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1.
Eur J Med Chem ; 96: 504-18, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25951294

RESUMO

Tubulin-interacting agents, like vinca alkaloid and taxanes, play a fundamental role in cancer chemotherapy, making cellular microtubules (MT), one of the few validated anticancer targets. Cancer resistance to classical MT inhibitors has motivated the development of novel molecules with increased efficacy and lower toxicity. Aiming at designing structurally-simple inhibitors of MT assembly, we synthesized a series of thirty-one 3,4,5-trimethoxy-hydrazones and twenty-five derivatives or analogs. Docking simulations suggested that a representative N-acylhydrazone could adopt an appropriate stereochemistry inside the colchicine-binding domain of tubulin. Several of these compounds showed anti-leukemia effects in the nanomolar concentration range. Interference with MT polymerization was validated by the compounds' ability to inhibit MT assembly at the biochemical and cellular level. Selective toxicity investigations done with the most potent compound, a 3,4,5-trimethoxy-hydrazone with a 1-naphthyl group, showed remarkably selective toxicity against leukemia cells in comparison with stimulated normal lymphocytes, and no acute toxicity in vivo. Finally, this molecule was as active as vincristine in a murine model of human acute lymphoblastic leukemia at a weekly dose of 1 mg/kg.


Assuntos
Anisóis/farmacologia , Antineoplásicos/farmacologia , Hidrazonas/farmacologia , Microtúbulos/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Animais , Anisóis/síntese química , Anisóis/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Microtúbulos/metabolismo , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Células Tumorais Cultivadas
2.
Eur J Med Chem ; 63: 501-10, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23524161

RESUMO

Based on classical colchicine site ligands and a computational model of the colchicine binding site on beta tubulin, two classes of chalcone derivatives were designed, synthesized and evaluated for inhibition of tubulin assembly and toxicity in human cancer cell lines. Docking studies suggested that the chalcone scaffold could fit the colchicine site on tubulin in an orientation similar to that of the natural product. In particular, a 3,4,5-trimethoxyphenyl ring adjacent to the carbonyl group appeared to benefit the ligand-tubulin interaction, occupying the same subcavity as the corresponding moiety in colchicine. Consistent with modeling predictions, several 3,4,5-trimethoxychalcones showed improved cytotoxicity to murine acute lymphoblastic leukemia cells compared with a previously described parent compound, and inhibited tubulin assembly in vitro as potently as colchicine. The most potent chalcones inhibited the growth of human leukemia cell lines at nanomolar concentrations, caused microtubule destabilization and mitotic arrest in human cervical cancer cells, and inhibited human breast cancer cell migration in scratch wound and Boyden chamber assays.


Assuntos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Chalconas/síntese química , Chalconas/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Chalconas/química , Relação Dose-Resposta a Droga , Humanos , Células Jurkat , Camundongos , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Células NIH 3T3 , Polimerização/efeitos dos fármacos , Tubulina (Proteína)/metabolismo
3.
Biometals ; 26(1): 151-65, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23344786

RESUMO

Complexes [Ga(2Ac4pFPh)(2)]NO(3) (1), [Ga(2Ac4pClPh)(2)]NO(3) (2), [Ga(2Ac4pIPh)(2)]NO(3) (3), [Ga(2Ac4pNO(2)Ph)(2)]NO(3)·3H(2)O (4) and [Ga(2Ac4pT)(2)]NO(3) (5) were obtained with 2-acetylpyridine N(4)-para-fluorophenyl-(H2Ac4pFPh), 2-acetylpyridine N(4)-para-chlorophenyl-(H2Ac4pClPh), 2-acetylpyridine N(4)-para-iodophenyl-(H2Ac4pIPh), 2-acetylpyridine N(4)-para-nitrophenyl-(H2Ac4pNO(2)Ph) and 2-acetylpyridine N(4)-para-tolyl-(H2Ac4pT) thiosemicarbazone. 1-5 presented antimicrobial and cytotoxic properties. Coordination to gallium(III) proved to be an effective strategy for activity improvement against Pseudomonas aeruginosa and Candida albicans. The complexes were highly cytotoxic against malignant glioblastoma and breast cancer cells at nanomolar concentrations. The compounds induced morphological changes characteristic of apoptotic death in tumor cells and showed no toxicity against erythrocytes. 2 partially inhibited tubulin assembly at high concentrations and induced cellular microtubule disorganization, but this does not appear to be the main mechanism of cytotoxic activity.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Gálio/química , Tiossemicarbazonas/química , Tubulina (Proteína)/química , Antibacterianos/química , Antifúngicos/química , Antineoplásicos/química , Candida albicans/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Complexos de Coordenação/química , Cristalografia por Raios X , Eritrócitos/efeitos dos fármacos , Células HeLa , Humanos , Concentração Inibidora 50 , Cinética , Células MCF-7 , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Multimerização Proteica/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Piridinas/química , Staphylococcus aureus/efeitos dos fármacos , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
4.
Bioorg Med Chem ; 20(11): 3396-409, 2012 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-22564383

