RESUMO
By analyzing the crystal structure of NQO1, an additional binding region for the ligand was discovered. In this study, a series of derivatives with a novel skeleton bearing two nitrogen redox centers were designed by introducing amines or hydrazines to fit with the novel binding region of NQO1. Compound 24 with a (4-fluorophenyl)hydrazine substituent was identified as the most efficient substrate for NQO1 with the reduction rate and catalytic efficiency of 1972 ± 82 µmol NADPH/min/µmol NQO1 and 6.4 ± 0.4 × 106 M-1s-1, respectively. Molecular dynamics (MD) simulation revealed that the distances between the nitrogen atom of the redox centers and the key Tyr128 and Tyr126 residues were 3.5 Å (N1-Tyr128) and 3.4 Å (N2-Tyr126), respectively. Compound 24 (IC50/A549 = 0.69 ± 0.09 µM) showed potent antitumor activity against A549 cells both in vitro and in vivo through ROS generation via NQO1-mediated redox cycling, leading to a promising NQO1-targeting antitumor candidate.
Assuntos
Antineoplásicos , Naftoquinonas , Antineoplásicos/química , Simulação de Dinâmica Molecular , Linhagem Celular Tumoral , NAD(P)H Desidrogenase (Quinona)/metabolismo , Oxirredução , Naftoquinonas/químicaRESUMO
Prodrugs are one of the most common strategies for the design of targeted anticancer agents. However, their application is often hampered by the modifiable groups available on parent drugs. Herein, a carbon-carbon (C-C) bond cleavage-based prodrug activation strategy is reported, which was successfully used to design prodrugs of ß-lapachone (ß-lap), an ortho-quinone natural product without traditional modifiable groups for the construction of C-N/C-O bond cleavage-based prodrugs. The designed ß-lap prodrug with a reactive oxygen species-specific trigger was quickly activated, releasing ß-lap. It exerted anticancer efficacy via NAD(P)H:quinone oxidoreductase 1 (NQO1)-mediated futile redox cycling, resulting in potent cytotoxicity that was highly selective for NQO1-rich cancer cells over normal cells both in vitro and in vivo. This significantly amplified the therapeutic window of ß-lap. This study provides a practical strategy for the design of prodrugs for parent drugs that do not contain traditional modifiable groups.
Assuntos
Antineoplásicos , Produtos Biológicos , Naftoquinonas , Neoplasias , Pró-Fármacos , Antineoplásicos/química , Carbono , Linhagem Celular Tumoral , NAD , NAD(P)H Desidrogenase (Quinona) , Naftoquinonas/química , Neoplasias/tratamento farmacológico , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Espécies Reativas de OxigênioRESUMO
The main uric acid-lowering agents in clinical use for hyperuricemia and gout are xanthine oxidase (XO) inhibitors or urate transporter 1 (URAT1) inhibitors. While these therapies can partially control the disease, they have various limitations. The development of XO/URAT1 dual inhibitors offers the potential to enhance therapeutic potency and reduce toxicity compared with single-target inhibitors. Through scaffold hopping from the XO inhibitor febuxostat (2) and the URAT1 inhibitor probenecid (3), followed by structure-activity relationship (SAR) studies, we identified compound 27 as a potent dual inhibitor of XO and URAT1. Compound 27 demonstrated significant dual inhibition in vitro (XO IC50 = 35 nM; URAT1 IC50 = 31 nM) and exhibited favorable pharmacology and pharmacokinetic (PK) profiles in multiple species including monkeys. Furthermore, toxicity studies in rats and monkeys revealed general safety profiles, supporting that compound 27 emerges as a promising novel drug candidate with potent XO/URAT1 dual inhibition for the treatment of gout.
RESUMO
Elevated levels of reactive oxygen species (ROS) have commonly been implicated in a variety of diseases, including cancer, inflammation, and neurodegenerative diseases. In light of significant differences in ROS levels between the nonpathogenic and pathological tissues, an increasing number of ROS-responsive prodrugs, probes, and theranostic prodrugs have been developed for the targeted treatment and precise diagnosis of ROS-related diseases. This review will summarize and provide insight into recent advances in ROS-responsive prodrugs, fluorescent probes, and theranostic prodrugs, with applications to different ROS-related diseases and various subcellular organelle-targetable and disease-targetable features. The ROS-responsive moieties, the self-immolative linkers, and the typical activation mechanism for the ROS-responsive release are also summarized and discussed.
