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1.
J Enzyme Inhib Med Chem ; 35(1): 139-144, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31724435

RESUMO

A series of naphthalene-chalcone derivatives (3a-3t) were prepared and evaluated as tubulin polymerisation inhibitor for the treatment of breast cancer. All compounds were evaluated for their antiproliferative activity against MCF-7 cell line. The most of compounds displayed potent antiproliferative activity. Among them, compound 3a displayed the most potent antiproliferative activity with an IC50 value of 1.42 ± 0.15 µM, as compared to cisplatin (IC50 = 15.24 ± 1.27 µM). Additionally, the promising compound 3a demonstrated relatively lower cytotoxicity on normal cell line (HEK293) compared to tumour cell line. Furthermore, compound 3a was found to induce significant cell cycle arrest at the G2/M phase and cell apoptosis. Compound 3a displayed potent tubulin polymerisation inhibitory activity with an IC50 value of 8.4 µM, which was slightly more active than the reference compound colchicine (IC50 = 10.6 µM). Molecular docking analysis suggested that 3a interact and bind at the colchicine binding site of the tubulin.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Chalconas/farmacologia , Naftalenos/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalconas/química , Colchicina/antagonistas & inibidores , Colchicina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Naftalenos/química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
2.
Eur J Med Chem ; 183: 111679, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31541870

RESUMO

Anti-tubulin polymerization agents can disrupt tumor-vascular to exhibit anti-cancer potency. In this study, a series of substituted (2-(phenylamino)thieno[3,2-d]pyrimidin-4-yl)(3,4,5-trimethoxyphenyl)methanone analogues were designed and synthesized as anti-tubulin polymerization agents that interact with colchicine binding site. The anti-proliferative assay indicated that most of the target compounds displayed moderate to high potencies towards five tumor cell lines. The structure-activity relationship of these analogues was summarized. The most potent compound 14 was selected to assay its inhibition on the tubulin polymerization. 14 displayed potent inhibition against tubulin polymerization with an IC50 value of 4.1 ±â€¯0.1 µM. The colchicine competition assay demonstrated that 14 inhibited tubulin polymerization by binding to the colchicine-binding site of tubulin. The molecular modeling study elucidated the binding mode of 14 in the colchicine binding site. The result of confocal immunofluorescent study proved that 14 can quickly disrupt the microtubules of Hela cells in a concentration dependent manner. Some experiments at cellular level were conducted to investigate the effects of 14 on cellular morphology, cell colony formation, cell cycle distribution, cell apoptosis and mitochondrial changes. The results demonstrated that 14 is a potent anti-tubulin agent with strong concentration dependent effect of inhibition of colony formation, induction of G2/M arrest and induction of apoptosis through mitochondrial pathway.


Assuntos
Antineoplásicos/síntese química , Pirimidinas/síntese química , Moduladores de Tubulina/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colchicina/metabolismo , Desenho de Drogas , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Moduladores de Tubulina/farmacologia
3.
Eur J Med Chem ; 183: 111697, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31536891

RESUMO

A series of cis restricted 1,2,4-triazole analogs of combretastatin A-4 (CA-4) were designed and synthesized. The antiproliferative activity of these compounds was measured on hepatocellular carcinoma HepG2, leukemia HL-60, and breast cancer MCF-7 cell lines. The obtained results showed a substantial ability of the synthesized anilides to inhibit tumor growth. On HepG2 cells, 5o and 5r showed potent IC50 values of 0.10 and 0.04 µM, respectively. While on HL-60 cells, the IC50 values were 0.004 and 0.01 µM for 5b and 5i, respectively. The inhibitory activity of tubulin polymerization was evaluated on HepG2 cells. The anilide 5r showed a remarkable tubulin inhibition compared to CA-4. Moreover, flow cytometry studies showed that HepG2 cells treated with the most potent compounds 5b and 5r were arrested in the G2/M phase of the cell cycle. This effect was accompanied by cellular apoptosis and activation of caspase-3. Molecular modeling showed several hydrogen bonding and van der Waals interactions with several important amino acids inside the colchicine binding site of tubulin.


