CYP21, and CYP11B1. The compiled data provide insight into the novel functionality of the compounds described in the patent. In this regard, an objective opinion on the effectiveness and novel biochemistry of these compounds in comparison to current CYP inhibitors used in the treatment of cortisol-related diseases is presented in this paper.


Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Dioxanos/farmacologia , Hidrocortisona/metabolismo , Inibidores das Enzimas do Citocromo P-450/química , Dioxanos/química , Desenho de Fármacos , Humanos , Patentes como Assunto , Esteroide 11-beta-Hidroxilase/antagonistas & inibidores , Esteroide 11-beta-Hidroxilase/metabolismo , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Esteroide 17-alfa-Hidroxilase/metabolismo , Esteroide 21-Hidroxilase/antagonistas & inibidores , Esteroide 21-Hidroxilase/metabolismo
12.
Molecules ; 19(9): 15196-212, 2014 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-25251190

RESUMO

The human epidermal growth factor receptor 2 (HER2) is a member of the erbB class of tyrosine kinase receptors. These proteins are normally expressed at the surface of healthy cells and play critical roles in the signal transduction cascade in a myriad of biochemical pathways responsible for cell growth and differentiation. However, it is widely known that amplification and subsequent overexpression of the HER2 encoding oncogene results in unregulated cell proliferation in an aggressive form of breast cancer known as HER2-positive breast cancer. Existing therapies such as trastuzumab (Herceptin®) and lapatinib (Tyverb/Tykerb®), a monoclonal antibody inhibitor and a dual EGFR/HER2 kinase inhibitor, respectively, are currently used in the treatment of HER2-positive cancers, although issues with high recurrence and acquired resistance still remain. Small molecule tyrosine kinase inhibitors provide attractive therapeutic targets, as they are able to block cell signaling associated with many of the proposed mechanisms for HER2 resistance. In this regard we aim to present a review on the available HER2 tyrosine kinase inhibitors, as well as those currently in development. The use of tyrosine kinase inhibitors as sequential or combinatorial therapeutic strategies with other HER family inhibitors is also discussed.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Feminino , Humanos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia
13.
J Med Chem ; 57(15): 6653-67, 2014 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-25007006

RESUMO

Fascin has recently emerged as a potential therapeutic target, as its expression in cancer cells is closely associated with tumor progression and metastasis. Following the initial discovery of a series of thiazole derivatives that demonstrated potent antimigration and antiinvasion activities via possible inhibition of fascin function, we report here the design and synthesis of 63 new thiazole derivatives by further structural modifications in search of more potent fascin inhibitors. The 5 series of analogues with longer alkyl chain substitutions on the thiazole nitrogen exhibited greater antimigration activities than those with other structural motifs. The most potent analogue, 5p, inhibited 50% of cell migration at 24 nM. Moreover, the thiazole analogues showed strong antiangiogenesis activity, blocking new blood vessel formation in a chicken embryo membrane assay. Finally, a functional study was conducted to investigate the mechanism of action via interaction with the F-actin bundling protein fascin.


Assuntos
Antineoplásicos/química , Tiazóis/química , Citoesqueleto de Actina/ultraestrutura , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Linhagem Celular Transformada , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/efeitos dos fármacos , Colágeno , Combinação de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Laminina , Proteínas dos Microfilamentos/antagonistas & inibidores , Proteínas dos Microfilamentos/genética , Invasividade Neoplásica , Metástase Neoplásica , Neovascularização Fisiológica/efeitos dos fármacos , Proteoglicanas , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologia
14.
Bioorg Med Chem Lett ; 24(1): 126-31, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24355130

RESUMO

HER2 overexpression is associated with aggressive breast cancer with high recurrence rate and poor patient prognosis. Treatment of HER2 overexpressing patients with the HER2 targeting therapy trastuzumab results in acquired resistance within a year. The HER2/EGFR dual kinase inhibitor lapatinib was shown to inhibit some trastuzumab resistant breast cancer cell lines and is currently in clinical trials. Our group has found two new quinone compounds that show excellent inhibition of breast tumor cells expressing HER2 or the trastuzumab resistant HER2 oncogenic isoform, HER2Δ16. Compound 4 ((1R,2S,3S)-1,2,3,5,8-pentahydroxy-1,2,3,4-tetrahydroanthracene-9,10-dione) and compound 5 (5,8-dihydroxy-2,3-bis(hydroxymethyl)naphthalene-1,4-dione) showed sub-micromolar inhibition potency against these cell lines. These compounds also inhibit auto-phosphorylation of the Y1248 and Y1068 residues of HER2 and EGFR, respectively.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Quinonas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Neoplasias da Mama/metabolismo , Relação Dose-Resposta a Droga , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Modelos Moleculares , Estrutura Molecular , Quinonas/química , Receptor ErbB-2/metabolismo , Relação Estrutura-Atividade , Trastuzumab
15.
J Med Chem ; 56(10): 4082-92, 2013 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-23600958