RESUMO

N(4)-Phenyl 2-acetylpyridine thiosemicarbazone (H2Ac4Ph; N-(phenyl)-2-(1-(pyridin-2-yl)ethylidene)hydrazinecarbothioamide) and its N(4)-ortho-, -meta- and -para-fluorophenyl (H2Ac4oFPh, H2Ac4mFPh, H2Ac4pFPh), N(4)-ortho-, -meta- and -para-chlorophenyl (H2Ac4oClPh, H2Ac4mClPh, H2Ac4pClPh), N(4)-ortho-, -meta- and -para-iodophenyl (H2Ac4oIPh, H2Ac4mIPh, H2Ac4pIPh) and N(4)-ortho-, -meta- and -para-nitrophenyl (H2Ac4oNO(2)Ph, H2Ac4mNO(2)Ph, H2Ac4pNO(2)Ph) derivatives were assayed for their cytotoxicity against human malignant breast (MCF-7) and glioma (T98G and U87) cells. The compounds were highly cytotoxic against the three cell lineages (IC(50): MCF-7, 52-0.16 nM; T98G, 140-1.0 nM; U87, 160-1.4 nM). All tested thiosemicarbazones were more cytotoxic than etoposide and did not present any haemolytic activity at up to 10(-5)M. The compounds were able to induce programmed cell death. H2Ac4pClPh partially inhibited tubulin assembly at high concentrations and induced cellular microtubule disorganization.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/patologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Etoposídeo/farmacologia , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Humanos , Concentração Inibidora 50 , Microtúbulos/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Proteína Supressora de Tumor p53/genética
5.
Eur J Med Chem ; 45(4): 1508-14, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20133028

RESUMO

5-HT(1A) receptor antagonists have been employed to treat depression, but the lack of structural information on this receptor hampers the design of specific and selective ligands. In this study, we have performed CoMFA studies on a training set of arylpiperazines (high affinity 5-HT(1A) receptor ligands) and to produce an effective alignment of the data set, a pharmacophore model was produced using Galahad. A statistically significant model was obtained, indicating a good internal consistency and predictive ability for untested compounds. The information gathered from our receptor-independent pharmacophore hypothesis is in good agreement with results from independent studies using different approaches. Therefore, this work provides important insights on the chemical and structural basis involved in the molecular recognition of these compounds.


Assuntos
Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Ligantes , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Receptor 5-HT1A de Serotonina/metabolismo
6.
Expert Opin Drug Discov ; 5(5): 405-12, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-22823126

RESUMO

Recently, fragment-based drug design has been established as a crucial strategy for hit identification and lead generation, which has strongly encouraged the development of approaches to specifically recognize and evaluate molecular fragments or structural scaffolds that preferentially interact with particular sites of important biological targets. In this context, fragment-based quantitative structure-activity relationship (FB-QSAR) has emerged as a versatile tool to explore the chemical and biological space of data sets of compounds. FB-QSAR approaches have evolved from a classical use in the generation of standard QSAR models into advanced drug design tools for database mining, pharmacokinetic property prediction and optimization of multiple parameters. This paper provides a brief perspective on the evolution and current status of FB-QSAR, highlighting new opportunities in drug design.

7.
J Chem Inf Model ; 49(11): 2606-16, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19863110

RESUMO

Most physiological effects of thyroid hormones are mediated by the two thyroid hormone receptor subtypes, TRalpha and TRbeta. Several pharmacological effects mediated by TRbeta might be beneficial in important medical conditions such as obesity, hypercholesterolemia and diabetes, and selective TRbeta activation may elicit these effects while maintaining an acceptable safety profile. To understand the molecular determinants of affinity and subtype selectivity of TR ligands, we have successfully employed a ligand- and structure-guided pharmacophore-based approach to obtain the molecular alignment of a large series of thyromimetics. Statistically reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) and three-dimensional quantitative structure-selectivity relationship (3D-QSSR) models were obtained using the comparative molecular field analysis (CoMFA) method, and the visual analyses of the contour maps drew attention to a number of possible opportunities for the development of analogs with improved affinity and selectivity. Furthermore, the 3D-QSSR analysis allowed the identification of a novel and previously unmentioned halogen bond, bringing new insights to the mechanism of activity and selectivity of thyromimetics.