Assuntos
Antineoplásicos/farmacologia , Simulação de Acoplamento Molecular , Estilbenos/farmacologia , Triazóis/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Estrutura Molecular , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-Atividade , Triazóis/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
4.
Eur J Med Chem ; 182: 111670, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31499359

RESUMO

A series of novel structurally-related tubulin polymerization inhibitors based on benzodiazepine were designed, synthesized, and evaluated for anticancer activity. Extensive structure modifications were performed to investigate the detailed structure and activity relationships (SARs). Most compounds exhibited potent antiproliferative activity against a panel of cancer cell lines. Among these compounds, the optimal compound, 9a, possessed the most superior activity, including cytotoxicity against five cancer cell lines (IC50 = 6-15 nM) and inhibition of tubulin polymerization (IC50 = 1.65 ±â€¯0.11 µM). Mechanistic studies revealed that 9a could disrupt intracellular microtubule organization, arrest cell cycle at the G2/M phase and eventually induce cell apoptosis. Compound 9a exhibited good metabolic stability with a t1/2 of 161.2 min, which was much better than the reference compound CA-4. Moreover, the disodium salt of 9a, 9a-P, exhibited excellent in vivo antitumor activity in xenograft mice model with inhibitory rate of 89.3%, which was better than the reference compounds CA-4P (inhibitory rate: 52.8%) and Y-01P (inhibitory rate: 77.7%). Altogether, 9a could serve as a promising lead compound for the development of highly efficient anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Benzodiazepinas/farmacologia , Desenho de Drogas , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Benzodiazepinas/química , Benzodiazepinas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismo
5.
Molecules ; 24(17)2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31480625

RESUMO

Tubulin inhibitors have been considered as potential drugs for cancer therapy. However, their drug resistance and serious side-effects are the main reasons for clinical treatment failure. Therefore, there is still an urgent need to develop effective therapeutic drugs. Herein, a structure-based pharmacophore model was developed based on the co-crystallized structures of the tubulin with a high resolution. The model including one hydrogen-bond acceptor feature, two aromatic features, and one hydrophobic feature was further validated using the Gunner-Henry score method. Virtual screening was performed by an integrated protocol that combines drug-likeness analysis, pharmacophore mapping, and molecular docking approaches. Finally, five hits were selected for biological evaluation. The results indicated that all these hits at the concentration of 40 µM showed an inhibition of more than 50% against five human tumor cells (MCF-7, U87MG, HCT-116, MDA-MB-231, and HepG2). Particularly, hit 1 effectively inhibited the proliferation of these tumor cells, with inhibition rates of more than 80%. The results of tubulin polymerization and colchicine-site competition assays suggested that hit 1 significantly inhibited tubulin polymerization by binding to the colchicine site. Thus, hit 1 could be used as a potential chemotherapeutic agent for cancer treatment. This work also demonstrated the potential of our screening protocol to identify biologically active compounds.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos , Relação Quantitativa Estrutura-Atividade , Moduladores de Tubulina/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colchicina/metabolismo , Humanos , Ligantes , Modelos Moleculares , Polimerização , Tubulina (Proteína)/metabolismo
6.
Eur J Med Chem ; 181: 111577, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400707

RESUMO

A series of 3-(3',4',5'-trimethoxyphenyl)-4-substituted 1H-pyrazole and their related 3-aryl-4-(3',4',5'-trimethoxyphenyl)-1-H-pyrazole regioisomeric derivatives, prepared as cis-rigidified combretastatin A-4 (CA-4) analogues, were synthesized and evaluated for their in vitro antiproliferative against six different cancer cell lines and, for selected highly active compounds, inhibitory effects on tubulin polymerization, cell cycle effects and in vivo potency. We retained the 3',4',5'-trimethoxyphenyl moiety as ring A throughout the present investigation, and a structure-activity relationship (SAR) information was obtained by adding electron-withdrawing (OCF3, CF3) or electron-releasing (alkyl and alkoxy) groups on the second aryl ring, corresponding to the B-ring of CA-4, either at the 3- or 4-position of the pyrazole nucleus. In addition, the B-ring was replaced with a benzo[b]thien-2-yl moiety. For many of the compounds, their activity was greater than, or comparable with, that of CA-4. Maximal activity was observed with the two regioisomeric derivatives characterized by the presence of a 4-ethoxyphenyl and a 3',4',5'-trimethoxyphenyl group at the C-3 and C-4 positions, and vice versa, of the 1H-pyrazole ring. The data showed that the 3',4',5'-trimethoxyphenyl moiety can be moved from the 3- to the 4-position of the 1H-pyrazole ring without significantly affecting antiproliferative activity. The most active derivatives bound to the colchicine site of tubulin and inhibited tubulin polymerization at submicromolar concentrations. In vivo experiments, on an orthotopic murine mammary tumor, revealed that 4c inhibited tumor growth even at low concentrations (5 mg/kg) compared to CA-4P (30 mg/kg).