RESUMO

Selective inhibition of P450 enzymes is the key to block the conversion of environmental procarcinogens to their carcinogenic metabolites in both animals and humans. To discover highly potent and selective inhibitors of P450s 1A1, 1A2, and 1B1, as well as to investigate active site cavities of these enzymes, 14 novel flavone derivatives were prepared as chemical probes. Fluorimetric enzyme inhibition assays were used to determine the inhibitory activities of these probes toward P450s 1A1, 1A2, 1B1, 2A6, and 2B1. A highly selective P450 1B1 inhibitor 5-hydroxy-4'-propargyloxyflavone (5H4'FPE) was discovered. Some tested compounds also showed selectivity between P450s 1A1 and 1A2. α-Naphthoflavone-like and 5-hydroxyflavone derivatives preferentially inhibited P450 1A2, while ß-naphthoflavone-like flavone derivatives showed selective inhibition of P450 1A1. On the basis of structural analysis, the active site cavity models of P450 enzymes 1A1 and 1A2 were generated, demonstrating a planar long strip cavity and a planar triangular cavity, respectively.


Assuntos
Hidrocarboneto de Aril Hidroxilases/efeitos dos fármacos , Citocromo P-450 CYP1A1/efeitos dos fármacos , Citocromo P-450 CYP1A2/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Flavonas/síntese química , Flavonas/farmacologia , Domínio Catalítico/efeitos dos fármacos , Citocromo P-450 CYP1B1 , Interpretação Estatística de Dados , Fluorometria , Humanos , Cinética , Ligantes , Modelos Moleculares , Bibliotecas de Moléculas Pequenas , Espectrometria de Fluorescência , Relação Estrutura-Atividade
16.
J Undergrad Chem Res ; 12(4): 92-95, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25580095

RESUMO

Carbazoles are a class of nitrogen-containing aromatic heterocyclic compounds. They not only have various biological activities (e.g. antibacterial, anti-inflammatory, antitumor), but also exhibit useful properties as organic materials due to their special structures. Cytochrome P450 enzymes are a superfamily of hemoproteins involved in the metabolism of endogenous and exogenous compounds including many drugs and environmental chemicals. Some aryl and arylalkyl acetylenes, and propargyl ethers have been shown to act as inhibitors of certain P450s. In an attempt to improve the potency and selectivity of inhibition, we have focused our attention on the design and synthesis of a new series of carbazole analogs, a few of which contain a propargyl ether functional group. For this project, eight carbazole analogs have been synthesized and characterized.

17.
Molecules ; 17(8): 9283-305, 2012 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-22864238

RESUMO

The cytochrome P450 (CYP) superfamily of heme enzymes play an important role in the metabolism of a large number of endogenous and exogenous compounds, including most of the drugs currently on the market. Inhibitors of CYP enzymes have important roles in the treatment of several disease conditions such as numerous cancers and fungal infections in addition to their critical role in drug-drug interactions. Structure activity relationships (SAR), and three-dimensional quantitative structure activity relationships (3D-QSAR) represent important tools in understanding the interactions of the inhibitors with the active sites of the CYP enzymes. A comprehensive account of the QSAR studies on the major human CYPs 1A1, 1A2, 1B1, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 and a few other CYPs are detailed in this review which will provide us with an insight into the individual/common characteristics of the active sites of these enzymes and the enzyme-inhibitor interactions.


