Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 546
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Molecules ; 25(7)2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32230894

RESUMO

Malaria is a life-threatening disease and, what is more, the resistance to available antimalarial drugs is a recurring problem. The resistance of Plasmodium falciparum malaria parasites to previous generations of medicines has undermined malaria control efforts and reversed gains in child survival. This paper describes a continuation of our ongoing efforts to investigate the effects against Plasmodium falciparum strains and human microvascular endothelial cells (HMEC-1) of a series of methoxy p-benzyl-substituted thiazinoquinones designed starting from a pointed antimalarial lead candidate. The data obtained from the newly tested compounds expanded the structure-activity relationships (SARs) of the thiazinoquinone scaffold, indicating that antiplasmodial activity is not affected by the inductive effect but rather by the resonance effect of the introduced group at the para position of the benzyl substituent. Indeed, the current survey was based on the evaluation of antiparasitic usefulness as well as the selectivity on mammalian cells of the tested p-benzyl-substituted thiazinoquinones, upgrading the knowledge about the active thiazinoquinone scaffold.


Assuntos
Antimaláricos/farmacologia , Células Endoteliais/efeitos dos fármacos , Malária/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Quinonas/química , Quinonas/farmacologia , Células Endoteliais/parasitologia , Concentração Inibidora 50 , Testes de Sensibilidade Parasitária , Quinonas/síntese química , Relação Estrutura-Atividade
2.
Eur J Med Chem ; 194: 112253, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32222678

RESUMO

The prevention and control of plant diseases and insect pests is the most crucial issue facing crop protection. To discover novel pesticide candidates with diverse chemical structures from natural products, a series of luotonin A analogues were designed, synthesized and evaluated for their antifungal and insecticidal activities. Most of these compounds exhibited potent activity against Botrytis cinerea, Magnaporthe oryzae and Aphis craccivora. Among them, the antifungal activity of compound 10s against B. cinerea was comparable to azoxystrobin (EC50 = 0.09 mM) and against M. oryzae (EC50 = 0.19 mM) was slightly weaker than that of azoxystrobin (EC50 = 0.17 mM). Compounds 10k and 10o are the most active compounds against A. craccivora having identical mortality value of 42.05% at 50 µg/mL, respectively, which were slightly lower than pymetrozine (51.14%) at the same concentration. Revealed morphological changes of the fungal cell surface by scanning electron microscopy indicated that luotonin A analogues might exert their antifungal activity by destroying fungal cell membrane and cell wall. Furthermore, the results of the in vivo protective and curative activities of the compound 10s against S. sclerotiorum and B. cinerea showed that the curative effect was stronger than its protective effect and the curative effects reached 67.17% and 73.82% at 80 µg/mL respectively. The above results further demonstrated the potential of luotonin A analogues as novel fungicides and insecticides.


Assuntos
Alcaloides/farmacologia , Produtos Biológicos/farmacologia , Descoberta de Drogas , Fungicidas Industriais/farmacologia , Inseticidas/farmacologia , Pirróis/farmacologia , Quinonas/farmacologia , Alcaloides/síntese química , Alcaloides/química , Animais , Afídeos/efeitos dos fármacos , Produtos Biológicos/síntese química , Produtos Biológicos/química , Botrytis/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fungicidas Industriais/síntese química , Fungicidas Industriais/química , Inseticidas/síntese química , Inseticidas/química , Magnaporthe/efeitos dos fármacos , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Quinonas/síntese química , Quinonas/química , Relação Estrutura-Atividade
3.
Org Biomol Chem ; 18(3): 557-568, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31894828

RESUMO

The isoquinolinequinone (IQQ) pharmacophore is a privileged framework in known cytotoxic natural product families, caulibugulones and mansouramycins. Exploiting both families as a chemical starting point, we report on the structured development of an IQQ N-oxide anticancer framework which exhibits growth inhibition in the nM range across melanoma, ovarian and leukaemia cancer cell lines. A new lead compound (16, R6 = benzyl, R7 = H) exhibits nM GI50 values against 31/57 human tumour cell lines screened as part of the NCI60 panel and shows activity against doxorubicin resistant tumour cell lines. An electrochemical study highlights a correlation between electropositivity of the IQQ N-oxide framework and cytotoxicity. Adduct binding to sulfur based biological nucleophiles glutathione and cysteine was observed in vitro. This new framework possesses significant anticancer potential.


