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1.
Proc Natl Acad Sci U S A ; 112(27): 8296-301, 2015 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-26106160

RESUMO

Tramadol, previously only known as a synthetic analgesic, has now been found in the bark and wood of roots of the African medicinal tree Nauclea latifolia. At present, no direct evidence is available as to the biosynthetic pathway of its unusual skeleton. To provide guidance as to possible biosynthetic precursors, we have adopted a novel approach of retro-biosynthesis based on the position-specific distribution of isotopes in the extracted compound. Relatively recent developments in isotope ratio monitoring by (13)C NMR spectrometry make possible the measurement of the nonstatistical position-specific natural abundance distribution of (13)C (δ(13)Ci) within the molecule with better than 1‰ precision. Very substantial variation in the (13)C positional distribution is found: between δ(13)Ci = -11 and -53‰. Distribution is not random and it is argued that the pattern observed can substantially be interpreted in relation to known causes of isotope fractionation in natural products. Thus, a plausible biosynthetic scheme based on sound biosynthetic principals of precursor-substrate relationships can be proposed. In addition, data obtained from the (18)O/(16)O ratios in the oxygen atoms of the compound add support to the deductions made from the carbon isotope analysis. This paper shows how the use of (13)C NMR at natural abundance can help with proposing a biosynthetic route to compounds newly found in nature or those difficult to tackle by conventional means.


Assuntos
Vias Biossintéticas , Marcação por Isótopo/métodos , Espectroscopia de Ressonância Magnética/métodos , Tramadol/metabolismo , Carbono/metabolismo , Isótopos de Carbono/metabolismo , Espectrometria de Massas , Estrutura Molecular , Oxigênio/metabolismo , Isótopos de Oxigênio/metabolismo , Casca de Planta/química , Raízes de Plantas/química , Rubiaceae/química , Tramadol/química , Tramadol/isolamento & purificação , Madeira/química
2.
J Antimicrob Chemother ; 69(3): 664-72, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24126793

RESUMO

OBJECTIVES: To identify reversal agents for the Leishmania ABCI4 transporter that confers resistance to antimony. METHODS: Selective ABCI4 inhibitors among a series of 15 flavonoid and trolox derivatives or analogues were investigated by evaluating their ability to reverse antimony resistance in Leishmania parasites overexpressing ABCI4. Among the compounds screened, N-ethyltrolox carboxamide (compound D2) produced the highest reversal activity. In order to optimize the activity of D2, we synthesized a series of 10 derivatives by condensation of various amines with trolox. RESULTS: Analysis of antimony resistance reversal activity showed that N-propyltrolox carboxamide (compound D4) was the most potent ABCI4 inhibitor, with reversal activity being maintained in the intracellular amastigote stage. In addition, trolox derivatives significantly reverted the resistance to zinc protoporphyrin. The mechanism of action of these active derivatives was found to be related to significant reversion of Sb(III) and zinc protoporphyrin accumulation and to a decrease in drug efflux. CONCLUSIONS: Our findings suggest that trolox derivatives D2 and D4 could be considered to be specific reversal agents targeting the Leishmania ABCI4 transporter. The structure-activity relationship obtained in the present study highlights the importance of the size and length of the alkyl substituent linked to trolox. Furthermore, the structural data obtained provide valuable information for the further development of new, even more specific and potent Leishmania ABCI4 reversal agents.


Assuntos
Antimônio/farmacologia , Antiprotozoários/isolamento & purificação , Cromanos/isolamento & purificação , Avaliação Pré-Clínica de Medicamentos/métodos , Flavonoides/isolamento & purificação , Leishmania/efeitos dos fármacos , Proteínas de Membrana Transportadoras/metabolismo , Antiprotozoários/química , Antiprotozoários/farmacologia , Cromanos/química , Cromanos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Relação Estrutura-Atividade
3.
Eur J Med Chem ; 130: 346-353, 2017 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-28273561

RESUMO

With the aim to develop anticancer agents acting selectively against resistant tumor cells, we investigated ferrocene embedded into chalcone, aurone and flavone skeletons. These compounds were conceived and then investigated based on the concept of collateral sensitivity, where the target is the Achilles Heel of cancer cells overexpressing the multidrug ABC transporter MRP1. The 14 synthesized compounds were evaluated for their ability to induce efflux of glutathione (GSH) from tumor cells overexpressing MRP1. When tested at 5 and 20 µM, at least one compound from each series was found to be a highly inducer of GSH efflux. The different compounds inducing a high efflux of GSH were evaluated on both sensitive and resistant cell lines, and two of them, belonging to the flavones class were found to be more cytotoxic on resistant cancer cells, with the best selectivity ratio >9.1. Our results bring chemical and biological bases for further optimization.