Assuntos
Inibidores das Enzimas do Citocromo P-450 , Inibidores Enzimáticos/química , Relação Quantitativa Estrutura-Atividade , Domínio Catalítico , Simulação por Computador , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Ligação Proteica , Termodinâmica
18.
J Med Chem ; 53(16): 6153-63, 2010 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-20669983

RESUMO

Daidzein (1) is a natural estrogenic isoflavone. We report here that 1 can be transformed into anti-estrogenic ligands by simple alkyl substitutions of the 7-hydroxyl hydrogen. To test the effect of such structural modifications on the hormonal activities of the resulting compounds, a series of daidzein analogues have been designed and synthesized. When MCF-7 cells were treated with the analogues, those resulting from hydrogen substitution by isopropyl (3d), isobutyl (3f), cyclopentyl (3g), and pyrano- (2) inhibited cell proliferation, estrogen-induced transcriptional activity, and estrogen receptor (ER) regulated progesterone receptor (PgR) gene expression. However, methyl (3a) and ethyl (3b) substitutions of the hydroxyl proton only led to moderate reduction of the estrogenic activities. These results demonstrated the structural requirements for the transformation of daidzein from an ER agonist to an antagonist. The most effective analogue, 2, was found to reduce in vivo estrogen stimulated MCF-7 cell tumorigenesis using a xenograft mouse model.


Assuntos
Antineoplásicos/síntese química , Antagonistas de Estrogênios/síntese química , Estrogênios/síntese química , Isoflavonas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama , Linhagem Celular Tumoral , Estradiol/farmacologia , Antagonistas de Estrogênios/química , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/antagonistas & inibidores , Estrogênios/química , Estrogênios/farmacologia , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Isoflavonas/química , Isoflavonas/farmacologia , Camundongos , Camundongos Nus , Modelos Moleculares , Receptores de Progesterona/biossíntese , Elementos de Resposta , Relação Estrutura-Atividade , Transcrição Gênica , Ensaios Antitumorais Modelo de Xenoenxerto
19.
ChemMedChem ; 1(2): 256-66, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16892358

RESUMO

Research by Klein and co-workers suggests that the inhibition of GSK-3beta by small molecules may offer an important strategy in the treatment of a number of central nervous system (CNS) disorders including Alzheimer's disease, Parkinson's disease, and bipolar disorders. Based on results from kinase-screening assays that identified a staurosporine analogue as a modest inhibitor of GSK-3beta, a series of 3-indolyl-4-indazolylmaleimides was prepared for study in both enzymatic and cell-based assays. Most strikingly, whereas we identified ligands having poor to high potency for GSK-3beta inhibition, only ligands with a Ki value of less than 8 nM, namely maleimides 18 and 22, were found to inhibit Tau phosphorylation at a GSK-3beta-specific site (Ser 396/404). Accordingly, maleimides 18 and 22 may protect neuronal cells against cell death by decreasing the level of alpha-Syn protein expression. We conclude that the GSK-3beta inhibitors described herein offer promise in defending cells against MPP+-induced neurotoxicity and that such compounds will be valuable to explore in animal models of Parkinson's disease as well as in other Tau-related neurodegenerative disease states.


Assuntos
Inibidores Enzimáticos/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau/antagonistas & inibidores , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Glicogênio Sintase Quinase 3 beta , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Fosforilação , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Relação Estrutura-Atividade , Proteínas tau/metabolismo
20.
AAPS J ; 8(1): E204-21, 2006 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-16584130

RESUMO

Members of the cyclin-dependent kinase (CDK) family play key roles in various cellular processes. There are 11 members of the CDK family known till now. CDKs are activated by forming noncovalent complexes with cyclins such as A-, B-, C-, D- (D1, D2, and D3), and E-type cyclins. Each isozyme of this family is responsible for particular aspects (cell signaling, transcription, etc) of the cell cycle, and some of the CDK isozymes are specific to certain kinds of tissues. Aberrant expression and overexpression of these kinases are evidenced in many disease conditions. Inhibition of isozymes of CDKs specifically can yield beneficiary treatment modalities with minimum side effects. More than 80 3-dimensional structures of CDK2, CDK5, and CDK6 complexed with inhibitors have been published. This review provides an understanding of the structural aspects of CDK isozymes and binding modes of various known CDK inhibitors so that these kinases can be better targeted for drug discovery and design. The amino acid residues that constitute the cyclin binding region, the substrate binding region, and the area around the adenosine triphosphate (ATP) binding site have been compared for CDK isozymes. Those amino acids at the ATP binding site that could be used to improve the potency and subtype specificity have been described.


Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/fisiologia , Quinases Ciclina-Dependentes/metabolismo , Humanos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
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