Assuntos
Antineoplásicos/farmacologia , Óxidos N-Cíclicos/farmacologia , Isoquinolinas/farmacologia , Quinonas/farmacologia , Antineoplásicos/síntese química , Benzilaminas/síntese química , Benzilaminas/farmacologia , Linhagem Celular Tumoral , Óxidos N-Cíclicos/síntese química , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoquinolinas/síntese química , Quinonas/síntese química
4.
Biomed Res Int ; 2019: 2514524, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815127

RESUMO

A- and D-ring-modified luotonin-inspired heterocycles have been synthesized and were evaluated for their activity against the viability of four cancer cell lines in vitro, namely, MCF7, HCT116, JURKAT, and NCI-H460. The analysis of results indicated that two of the synthesized derivatives displayed good inhibition against the growth of the human colon cancer HCT116 cell line, with potencies lower than but in the same order of magnitude as camptothecin (CPT). These two luotonin analogues also showed an activity similar to that of the highly potent alkaloid CPT as inhibitors of topoisomerase I and also inhibited topoisomerase II. These results show that complete planarity is not a strict requirement for topoisomerase inhibition by luotonin-related compounds, paving the way to the design of analogues with improved solubility.


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/efeitos dos fármacos , DNA Topoisomerases Tipo I/efeitos dos fármacos , Proteínas de Ligação a Poli-ADP-Ribose/efeitos dos fármacos , Pirróis/síntese química , Pirróis/farmacologia , Quinonas/síntese química , Quinonas/farmacologia , Inibidores da Topoisomerase/farmacologia , Alcaloides/farmacologia , Camptotecina/análogos & derivados , Camptotecina/síntese química , Linhagem Celular Tumoral/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Solubilidade , Relação Estrutura-Atividade
5.
Molecules ; 24(22)2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31731682

RESUMO

Twenty-seven L-shaped ortho-quinone analogs were designed and synthesized using a one pot double-radical synthetic strategy followed by removing methyl at C-3 of the furan ring and introducing a diverse side chain at C-2 of the furan ring. The synthetic derivatives were investigated for their cytotoxicity activities against human leukemia cells K562, prostate cancer cells PC3, and melanoma cells WM9. Compounds TB1, TB3, TB4, TB6, TC1, TC3, TC5, TC9, TC11, TC12, TC14, TC15, TC16, and TC17 exhibited a better broad-spectrum cytotoxicity on three cancer cells. TB7 and TC7 selectively displayed potent inhibitory activities on leukemia cells K562 and prostate cancer cells PC3, respectively. Further studies indicated that TB3, TC1, TC3, TC7, and TC17 could significantly induce the apoptosis of PC3 cells. TC1 and TC17 significantly induced apoptosis of K562 cells. TC1, TC11, and TC14 induced significant apoptosis of WM9 cells. The structure-activity relationships evaluation showed that removing methyl at C-3 of the furan ring and introducing diverse side chains at C-2 of the furan ring is an effective strategy for improving the anticancer activity of L-shaped ortho-quinone analogs.


Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citotoxinas , Neoplasias , Quinonas , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células K562 , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Células PC-3 , Quinonas/síntese química , Quinonas/química , Quinonas/farmacologia , Relação Estrutura-Atividade
6.
Bioorg Chem ; 91: 103131, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31377387

RESUMO

For the development of novel anticancer agents, we designed and synthesized a total of 37 perimidine o-quinone derivatives containing the o-quinone group at the A or B ring and different substituents (alkyl groups, aryl groups or heterocycles) at the C ring of the compounds. The structure-activity relationships (SARs) were established based on the cytotoxicity data of compounds from the HL-60, Huh7, Hct116, and Hela cell lines. The cytotoxicity results showed that most compounds exhibited potent cytotoxicity. In particular, compound b-12 showed the best anti-proliferative activity (IC50 ≤ 1 µM) against four cancer cell lines and strong potency against the HL-60/MX2 (0.47 µM) cell line, which is resistant to Topo II poisons. Further studies showed that b-12 exhibited potent Topo IIα inhibitory activity (IC50 = 7.54 µM) compared with Topo I, which acted as a class of non-intercalative Topo IIα catalytic inhibitor by inhibiting the ATP binding site of Topo II. Cell apoptosis and cell cycle assays confirmed that b-12 could induce the apoptosis of Huh7 cells in a dose-dependent manner.


Assuntos
Antineoplásicos/farmacologia , Quinazolinas/farmacologia , Quinonas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/metabolismo , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Quinazolinas/síntese química , Quinazolinas/metabolismo , Quinonas/síntese química , Quinonas/metabolismo , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/metabolismo
7.
J Org Chem ; 84(15): 9811-9818, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31293163

RESUMO

The reactivity of hydrogen peroxide and catalytic hydroiodic acid toward 3,6-dimethoxy-2-(cycloamino)anilines is tunable to give ring-fused benzimidazoles or 1,4,6,9-tetramethoxyphenazine in high yield. Mechanisms via a detected nitroso-intermediate are proposed for oxidative cyclization and the unexpected intermolecular displacement of the oxazine. An aqueous solution of molecular iodine is capable of the same transformations. Oxidative demethylation gave targeted benzimidazolequinones, including without cleavage of the incorporated oxetane.


Assuntos
Antineoplásicos/química , Benzimidazóis/química , Descoberta de Drogas , Éteres Cíclicos/química , Morfolinas/química , Fenazinas/química , Quinonas/química , Ácidos/química , Antineoplásicos/síntese química , Benzimidazóis/síntese química , Catálise , Ciclização , Peróxido de Hidrogênio/química , Compostos de Iodo/química , Estrutura Molecular , Oxirredução , Fenazinas/síntese química , Quinonas/síntese química
8.
Bioorg Med Chem ; 27(17): 3938-3946, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31327676

RESUMO

Herein we designed a collection of trimethyl-lock quinone profluorophores as activity-based probes for imaging NAD(P)H:quinone oxidoreductase (NQO1) in cancer cells and tumour tissues. Profluorophores were prepared via synthetic routes from naturally-occurring quinones and characterised in vitro using recombinant enzymes, to be further validated in cells and fresh frozen canine tumour tissues as potential new tools for cancer detection and imaging.


Assuntos
Adenocarcinoma/diagnóstico por imagem , Produtos Biológicos/química , Neoplasias Colorretais/diagnóstico por imagem , Corantes Fluorescentes/química , NAD(P)H Desidrogenase (Quinona)/metabolismo , Imagem Óptica , Quinonas/química , Animais , Produtos Biológicos/síntese química , Linhagem Celular , Colo/diagnóstico por imagem , Cães , Corantes Fluorescentes/síntese química , Células HL-60 , Células HeLa , Humanos , Cinética , Microscopia de Fluorescência , Estrutura Molecular , NAD(P)H Desidrogenase (Quinona)/análise , Quinonas/síntese química
9.
Bioorg Med Chem ; 27(16): 3532-3545, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31262663