Assuntos
Bibenzilas/química , Bibenzilas/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Bibenzilas/síntese química , Linhagem Celular Tumoral , Desenho de Drogas , Humanos , Camundongos , Modelos Moleculares , Pirazóis/síntese química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química
7.
Eur J Med Chem ; 181: 111583, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400710

RESUMO

3-(Alkyl(dialkyl)amino)benzothieno[2,3-f]quinazolin-1(2H)-ones (4-9) have been designed using Ellipticine structure as a model, replacing the carbazole core and the pyridine ring with a dibenzothiophene and a pyrimidine moiety, respectively. New benzothienoquinazolinones (4-9) have been synthesized by a simple one-pot reaction employing 3-aminodibenzothiophene as starting material. The benzothienoquinazolinones obtained (4-9), were evaluated for their anticancer activity against two breast cancer cell lines, MDA-MB-231 and MCF-7. The results revealed that compounds 4 and 7 presented a good antitumor activity toward the triple negative MDA-MB-231, without cytotoxicity against non-tumoral cells. Furthermore, the compounds 4 and 7 can be considered important molecular multi-target tools for their dual inhibition of different cellular proteins, i.e. Tubulin and human Topoisomerase I, involved in relevant cellular processes, as predicted by in silico studies and demonstrated by in vitro assays (for compound 4).


Assuntos
DNA Topoisomerases Tipo I/metabolismo , Inibidores da Topoisomerase I/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Desenho de Drogas , Feminino , Humanos , Simulação de Acoplamento Molecular , Quinazolinonas/química , Quinazolinonas/farmacologia , Tiofenos/química , Tiofenos/farmacologia , Inibidores da Topoisomerase I/química , Moduladores de Tubulina/química
8.
J Enzyme Inhib Med Chem ; 34(1): 1380-1387, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401884

RESUMO

Novel sulfonamide-dithiocarbamate hybrids were designed and synthesised via the molecular hybridisation strategy. Among them, compound 13d displayed a potent activity with IC50 values of 0.9, 0.7, 1.9 and 2.6 µM against UM-UC-3, RT-112, RT4 and T24. Compound 13d inhibited the migration and regulated the migration-related markers (E-cadherin, N-cadherin, Vimentin, Snail and Slung) against RT-112 cells in a concentration dependent manner. By the tubulin polymerisation assay in vitro and immunostaining assay, compound 13d was identified as a novel tubulin polymerisation inhibitor. Intragastric administration of compound 13d could inhibit the growth of RT-112 cells in vivo in a xenograft mouse model with the low toxicity, indicating that it may be a leading candidate with antitumor properties to treat bladder cancer.


Assuntos
Antineoplásicos/farmacologia , Sulfonamidas/farmacologia , Moduladores de Tubulina/farmacologia , Neoplasias da Bexiga Urinária/patologia , Animais , Antineoplásicos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectrometria de Massas , Camundongos , Camundongos Nus , Espectroscopia de Prótons por Ressonância Magnética , Sulfonamidas/química , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Eur J Med Chem ; 181: 111584, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31419740

RESUMO

Developing new therapeutic strategies to overcome drug resistance of cancer cells is an ongoing endeavor. From among 2 million chemicals, we identified ethyl 4-oxo-2-phenyl-1,4-dihydroquinoline-6-carboxylate (AS1712) as a low-toxicity inhibitor of lung cancer cell proliferation and xenograft tumor growth. We show that AS1712 is active against broad cancer cell lines and is able to bind in the colchicine-binding pocket of ß-tubulin, thereby inhibiting microtubule assembly and, consequently, inducing mitotic arrest and apoptosis. Our cell-based structure-activity relationship study identified a new lead compound, RJ-LC-15-8, which had a greater anti-proliferative potency for H1975 cells than did AS1712, while maintaining a similar mechanism of action. Notably, AS1712 and RJ-LC-15-8 overcame P-glycoprotein efflux pump and ß-tubulin alterations that lead to acquired resistance against microtubule-targeting drugs of cancer cells. AS1712 and RJ-LC-15-8 may be lead compounds that overcome acquired resistance to microtubule-targeting agents of cancer cells.