Assuntos
Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Compostos Ferrosos/química , Flavonoides/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Citotoxinas/química , Citotoxinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Flavonoides/química , Glutationa/metabolismo , Humanos , Metalocenos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/biossíntese , Sensibilidade e Especificidade
4.
Eur J Med Chem ; 122: 291-301, 2016 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-27376492

RESUMO

Breast cancer resistance protein (BCRP/ABCG2) is one of the major transporters involved in the efflux of anticancer compounds, contributing to multidrug resistance (MDR). Inhibition of ABCG2-mediated transport is then considered a promising strategy for overcoming MDR in tumors. We recently identified a chromone derivative, namely MBL-II-141 as a selective ABCG2 inhibitor, with relevant in vivo activity. Here, we report the pharmacomodulation of MBL-II-141, with the aim of identifying key pharmacophoric elements to design more potent selective and non-toxic inhibitors. Through rational structural modifications of MBL-II-141, using simple and affordable chemistry, we obtained highly active and easily-made inhibitors of ABCG2. Among the investigated compounds, derivative 4a, was found to be 3-fold more potent than MBL-II-141. It was similarly efficient as the reference inhibitor Ko143 but with the advantage of a lower intrinsic cytotoxicity, and therefore constitutes the best ABCG2 inhibitor ever reported displaying a very high therapeutic ratio.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Neoplasias da Mama , Cromonas/química , Cromonas/farmacologia , Desenho de Fármacos , Cromonas/síntese química , Células HEK293 , Humanos , Relação Estrutura-Atividade
5.
Chem Commun (Camb) ; 51(77): 14451-3, 2015 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-26267411

RESUMO

Tramadol has recently been isolated from the roots and bark of Nauclea latifolia. A plausible biosynthetic pathway has been proposed and the product-precursor relationship has been probed by (13)C position-specific isotope analysis. By further exploring this pathway, we demonstrate that a key step of the proposed pathway can be achieved using mild conditions that mimic in vivo catalysis.


Assuntos
Analgésicos Opioides/síntese química , Biomimética , Tramadol/síntese química , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética , Espectrometria de Massas
6.
Oncotarget ; 5(23): 11957-70, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25474134

RESUMO

ABCG2 is responsible for the multidrug resistance (MDR) phenotype, and strongly modulates cancer outcomes. Its high expression at a number of physiological barriers, including blood-brain and intestinal barriers, impacts on drug pharmacokinetics parameters. We characterized MBL-II-141, a specific and potent ABCG2 inhibitor. Combination of 10 mg/kg MBL-II-141 with the anticancer agent CPT-11 completely blocked the growth of 90% freshly implanted ABCG2-positive tumors. Moreover, the same combination slowed the growth of already established tumors. As required for preclinical development, we defined the main pharmacokinetics parameters of MBL-II-141 and its influence on the kinetics of CPT-11 and its active metabolite SN-38 in mice. MBL-II-141 distribution into the brain occurred at a low, but detectable, level. Interestingly, preliminary data suggested that MBL-II-141 is well tolerated (at 50 mg/kg) and absorbed upon force-feeding. MBL-II-141 induced a potent sensitization of ABCG2-positive xenografts to CPT-11 through in vivo ABCG2 inhibition. MBL-II-141 strongly increased CPT-11 levels in the brain, and therefore would be a valuable agent to improve drug distribution into the brain to efficiently treat aggressive gliomas. Safety and other pharmacological data strongly support the reglementary preclinical development of MBL-II-141.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cromonas/farmacologia , Indóis/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Cromatografia Líquida de Alta Pressão , Cromonas/farmacocinética , Células HEK293 , Humanos , Indóis/farmacocinética , Irinotecano , Espectrometria de Massas , Camundongos , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Biochem Pharmacol ; 90(3): 235-45, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24875445