RESUMO

A library of thirty-two quinolinequinones (QQs) with various amine substituents at the 6- and 7-positions were synthesised efficiently and in good yields for evaluation as potential anti-tuberculosis agents. Mycobacterium tuberculosis growth inhibition assays demonstrated that QQs bearing moderate length alkyl chains (i.e. heptylphenylamino- and octylamino-QQs), and aryl groups (i.e. phenylethylamino- and benzylamino-QQs) exhibited encouraging inhibitory activity, while QQ analogue 7-chloro-6-propargylamino-quinoline-5,8-dione (16b) had excellent inhibitory activity (MIC = 8 µM). The cLogP values and redox activities of the QQs were determined, and neither readout correlated with the anti-mycobacterial activities of the compounds. Notwithstanding, mode of action studies of 16b revealed that treatment of M. tuberculosis with this compound led to activation of NADH-dependent oxygen consumption suggesting a redox cycling mechanism. To this end, the promising anti-mycobacterial activity of several QQs and their ability to perturb oxygen management leading to an uncontrolled respiratory burst, as identified in this work and by others, demonstrates the merit of further optimising the anti-mycobacterial activity of this readily synthesised class of compound.


Assuntos
Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Quinonas/síntese química , Antituberculosos/farmacologia , Humanos , Estrutura Molecular
10.
Eur J Med Chem ; 179: 863-915, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31306817

RESUMO

Naphthoquinones are of key importance in organic synthesis and medicinal chemistry. In the last few years, various synthetic routes have been developed to prepare bioactive compounds derived or based on lapachones. In this sense, this review is mainly focused on the synthetic aspects and strategies used for the design of these compounds on the basis of their biological activities for the development of drugs against the neglected diseases leishmaniases and Chagas disease and also cancer. Three strategies used to develop bioactive quinones are discussed and categorized: (i) C-ring modification, (ii) redox centre modification and (iii) A-ring modification. Framed within these strategies for the development of naphthoquinoidal compounds against T. cruzi. Leishmania and cancer, reactions including copper-catalyzed azide-alkyne cycloaddition (click chemistry), palladium-catalysed cross couplings, C-H activation reactions, Ullmann couplings and heterocyclisations reported up to July 2019 will be discussed. The aim of derivatisation is the generation of novel molecules that can potentially inhibit cellular organelles/processes, generate reactive oxygen species and increase lipophilicity to enhance penetration through the plasma membrane. Modified lapachones have emerged as promising prototypes for the development of drugs against leishmaniases, Chagas disease and cancer.


Assuntos
Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Doença de Chagas/tratamento farmacológico , Doenças Negligenciadas/tratamento farmacológico , Neoplasias/tratamento farmacológico , Quinonas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antiprotozoários/síntese química , Antiprotozoários/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Leishmania/efeitos dos fármacos , Neoplasias/patologia , Quinonas/síntese química , Quinonas/química , Trypanosoma cruzi/efeitos dos fármacos
11.
Eur J Med Chem ; 177: 302-315, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158746

RESUMO

Betulin-1,4-quinone hybrids were obtain by connecting two active structures with a linker. This strategy allows for obtaining compounds showing a high biological activity and better bioavailability. In this research, synthesis, anticancer activity and molecular docking study of betulin-1,4-quinone hybrids are presented. Newly synthesized compounds were characterized by 1H, 13C NMR, IR and HR-MS. Hybrids were tested in vitro against a panel of human cell lines including glioblastoma, melanoma, breast and lung cancer. They showed a high cytotoxic activity depending on the type of 1,4-quinone moiety and the applied tumor cell lines. It was found that cytotoxic activities of the studied hybrids were increasing against the cell line with higher NQO1 protein level, like melanoma (C-32), breast (MCF-7) and lung (A-549) cancer. Selected hybrids were tested on the transcriptional activity of the gene encoding a proliferation marker (H3 histone), a cell cycle regulators (p53 and p21) and an apoptosis pathway (BCL-2 and BAX). The obtained results suggested that the tested compounds caused a mitochondrial apoptosis pathway in A549 and MCF-7 cell lines. The molecular docking was used to examine the probable interaction between the hybrids and human NAD[P]H-quinone oxidoreductase (NQO1) protein. The computational studies showed that the type of the 1,4-quinone moiety affected the location of the compound in the active site of the enzyme. Moreover, it was shown that an interaction of 1,4-quinone fragment with the hydrophobic matrix of the active site near Tyr128, Phe178, Trp105 and FAD cofactor could explain the observed increase of TP53 gene expression.