Assuntos
Quinolonas/química , Quinolonas/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colchicina/metabolismo , Resistencia a Medicamentos Antineoplásicos , Humanos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Tubulina (Proteína)/química
10.
Expert Opin Ther Pat ; 29(9): 703-731, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31369715

RESUMO

Introduction: Combretastatins represent a potent class of phenolic-stilbene natural products that function as colchicine binding site inhibitors of tubulin polymerization and have been advanced as promising anticancer lead compounds. Among them, combretastatin A-4 is the most potent lead molecule due to its broad spectrum cytotoxicity against a variety of tumors. However, low water solubility due to its high lipophilic nature and inter-conversion of olefinic double bond from more active cis to less active trans-conformation poses limitations to its clinical utility. However, different approaches including prodrugs, salt formations, structural modifications, prevention of inter-conversion of the olefinic bond and changes to the substitution pattern on the rings of combretastatin A-4 were investigated and successfully resulted in different combretastatin-based molecules that demonstrated varying levels of potency against different types of tumors during their in-vitro and in-vivo studies. Areas covered: This review covers the patents over a period of 2008-2018. Expert opinion: Molecular hybridization and prodrug designing imparted multi-targeted actions to combretastatin derivatives. Currently, various combretastatin derivatives are under clinical trials. These derivatives could be used to treat disorders other than cancer, due to their vascular disrupting action.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Bibenzilas/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/química , Bibenzilas/química , Desenho de Drogas , Humanos , Patentes como Assunto , Solubilidade , Relação Estrutura-Atividade , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
11.
Molecules ; 24(15)2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366123

RESUMO

Colchicine was extracted from Gloriosa superba seeds using the Super Critical Fluid (CO2) Extraction (SCFE) technology. The seeds were purified upto 99.82% using column chromatography. Colchicine affinity was further investigated for anticancer activity in six human cancer cell lines, i.e., A549, MCF-7, MDA-MB231, PANC-1, HCT116, and SiHa. Purified colchicine showed the least cell cytotoxicity and antiproliferation and caused no G2/M arrest at clinically acceptable concentrations. Mitotic arrest was observed in only A549 and MDA-MB231 cell lines at 60nM concentration. Our finding indicated the possible use of colchicine at a clinically acceptable dose and provided insight into the science behind microtubule destabilization. However, more studies need to be conducted beforethese findings could be established.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Cromatografia com Fluido Supercrítico/métodos , Colchicaceae/química , Colchicina/farmacologia , Sementes/química , Moduladores de Tubulina/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Dióxido de Carbono/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida , Colchicina/isolamento & purificação , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Extratos Vegetais/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Moduladores de Tubulina/isolamento & purificação
12.
Neurochem Res ; 44(8): 1796-1806, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31292803

RESUMO

Noscapine is a phthalide isoquinoline alkaloid that easily traverses the blood brain barrier and has been used for years as an antitussive agent with high safety. Despite binding opioid receptors, noscapine lacks significant hypnotic and euphoric effects rendering it safe in terms of addictive potential. In 1954, Hans Lettré first described noscapine as a mitotic poison. The drug was later tested for cancer treatment in the early 1960's, yet no effect was observed likely as a result of its short biological half-life and limited water solubility. Since 1998, it has regained interest thanks to studies from Emory University, which showed its anticancer activity in animal models with negligible toxicity. In contrast to other microtubule-inhibitors, noscapine does not affect the total intracellular tubulin polymer mass. Instead, it forces the microtubules to spend an increased amount of time in a paused state leading to arrest in mitosis and subsequently inducing mitotic slippage/mitotic catastrophe/apoptosis. In experimental models, noscapine does not induce peripheral neuropathy, which is common with other microtubule inhibitors. Noscapine also inhibits tumor growth and enhances cancer chemosensitivity via selective blockage of NF-κB, an important transcription factor in glioblastoma pathogenesis. Due to their anticancer activities and high penetration through the blood-brain barrier, noscapine analogues strongly deserve further study in various animal models of glioblastoma as potential candidates for future patient therapy.