Assuntos
Halogênios/química , Hormônios Tireóideos/metabolismo , Cristalografia por Raios X , Ligantes , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Hormônios Tireóideos/química
8.
Curr Top Med Chem ; 9(9): 771-90, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19754394

RESUMO

A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the development of high quality drug candidates. Structure-based drug design (SBDD) methods are becoming increasingly powerful, versatile and more widely used. This review summarizes current developments in structure-based virtual screening and receptor-based pharmacophores, highlighting achievements as well as challenges, along with the value of structure-based lead optimization, with emphasis on recent examples of successful applications for the identification of novel active compounds.


Assuntos
Desenho de Fármacos , Proteínas/química , Relação Quantitativa Estrutura-Atividade , Química Farmacêutica/métodos , Simulação por Computador , Modelos Moleculares , Ligação Proteica , Proteínas/efeitos dos fármacos
9.
Mol Divers ; 13(3): 277-85, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19184499

RESUMO

Drug design is a process driven by innovation and technological breakthroughs involving a combination of advanced experimental and computational methods. A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the optimization of leads into drug candidates. Quantitative structure-activity relationship (QSAR) methods are among the most important strategies that can be applied for the successful design of small molecule modulators having clinical utility. Hologram QSAR (HQSAR) is a modern 2D fragment-based QSAR method that employs specialized molecular fingerprints. HQSAR can be applied to large data sets of compounds, as well as traditional-size sets, being a versatile tool in drug design. The HQSAR approach has evolved from a classical use in the generation of standard QSAR models for data correlation and prediction into advanced drug design tools for virtual screening and pharmacokinetic property prediction. This paper provides a brief perspective on the evolution and current status of HQSAR, highlighting present challenges and new opportunities in drug design.


Assuntos
Desenho de Fármacos , Relação Quantitativa Estrutura-Atividade , Antineoplásicos/química , Antineoplásicos/farmacologia , Modelos Químicos , Modelos Moleculares , Farmacocinética
10.
J Chem Inf Model ; 48(11): 2243-53, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18937440

RESUMO

Estrogens exert important physiological effects through the modulation of two human estrogen receptor (hER) subtypes, alpha (hERalpha) and beta (hERbeta). Because the levels and relative proportion of hERalpha and hERbeta differ significantly in different target cells, selective hER ligands could target specific tissues or pathways regulated by one receptor subtype without affecting the other. To understand the structural and chemical basis by which small molecule modulators are able to discriminate between the two subtypes, we have applied three-dimensional target-based approaches employing a series of potent hER-ligands. Comparative molecular field analysis (CoMFA) studies were applied to a data set of 81 hER modulators, for which binding affinity values were collected for both hERalpha and hERbeta. Significant statistical coefficients were obtained (hERalpha, q(2) = 0.76; hERbeta, q(2) = 0.70), indicating the internal consistency of the models. The generated models were validated using external test sets, and the predicted values were in good agreement with the experimental results. Five hER crystal structures were used in GRID/PCA investigations to generate molecular interaction fields (MIF) maps. hERalpha and hERbeta were separated using one factor. The resulting 3D information was integrated with the aim of revealing the most relevant structural features involved in hER subtype selectivity. The final QSAR and GRID/PCA models and the information gathered from 3D contour maps should be useful for the design of novel hER modulators with improved selectivity.


Assuntos
Receptores de Estrogênio/química , Sítios de Ligação , Simulação por Computador , Bases de Dados Factuais , Desenho de Fármacos , Feminino , Humanos , Informática , Ligantes , Estrutura Molecular , Conformação Proteica , Relação Quantitativa Estrutura-Atividade , Receptores de Estrogênio/classificação , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Termodinâmica
11.
Open Med Chem J ; 2: 87-96, 2008 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-19696872

RESUMO

Liver X receptor (LXR) is an attractive drug target for the development of novel therapeutic agents for the treatment of dyslipidaemia and cholestasis. In the present work, comparative molecular field analysis (CoMFA) and hologram quantitative structure-activity relationship (HQSAR) studies were conducted on a series of potent LXR ligands. Significant correlation coefficients (CoMFA, r(2) = 0.98 and q(2) = 0.69; HQSAR, r(2) = 0.99 and q(2) = 0.85) were obtained, indicating the potential of the models for untested compounds. The models were then used to predict the potency of an external test set, and the predicted values obtained from the 2D and 3D models were in good agreement with the experimental results. The final QSAR models, along with the information obtained from 3D steric and electrostatic contour maps and 2D contribution maps should be useful for the design of novel LXR ligands having improved potency.

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