Assuntos
Antineoplásicos/farmacologia , NAD(P)H Desidrogenase (Quinona)/metabolismo , Quinonas/farmacologia , Triterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Betula/química , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/genética , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , NAD(P)H Desidrogenase (Quinona)/química , Ligação Proteica , Quinonas/síntese química , Quinonas/química , Quinonas/metabolismo , Relação Estrutura-Atividade , Triterpenos/síntese química , Triterpenos/química , Triterpenos/isolamento & purificação , Triterpenos/metabolismo , Proteína Supressora de Tumor p53/genética
12.
Spectrochim Acta A Mol Biomol Spectrosc ; 218: 206-212, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-30995578

RESUMO

Hydrogen sulfide (H2S) is a kind of gaseous signal molecule in many physiological processes. In order to detect H2S, a novel "turn on" fluorescent probe 6,12-dihydroxyperylene-1,7-dione (DPD) was designed and synthesized. The probe DPD is fluorescence silence, while the addition of H2S induces an obvious green fluorescence with an obvious color change from dark blue to yellow-green. The probe shows excellent selectivity, fast response (2.5min) and linear curve (0-90µM) in wide effective pH range (4-10). Competition experiments are also revealed in corresponding studies and the detection limit is 3.6µM. The response mechanism is proved to be the reduction of the probe by H2S, which is confirmed by 1H NMR. Furthermore, through the fluorescence turn-on signal toward H2S in Hela cells, probe DPD was successfully applied to monitor H2S in living Hela cells.


Assuntos
Corantes Fluorescentes/química , Sulfeto de Hidrogênio/análise , Perileno/análogos & derivados , Quinonas/química , Fluorescência , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Limite de Detecção , Microscopia Confocal , Imagem Óptica , Perileno/síntese química , Perileno/química , Quinonas/síntese química , Espectrometria de Fluorescência
13.
Eur J Med Chem ; 167: 357-366, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30776695

RESUMO

Schistosomiasis ranks second only to malaria as the most common parasitic disease worldwide. 700 million people are at risk and 240 million are already infected. Praziquantel is the anthelmintic of choice but decreasing efficacy has already been documented. In this work, we exploited the inhibition of Schistosoma mansoni dihydroorotate dehydrogenase (SmDHODH) as a strategy to develop new therapeutics to fight schistosomiasis. A series of quinones (atovaquone derivatives and precursors) was evaluated regarding potency and selectivity against both SmDHODH and human DHODH. The best compound identified is 17 (2-hydroxy-3-isopentylnaphthalene-1,4-dione) with IC50 = 23 ±â€¯4 nM and selectivity index of 30.83. Some of the new compounds are useful pharmacological tools and represent new lead structures for further optimization.


Assuntos
Anti-Helmínticos/química , Desenho de Fármacos , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Schistosoma mansoni/enzimologia , Esquistossomose mansoni/tratamento farmacológico , Animais , Anti-Helmínticos/farmacologia , Humanos , Ligantes , Quinonas/síntese química , Quinonas/farmacologia , Relação Estrutura-Atividade
14.
Molecules ; 24(4)2019 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-30781470

RESUMO

Following two orthogonal synthetic routes, a series of all four possible A-ring amino derivatives of the natural product Luotonin A (a known Topoisomerase I inhibitor) was synthesized. In both strategies, intramolecular cycloaddition reactions are the key step. The target compounds were obtained in good yields by mild catalytic transfer hydrogenation of the corresponding nitro precursors. In-vitro evaluation of the antiproliferative activity towards human tumor cell lines revealed the 4-amino compound (5b) to be the most effective agent, showing an interesting profile of cytotoxic activity. Among other effects, a significant G2/M cell cycle arrest was observed for this compound, suggesting that either Topoisomerase I is not the only biological target, or that some atypical mechanism is responsible for inhibition of this enzyme.