Assuntos
Antimitóticos/uso terapêutico , Glioblastoma/tratamento farmacológico , Noscapina/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Animais , Antimitóticos/farmacologia , Linhagem Celular Tumoral , Humanos , Mitose/efeitos dos fármacos , Noscapina/farmacologia , Moduladores de Tubulina/farmacologia
13.
Expert Opin Ther Pat ; 29(8): 623-641, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31353978

RESUMO

Introduction: About 20 patents have been published from 2013 to 2018 for developing advanced cancer therapeutics by targeting tubulin polymerization. Currently, there are several tubulin inhibitors that are in the drug development pipeline for various cancers alone or in combination including antibody-conjugated drugs (ACDs). Areas covered: Important patents focusing on the development of tubulin inhibitors published from 2013 to 2018 are covered. This review mainly focuses on the tubulin inhibitors that are being synthesized and studied in cancer research along with their structures and their phases of development in preclinical and clinical research. Expert opinion: Regulation of microtubules is important for cell division, cell motility, intracellular transport, and cell shape maintenance. Modulating its activity proved to be very effective in various diseases including different types of cancers. Microtubules are composed of two units, namely, alpha and beta-tubulin, and modifications at these ends affect both its functions and dynamics. A number of compounds that have been designed and synthesized bearing various heterocyclic scaffolds have been proven to modulate its activity and have emerged as potent tubulin inhibitors. This encourages more to study microtubules in order to find a variety of novel, potent compounds as anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Animais , Antineoplásicos/química , Desenho de Drogas , Desenvolvimento de Medicamentos/métodos , Humanos , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Neoplasias/patologia , Patentes como Assunto , Relação Estrutura-Atividade , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química
14.
Eur J Med Chem ; 177: 448-456, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31174062

RESUMO

The colchicine site inhibitors (CSIs) showed promising prospects as antitumor agents due to their vascular disrupting activities besides antimitotic activities. 1-Phenyl-dihydrobenzoindazole was found as a novel scaffold of CSI without the cis-trans isomerization problem. The X-ray co-crystal structure of the lead compound with tubulin was determined, which revealed the binding mode including special water-bridged hydrogen bonds. The structure also provided guidance for the structural optimization of this type of CSI, which led to the discovery of the most potent inhibitor A3, with growth IC50 lower than 1 nM against human colon cancer cell lines and tubulin polymerization IC50 of 1.6 µM. In addition, its water-soluble prodrug B1 showed good in vivo antitumor activity on two human colon cancer xenograft nude mice models, encouraging further study of this type of antitumor compound.


Assuntos
Antineoplásicos/farmacologia , Sítios de Ligação/efeitos dos fármacos , Indazóis/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Feminino , Células HCT116 , Humanos , Indazóis/síntese química , Indazóis/química , Indazóis/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Ligação Proteica/efeitos dos fármacos , Solubilidade , Tubulina (Proteína)/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Eur J Med Chem ; 178: 297-314, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31195171

RESUMO

A small number of fluorinated 7-phenyl-pyrroloquinolinone (7-PPyQ) derivatives was synthesized in an attempt to improve the metabolic stability of 3N-ethyl-7-PPyQ and 3N-benzoyl-7-PPyQ. The possible impacts of the fluorine-hydrogen isosterism on both biological activity and metabolic stability were evaluated. Introduction of a fluorine atom in the 2 or 3 position of the 7-phenyl ring yielded the 7-PPyQ derivatives 12, 13 and 15, which showed potent cytotoxicity (low micromolar and sub-nanomolar GI50s) both in human leukemic and solid tumor cell lines. None of them induced significant cell death in quiescent and proliferating human lymphocytes. Moreover, 12, 13 and 15 exhibited remarkable cytotoxic activity in the multidrug-resistant cell line CEMVbl100, suggesting that they are not substrates for P-glycoprotein. All compounds inhibited tubulin assembly and the binding of [3H]colchicine to tubulin, with the best activity occurring with compound 15. Mechanistic studies carried out on compound 12 indicated that it caused (a) a strong G2/M arrest; (b) apoptosis in a time- and concentration-dependent manner; (c) a significant production of ROS (in good agreement with the observed mitochondrial depolarization); (d) caspase-3 and poly (ADP-ribose) polymerase activation; and (e) a decrease in the expression of anti-apoptotic proteins. In vivo experiments in a murine syngeneic tumor model demonstrated that compounds 12 and 15 significantly reduced tumor mass at doses four times lower than that required for the reference compound combretastatin A-4 phosphate. Neither monofluorination of the 7-phenyl ring of 3N-ethyl-7-PPyQ nor replacement of the benzoyl function of 3N-benzoyl-7-PPyQ with a 2-fluorobenzoyl moiety led to any improvement in the metabolic stability.