RESUMO

The multidrug resistance protein 1 (MRP1) is involved in multidrug resistance of cancer cells by mediating drug efflux out of cells, often in co-transport with glutathione (GSH). GSH efflux mediated by MRP1 can be stimulated by verapamil. In cells overexpressing MRP1, we have previously shown that verapamil induced a huge intracellular GSH depletion which triggered apoptosis of the cells. That phenomenon takes place in the more global anticancer strategy called "collateral sensitivity" and could be exploited to eradicate some chemoresistant cancer cells. Seeking alternative compounds to verapamil, we screened a library of natural flavonoids and synthetic derivatives. A large number of these compounds stimulate MRP1-mediated GSH efflux and the most active ones have been evaluated for their cytotoxic effect on MRP1-overexpressing cells versus parental cells. Interestingly, some are highly and selectively cytotoxic for MRP1-cells, leading them to apoptosis. However, some others do not exhibit any cytotoxicity while promoting a strong GSH efflux, indicating that GSH efflux is necessary but not sufficient for MRP1-cells apoptosis. In support to this hypothesis, structure activity relationships show that the absence of a hydroxyl group at position 3 of the flavonoid C ring is an absolute requirement for induction of MRP1-cells death, but is not for GSH efflux stimulation. Chrysin (compound 8) and its derivatives, compounds 11 and 22, exhibit a high selectivity toward MRP1-cells with a IC50 value of 4.1 µM for compound 11 and 4.9 µM for chrysin and compound 22, making them among the best described selective killer compounds of multidrug ABC transporter-overexpressing cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Descoberta de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Flavonoides/farmacologia , Glutationa/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/agonistas , Regulação para Cima/efeitos dos fármacos , Animais , Antineoplásicos Fitogênicos/química , Antioxidantes/química , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Flavonoides/química , Humanos , Concentração Inibidora 50 , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/agonistas , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Relação Quantitativa Estrutura-Atividade , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Bibliotecas de Moléculas Pequenas
8.
Future Med Chem ; 5(9): 1037-45, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23734686

RESUMO

ABCG2 impacts oral availability, tissue distribution and excretion of its substrates, including anticancer and anti-infectious drugs. Highly expressed at physiological barriers, its secretion level significantly controls drug distribution. Furthermore, its increased content into many types of cancer may lead to cell chemoresistance. Owing to the clinical relevance of ABCG2 in the multidrug resistance phenomenon, ABCG2 constitutes an appealing therapeutic target to increase drug distribution. Development of ABCG2 inhibitors can be used in combination with anticancer drugs to block the drug secretion from cancer cells. Very recently, an alternative use of ABCG2 inhibitors in enhancing the bioavailability of ABCG2 substrates has emerged. Hence, it is important to investigate ABCG2 inhibitors with high selectivity, high potency and safety. New inhibitors discovered during the last 5 years will be presented and discussed.


Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/uso terapêutico , Chalconas/química , Chalconas/farmacologia , Chalconas/uso terapêutico , Cromonas/química , Cromonas/farmacologia , Cromonas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Quinolinas/química , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Estilbenos/química , Estilbenos/farmacologia , Estilbenos/uso terapêutico
9.
J Med Chem ; 56(24): 9849-60, 2013 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-24304387

RESUMO

We recently identified a chromone derivative, 5-(4-bromobenzyloxy)-2-(2-(5-methoxyindolyl)ethyl-1-carbonyl)-4H-chromen-4-one, named here as chromone 1, as a potent, selective, nontoxic, and nontransported inhibitor of ABCG2-mediated drug efflux (Valdameri et al. J. Med. Chem. 2012, 55, 966). We have now synthesized a series of 14 derivatives to study the structure-activity relationships controlling both drug efflux and ATPase activity of ABCG2 and to elucidate their molecular mechanism of interaction and inhibition. It was found that the 4-bromobenzyloxy substituent at position 5 and the methoxyindole are important for both inhibition of mitoxantrone efflux and inhibition of basal ATPase activity. Quite interestingly, methylation of the central amide nitrogen strongly altered the high affinity for ABCG2 and the complete inhibition of mitoxantrone efflux and coupled ATPase activity. These results allowed the identification of a critical central inhibitory moiety of chromones that has never been investigated previously in any series of inhibitors.


Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Cromonas/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/química , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Proteínas de Neoplasias/química , Relação Estrutura-Atividade
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