RESUMO
In this article, we describe the synthesis of 3-phenylquinoxaline-2-carbonitrile 1,4-dioxides bearing cyclic diamine residues at positions 6 or 7; the synthesis is based on the nucleophilic substitution of halogens. All synthesized 6(7)-aminoquinoxaline-2-carbonitrile 1,4-dioxides 3-6 demonstrated higher cytotoxicity and hypoxia selectivity compared to the reference agent tirapazamine against breast adenocarcinoma cell lines (MCF7, MDA-MB-231). The structure and position of the diamine residue considerably affects the antiproliferative properties of the quinoxaline-2-carbonitrile 1,4-dioxides. The introduction of a halogen atom at position 7 in the quinoxaline ring of 4a considerably increases the cytotoxicity of compounds 5a and 6a under both normoxic and hypoxic conditions. However, the most hypoxia-selective derivatives were non-halogenated 7-aminosubstituted 3-phenylquinoxaline-2-carbonitrile 1,4-dioxides 3a-j. Of the 32 novel synthesized derivatives, approximately 20 of the 6(7)-amino-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides demonstrated high antiproliferative potency against wild type leukemia cells K562 and drug-resistant subline K562/4 with the expression of p-glycoprotein (p-gp) compared to the reference agent doxorubicin, which exhibited one order of magnitude lower activity towards K562/4 cells than towards K562 cells. Lead compounds 5a and 3f inhibited HIF-1α expression and activity and induced apoptosis in hypoxic tumor cells, which was confirmed by poly(ADP-ribose)polymerase (PARP) cleavage. Moreover, 5a and 3f showed strong antiestrogenic potencies in MCF7 breast cancer cells. Thus, the described series of quinoxaline 1,4-dioxides has high anticancer potential and good aqueous solubility. Therefore, these compounds are promising for further drug development of hypoxia-targeted anticancer agents.
Assuntos
Antineoplásicos/farmacologia , Hipóxia Celular/efeitos dos fármacos , Descoberta de Drogas , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Nitrilas/farmacologia , Quinoxalinas/farmacologia , Receptores de Estrogênio/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Estrutura Molecular , Nitrilas/síntese química , Nitrilas/química , Quinoxalinas/síntese química , Quinoxalinas/química , Receptores de Estrogênio/metabolismo , Relação Estrutura-AtividadeRESUMO
Amphotericin B (AmB, 1) is the drug of choice for treating the most serious systemic fungal or protozoan infections. Nevertheless, its application is limited by low solubility in aqueous media and serious side effects such as infusion-related reactions, hemolytic toxicity, and nephrotoxicity. Owing to these limitations, it is essential to search for the polyene derivatives with better chemotherapeutic properties. With the objective of obtaining AmB derivatives with lower self-aggregation and improved solubility, we synthesized a series of amides of AmB bearing an additional basic group in the introduced residue. The screening of antifungal activity in vitro revealed that N-(2-aminoethyl)amide of AmB (amphamide, 6) had superior antifungal activity compared to that of the paternal AmB. Preclinical studies in mice confirmed that compound 6 had a much lower acute toxicity and higher antifungal efficacy in the model of mice candidosis sepsis compared with that of AmB (1). Thus, the discovered amphamide is a promising drug candidate for the second generation of polyene antibiotics and is also prospective for in-depth preclinical and clinical evaluation.
Assuntos
Antibacterianos , Preparações Farmacêuticas , Anfotericina B/farmacologia , Animais , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Camundongos , Polienos/farmacologia , Estudos ProspectivosRESUMO
A series of amides of the antifungal antibiotic amphotericin B (AmB) and its conjugates with benzoxaboroles was tested to determine whether they form pores in lipid bilayers and to compare their channel characteristics. The tested derivatives produced pores of larger amplitude and shorter lifetime than those of the parent antibiotic. The pore conductance was related to changes in the partial charge of the hydrogens of the hydroxyl groups in the lactone ring that determined the anion coordination in the channel. Neutralization of one of the polar group charges in the AmB head during chemical modification produced a pronounced effect by diminishing the dwell time of the polyene channel compared to modification of both groups. In this study, compounds that had a modification of one carboxyl or amino group were less effective in initializing phase separation in POPC-membranes compared to derivatives that had modifications of both polar groups as well as the parent antibiotic. The effects were attributed to the restriction of the aggregation process by electrical repulsion between charged derivatives in contrast to neutral compounds. The significant correlation between the ability of derivatives to increase the permeability of model membranes-causing the appearance of single channels in lipid bilayers or inducing calcein leakage from unilamellar vesicles-and the minimal inhibitory concentration indicated that the antifungal effect of the conjugates was due to pore formation in the membranes of target cells.
Assuntos
Anfotericina B/farmacologia , Antibacterianos/farmacologia , Anfotericina B/química , Antibacterianos/química , Fluoresceínas/química , Bicamadas Lipídicas/química , Microscopia de Fluorescência , Fosfatidilcolinas/químicaRESUMO
Triarylmethane derivatives are extensively investigated as antitumor and antibacterial drug candidates alone and as photoactivatable compounds. In the series of tris(1-alkylindol-3-yl)methylium salts (TIMs) these two activities differed depending on the length of N-alkyl chain, with C4-5 derivatives being the most potent compared to the shorter or longer chain analogs and to the natural compound turbomycin A (no N-substituent). Given that the human serum albumin (HSA) is a major transporter protein with which TIMs can form stable complexes, and that the formation of these complexes might be advantageous for phototoxicity of TIMs we determined the quantitative parameters of TIMs-HSA binding using spectroscopic methods and molecular docking. TIMs bound to HSA (1:1 stoichiometry) altered the protein's secondary structure by changing the α-helix/ß-turn ratio. The IIa subdomain (Sudlow site I) is the preferred TIM binding site in HSA as determined in competition experiments with reference drugs ibuprofen and warfarin. The values of binding constants increased with the number of CH2 groups from 0 to 6 and then dropped down for C10 compound, a dependence similar to the one observed for cytocidal potency of TIMs. We tend to attribute this non-linear dependence to an interplay between hydrophobicity and steric hindrance, the two key characteristics of TIMs-HSA complexes calculated in the molecular docking procedure. These structure-activity relationships provide evidence for rational design of TIMs-based antitumor and antimicrobial drugs.