Assuntos
Antineoplásicos/farmacologia , Flúor/farmacologia , Quinolonas/farmacologia , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Flúor/química , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Quinolonas/química , Quinolonas/metabolismo , Relação Estrutura-Atividade , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismo
16.
Expert Opin Investig Drugs ; 28(6): 513-523, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31159588

RESUMO

INTRODUCTION: The management of non-small cell lung cancer (NSCLC) has been substantially improved in the last few years; it has been revolutionized by a patient-tailored approach, especially in the oncogene addicted disease, and by novel combinations containing immune checkpoint inhibitors. However, chemotherapy still represents a mainstay that persists over the decades with limited novelties. Tubulin inhibitors belong to different sub-classes of drugs that share the capability to interfere with mitosis by a direct action on the microtubule system. Among them, taxanes and vinca alkaloids still have a prominent role in clinical practice. AREAS COVERED: This review summarizes the mechanisms of action, current role and future directions of microtubule targeting agents; we focus on investigational agents in phase I and II clinical trials. EXPERT OPINION: Chemotherapy maintains a pivotal role in the treatment of NSCLC. New generation agents that have the potential to overcome the mechanisms of resistance to the available drugs may provide new therapeutic opportunities. Predictive biomarkers derived from combination strategies and phase III studies are necessary going forward.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Moduladores de Tubulina/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Desenho de Drogas , Drogas em Investigação/administração & dosagem , Drogas em Investigação/farmacologia , Humanos , Neoplasias Pulmonares/patologia , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Moduladores de Tubulina/farmacologia
17.
Org Biomol Chem ; 17(25): 6184-6200, 2019 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-31173031

RESUMO

Microtubules are a validated clinical target for the treatment of many cancers. We describe the design, synthesis, biochemical evaluation, and molecular modelling studies of a series of analogues of the microtubule-destabilising agent, combretastatin A-4 (CA-4). Our series of 33 novel compounds contain the CA-4 core structure with modifications to the stilbene linking group, and are predominantly piperazine derivatives. Synthesis was achieved in a two-step process by firstly obtaining the acrylic acid via a Perkin reaction using microwave enhanced synthesis, followed by coupling using either DCC or Mukaiyama's reagent. All target compounds were screened for antiproliferative activity in MCF-7 breast cancer cells. Hydroxyl derivative (E)-3-(4-hydroxy-3-methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-2-(3,4,5-trimethoxyphenyl) propenone (4m) displayed potent antiproliferative activity (IC50 = 190 nM). Two amino-containing derivatives, (E)-3-(3-amino-4-methoxyphenyl)-1-(4-phenylpiperazin-1-yl)-2-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (4q) and (E)-3-(3-amino-4-methoxyphenyl)-1-(4-(p-tolyl)piperazin-1-yl)-2-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (4x), were the most potent with IC50 values of 130 nM and 83 nM respectively. Representative compounds were shown to depolymerise tubulin, induce G2/M arrest and apoptosis in MCF-7 cells but not peripheral blood mononuclear cells, and induce cleavage of the DNA repair enzyme poly ADP ribose polymerase (PARP) in MCF-7 cells. Modelling studies predict that the compounds bind to tubulin within the colchicine-binding site. These compounds are a valuable addition to the library of CA-4 analogues and 4m, 4q and 4x will be developed further as novel, water-soluble molecules targeting microtubules.


Assuntos
Antineoplásicos/farmacologia , Piperazinas/farmacologia , Estilbenos/farmacologia , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Sítios de Ligação , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Piperazinas/síntese química , Piperazinas/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Ligação Proteica , Estilbenos/síntese química , Estilbenos/metabolismo , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/metabolismo
18.
Int J Mol Sci ; 20(11)2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31146360