Assuntos
Alcaloides/síntese química , Alcaloides/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Quinonas/síntese química , Quinonas/farmacologia , Alcaloides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Pirróis/química , Quinonas/química , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologia
15.
Drug Res (Stuttg) ; 69(7): 406-414, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30654398

RESUMO

Two series of diaziridinyl quinone isoxazole derivatives were prepared and evaluated for their cytotoxic activity against MCF7, HeLa, BT549, A549 and HEK293 cell lines and interaction with tubulin. Compounds (6A-M: ) showed promising activity against all the 5 human cancer cell lines. Compounds 6A: , 6E: and 6 M: were potent [IC50 ranging between 2.21 µg to 2.87 µg] on ER-positive MCF7 cell line similar to the commercially available drug molecule Doxorubicin. The results from docking models are in consistent with the experimental values which demonstrated the favourable binding modes of compounds 6A-M: to the interface of α- and ß-tubulin dimer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Azirinas/síntese química , Azirinas/farmacologia , Linhagem Celular Tumoral , Técnicas de Química Sintética , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Concentração Inibidora 50 , Isoxazóis/síntese química , Isoxazóis/farmacologia , Quinonas/síntese química , Quinonas/farmacologia , Testes de Toxicidade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química
16.
Bioorg Chem ; 85: 240-252, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30640072

RESUMO

A small library of antiplasmodial methoxy-thiazinoquinones, rationally designed on the model of the previously identified hit 1, has been prepared by a simple and inexpensive procedure. The synthetic derivatives have been subjected to in vitro pharmacological screening, including antiplasmodial and toxicity assays. These studies afforded a new lead candidate, compound 9, endowed with higher antiplasmodial potency compared to 1, a good selectivity index when tested against a panel of mammalian cells, no toxicity against RBCs, a synergistic antiplasmodial action in combination with dihydroartemisinin, and a promising inhibitory activity on stage V gametocyte growth. Computational studies provided useful insights into the structural requirements needed for the antiplasmodial activity of thiazinoquinone compounds and on their putative mechanism of action.


Assuntos
Antimaláricos/farmacologia , Quinonas/farmacologia , Tiazinas/farmacologia , Animais , Antimaláricos/síntese química , Antimaláricos/toxicidade , Artemisininas/farmacologia , Linhagem Celular Tumoral , Células Cultivadas , Teoria da Densidade Funcional , Sinergismo Farmacológico , Eritrócitos/efeitos dos fármacos , Humanos , Camundongos Endogâmicos C57BL , Modelos Químicos , Simulação de Dinâmica Molecular , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Quinonas/síntese química , Quinonas/toxicidade , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/toxicidade
17.
Eur J Med Chem ; 163: 453-480, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30530196

RESUMO

Here we first time report an unprecedented and unnatural six-membered 1,5-oxaza spiroquinone scaffold with structural novelty, a convenient and efficient synthetic route was developed for the synthesis of new 1,5-oxaza spiroquinone derivatives (1a-1r) in high yields from readily available starting materials. The logic of the present work consists of (1) the identification of a promising unprecedented scaffold from privileged scaffolds of biological active molecules through our 'Chemistry-oriented Synthesis' (ChOS) approach, a compensatory strategy for target-based drug discovery, (2) the positioning of the identified 1,5-oxaza spiroquinone scaffold on neuroinflammation and neurodegenerative disease through nitric oxide (NO) inhibitory activity without cytotoxicity in hyper-activated microglia (IC50 of NO production: 0.07-1.82 µM) to establish structure-activity relationship (SAR), (3) the investigation on the possibility as a selective kinase inhibitor related to neurodegenerative diseases (eg. JNK1, CDK2, DAPK1) through kinase full panel screening of the most potent compound 1n, and (4) the evaluation on in vivo efficacy of the compound 1n through Y-maze test.