Assuntos
Sondas Moleculares/metabolismo , Medicina de Precisão , Pró-Fármacos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , HumanosRESUMO
ß-Lapachone (ß-lap, 1), an ortho-naphthoquinone natural product isolated from the lapacho tree (Tabebuia avellanedae) in many regions of South America, has received extensive attention due to various pharmacological activities, such as antitumor, anti-Trypanosoma cruzi, anti-Mycobacterium tuberculosis, antibacterial, and antimalarial activities. Related mechanisms of ß-lap have been widely investigated for a full understanding of its therapeutic potentials. Numerous derivatives of ß-lap have been reported with aims to generate new chemical entities, improve the corresponding biological potency, and overcome disadvantages of its physical and chemical properties and safety profiles. This review will give insight into the pharmacological mechanisms of ß-lap and provide a comprehensive understanding of its structural modifications with regard to different therapeutic potentials. The available clinical trials related to ß-lap and its derivatives are also summarized.
Assuntos
Naftoquinonas/química , Naftoquinonas/farmacologia , Tabebuia/química , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Descoberta de Drogas , Humanos , Naftoquinonas/uso terapêutico , Neoplasias/tratamento farmacológicoRESUMO
Since NQO1 is overexpressed in many cancer cells, it can be used as a biomarker for cancer diagnosis and targeted therapy. NQO1 substrates show potent anticancer activity through the redox cycle mediated by NQO1, while the NQO1 probes can monitor NQO1 levels in cancers. High sensitivity of probes is needed for diagnostic imaging in clinic. In this study, based on the analysis of NQO1 catalytic pocket, the naphthoquinone trigger group 13 rationally designed by expanding the aromatic plane of the benzoquinone trigger group 10 shows significantly increased sensitivity to NQO1. The sensitivity of the naphthoquinone trigger group-based probe A was eight times higher than that of benzoquinone trigger group-based probe B in vivo. Probe A was selectively and efficiently sensitive to NQO1 with good safety profile and plasma stability, enabling its combination with NQO1 substrates in vivo for NQO1-overexpressing cancer theranostics for the first time.
Assuntos
Antineoplásicos/química , Desenho de Fármacos , Corantes Fluorescentes/química , NAD(P)H Desidrogenase (Quinona)/metabolismo , Naftoquinonas/química , Nanomedicina Teranóstica , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzoquinonas/química , Benzoquinonas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , NAD(P)H Desidrogenase (Quinona)/genética , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Imagem Óptica , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Cation-π interaction is a type of noncovalent interaction formed between the π-electron system and the positively charged ion or moieties. In this study, we designed a series of novel NQO1 substrates by introducing aliphatic nitrogen-containing side chains to fit with the L-shaped pocket of NQO1 by the formation of cation-π interactions. Molecular dynamics (MD) simulation indicated that the basic N atom in the side chain of NQO1 substrates, which is prone to be protonated under physiological conditions, can form cation-π interactions with the Phe232 and Phe236 residues of the NQO1 enzyme. Compound 4 with a methylpiperazinyl substituent was identified as the most efficient substrate for NQO1 with the reduction rate and catalytic efficiency of 1263 ± 61 µmol NADPH/min/µmol NQO1 and 2.8 ± 0.3 × 106 M-1s-1, respectively. Notably, compound 4 exhibited increased water solubility (110 µg/mL) compared to that of ß-lap (43 µg/mL), especially under acidic condition (pH = 3, solubility > 1000 µg/mL). Compound 4 (IC50/A549 = 2.4 ± 0.6 µM) showed potent antitumor activity against NQO1-rich cancer cells through ROS generation via NQO1-mediated redox cycling. These results emphasized that the application of cation-π interactions by introducing basic aliphatic amine moiety is beneficial for both the water solubility and the NQO1-substrate binding, leading to promising NQO1-targeting antitumor candidates with improved druglike properties.