RESUMO

The plant disease Phytophthora blight, caused by the oomycete pathogen Phytophthora capsici, is responsible for major economic losses in pepper production. Microtubules have been an attractive target for many antifungal agents as they are involved in key cellular events such as cell proliferation, signaling, and migration in eukaryotic cells. In order to design a novel biocompatible inhibitor, we screened and identified inhibitory peptides against alpha- and beta-tubulin of P. capsici using a phage display method. The identified peptides displayed a higher binding affinity (nanomolar range) and improved specificity toward P. capsici alpha- and beta-tubulin in comparison to Homo sapiens tubulin as evaluated by fluorometric analysis. One peptide demonstrated the high inhibitory effect on microtubule formation with a nanomolar range of IC50 values, which were much lower than a well-known chemical inhibitor-benomyl (IC50 = 500 µM). Based on these results, this peptide can be employed to further develop promising candidates for novel antifungal agents against Phytophthora blight.


Assuntos
Antifúngicos/farmacologia , Microtúbulos/efeitos dos fármacos , Peptídeos/farmacologia , Phytophthora/efeitos dos fármacos , Moduladores de Tubulina/farmacologia , Microtúbulos/metabolismo , Phytophthora/metabolismo , Ligação Proteica , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/metabolismo
19.
Molecules ; 24(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31197105

RESUMO

Molecular hybridization has proven to be a successful multi-target strategy in the design and development of new antitumor agents. Based on this rational approach, we have planned hybrid molecules containing covalently linked pharmacophoric units, present individually in compounds acting as inhibitors of the cancer protein targets tubulin, human topoisomerase II and ROCK1. Seven new molecules, selected by docking calculation of the complexes with each of the proteins taken into consideration, have been efficiently synthesized starting from 2,3-dichloro-1,4-naphtoquinone or 6,7-dichloro-5,8-quinolinquinone. By screening the full National Cancer Institute (NCI) panel, including 60 human cancer cell lines, four molecules displayed good and sometimes better growth inhibition GI50 than the ROCK inhibitor Y-27632, the Topo II inhibitor podophyllotoxin and the tubulin inhibitor combretastatin A-4. The relative position of N,N heteroatoms in the structures of the tested compounds was crucial in affecting bioactivity and selectivity. Furthermore, compound 3 (2-(4-(2-hydroxyethyl)piperazin-1-yl)-3-(3,4,5-trimethoxyphenoxy)naphthalene-1,4-dione) emerged as the most active in the series, showing a potent and selective inhibition of breast cancer BT-549 cells (GI50 < 10 nM).


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase II/farmacologia , Moduladores de Tubulina/farmacologia , Amidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/genética , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/química , Neoplasias/genética , Podofilotoxina/farmacologia , Piridinas/farmacologia , Quinolinas/síntese química , Quinolinas/química , Estilbenos/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Tubulina (Proteína)/química , Tubulina (Proteína)/genética , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/química , Quinases Associadas a rho/genética
20.
Org Biomol Chem ; 17(25): 6201-6214, 2019 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-31179474

RESUMO

We have recently reported computational models for prediction of cell-based anticancer activity using machine learning methods. Herein, we have developed an integrated strategy to discover new anticancer agents using a cascade of the established screening models. Application of this strategy identified 17 compounds with antitumor activity. Among these compounds, h2 (containing a pyrazolo[3,4-b]pyridin-6-one scaffold) exhibited anticancer activity against six tumor cell lines, including MDA-MB-231, HeLa, MCF-7, HepG2, CNE2 and HCT116, with IC50 values of 13.37, 13.04, 15.45, 7.05, 9.30 and 8.93 µM. Subsequently, a total of 61 h2 analogues were obtained by similarity searching and tested for their anticancer activities. I2 was identified as a novel anticancer agent having activity against MDA-MB-231, HeLa, MCF-7, HepG2, CNE2 and HCT116 tumor cell lines with IC50 values of 3.30, 5.04, 5.08, 3.71, 2.99 and 5.72 µM. I2 also showed potent cytotoxicity against adriamycin-resistant human breast and hepatocarcinoma cells. Further investigation revealed that I2 inhibited the microtubule polymerization by binding to the colchicine site, resulting in inhibition of cell migration, cell cycle arrest in the G2/M phase and apoptosis of cancer cells. Finally, molecular docking and molecular dynamics provided insights into the binding interactions of I2 with tubulin. This study identified I2 as a novel starting point for further development of anticancer agents that target tubulin.


Assuntos
Antineoplásicos/farmacologia , Pirazóis/farmacologia , Piridonas/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/química , Piridonas/química , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
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