Assuntos
Descoberta de Drogas , Fármacos Neuroprotetores/síntese química , Quinonas/síntese química , Compostos de Espiro/síntese química , Inflamação/tratamento farmacológico , Microglia/metabolismo , Microglia/patologia , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinonas/química , Quinonas/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
18.
Eur J Med Chem ; 159: 317-323, 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30300844

RESUMO

Compared with normal cells, cancer cells harbor increased levels of reactive oxygen species (ROS) including hydrogen peroxide (H2O2), and therefore are more vulnerable to further ROS production. This biochemical difference favors the idea of developing new powerful selective prooxidative anticancer agents. However, it still remains a challenge to design them by targeting this difference. Herein, we report the designed dichlorobinaphthoquinone as a prooxidative anticancer agent which is capable of exploiting increased levels of H2O2 of cancer cells to produce in situ lethal hydroxyl radicals (HO•) and thereby kill them selectively, a design strategy inspired from Zhu et al.'s work on the molecular mechanism for metal-independent production of HO•.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Peróxido de Hidrogênio/farmacologia , Radical Hidroxila/farmacologia , Quinonas/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 , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Radical Hidroxila/química , Radical Hidroxila/metabolismo , Estrutura Molecular , Quinonas/síntese química , Quinonas/química , Relação Estrutura-Atividade
19.
Eur J Med Chem ; 160: 256-265, 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30368201

RESUMO

Structural analogues of anti-cancer natural product, dysideanone, were synthesized starting from Wieland-Miescher ketone derivative. In vitro studies have been conducted to evaluate the anti-cancer potential of these unnatural meroterpenoids against colon cancer. Synthesized carbotetracycles were found to be more active as compared to their acyclic carbinol-derivatives. Unnatural carbotetracycles 4b-e, 4h, 4i and 12 were found to be highly effective against the human colon adenocarcinoma cells with IC50 concentrations of 7.5-20 µM. In this series, the carbotetracyclic catechol 4e (IC50 = 7.5 µM) and quinone 12 (IC50 = 8 µM) were found to be the most potent compounds having the IC50 of less than 10 µM with no cytotoxic effect on the normal cells. Downregulation of Cox-2 and survivin and cell cycle arrest eventually leading to apoptosis were found to be the underlying mechanism of the anti-cancer effect of these unnatural meroterpenoids.


Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Quinonas/farmacologia , Sesquiterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Neoplasias do Colo/patologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Conformação Molecular , Quinonas/síntese química , Quinonas/química , Sesquiterpenos/síntese química , Sesquiterpenos/química , Relação Estrutura-Atividade
20.
Food Chem Toxicol ; 120: 700-707, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30063944

RESUMO

The formation of o-quinones from direct 2-electron oxidation of catechols and/or two successive one electron oxidations could explain the cytotoxic/genotoxic and/or chemopreventive effects of several phenolic botanical extracts. For example, poison ivy contains urushiol, an oily mixture, which is oxidized to various o-quinones likely resulting in skin toxicity through oxidative stress and alkylation mechanisms resulting in immune responses. Green tea contains catechins which are directly oxidized to o-quinones by various oxidative enzymes. Alternatively, phenolic botanicals could be o-hydroxylated by P450 to form catechols in vivo which are oxidized to o-quinones. Examples include, resveratrol which is oxidized to piceatannol and further oxidized to the o-quinone. Finally, botanical o-quinones can be formed by O-dealkylation of O-alkoxy groups or methylenedioxy rings resulting in catechols which are further oxidized to o-quinones. Examples include safrole, eugenol, podophyllotoxin and etoposide, as well as methysticin. Once formed these o-quinones have a variety of biological targets in vivo resulting in various biological effects ranging from chemoprevention -> no effect -> toxicity. This U-shaped biological effect curve has been described for a number of reactive intermediates including o-quinones. The current review summarizes the latest data on the formation and biological targets of botanical o-quinones.


Assuntos
Plantas/química , Quinonas/síntese química , Quinonas/farmacologia , Ativação Metabólica , Alquilação , DNA/química , Glutationa/química , Hidroxilação , Oxirredução , Proteínas/química , Quinonas/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA