RESUMO
Sulfur-containing heterocyclic derivatives have been disclosed for binding with a wide range of cancer-specific protein targets. Various interesting derivatives of sulfur-containing heterocyclics such as benzothiazole, thiazole, thiophene, thiazolidinedione, benzothiophene, and phenothiazine, etc have been shown to inhibit diverse signaling pathways implicated in cancer. Significant progress has also been made in molecular targeted therapy against specific enzymes such as kinase receptors due to potential binding interactions inside the ATP pocket. Sulfur-containing heterocyclic ring metal complexes i. e., benzothiazole, thiazole, thiophene, benzothiophene and phenothiazines are among the most promising active anticancer compounds. However, sulfur heteroaromatic rings, particularly thiophene, are of high structural alert due to their metabolism to reactive metabolites. The mere presence of a structural alert itself does not determine compound toxicity therefore, this review focuses on some specific findings that shed light on factors influencing the toxicity. In the current review, synthetic strategies of introducing the sulfur core ring in the synthesized derivatives are discussed with their structure-activity relationships to enhance our understanding of toxicity mechanisms and develop safer therapeutic options. The sulfur-containing marketed anticancer drugs included in this review direct the synthesis of novel compounds and will help in the development of potent, safer sulfur-based anticancer drugs in near future.
Assuntos
Antineoplásicos , Compostos Heterocíclicos , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/metabolismo , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologia , Tiofenos/metabolismo , Tiofenos/síntese química , Benzotiazóis/química , Benzotiazóis/metabolismo , Benzotiazóis/farmacologiaRESUMO
Mangroves are of important economic and environmental value and research suggests that their carbon sequestration and climate change mitigation potential is significantly larger than other forests. However, increasing salinity and heavy metal pollution significantly affect mangrove ecosystem function and productivity. This study investigates the tolerance mechanisms of rhizobacteria in the rhizosphere of Avicennia marina under salinity and copper (Cu) stress during a 4-y stress period. The results exhibited significant differences in antioxidant levels, transcripts, and secondary metabolites. Under salt stress, the differentially expressed metabolites consisted of 30% organic acids, 26.78% nucleotides, 16.67% organic heterocyclic compounds, and 10% organic oxides as opposed to 27.27% organic acids, 24.24% nucleotides, 15.15% organic heterocyclic compounds, and 12.12% phenyl propane and polyketides under Cu stress. This resulted in differential regulation of metabolic pathways, with phenylpropanoid biosynthesis being unique to Cu stress and alanine/aspartate/glutamate metabolism and α-linolenic acid metabolism being unique to salt stress. The regulation of metabolic pathways enhanced antioxidant defenses, nutrient recycling, accumulation of osmoprotectants, stability of plasma membrane, and chelation of Cu, thereby improving the stress tolerance of rhizobacteria and A. marina. Even though the abundance and community structure of rhizobacteria were significantly changed, all the samples were dominated by Proteobacteria, Chloroflexi, Actinobacteriota, and Firmicutes. Since the response mechanisms were unbalanced between treatments, this led to differential growth trends for A. marina. Our study provides valuable inside on variations in diversity and composition of bacterial community structure from mangrove rhizosphere subjected to long-term salt and Cu stress. It also clarifies rhizobacterial adaptive mechanisms to these stresses and how they are important for mitigating abiotic stress and promoting plant growth. Therefore, this study can serve as a reference for future research aimed at developing long-term management practices for mangrove forests.
Assuntos
Avicennia , Compostos Heterocíclicos , Cobre/toxicidade , Cobre/metabolismo , Ecossistema , Avicennia/metabolismo , Solo , Antioxidantes/metabolismo , Multiômica , Estresse Salino , Nucleotídeos/metabolismo , Compostos Heterocíclicos/metabolismoRESUMO
Objective Several institutions outsource CD34+ cell counting of leukapheresis products, limiting rapid measurements, as results are obtained the next day. This problem is compounded with plerixafor use, a stem cell-mobilizing drug that increases leukapheresis efficiency but requires administration the day before leukapheresis. Use of this drug for a second leukapheresis procedure before the first-day leukapheresis CD34+ count results are confirmed causes unnecessary leukapheresis and expensive plerixafor administration. We investigated whether or not measuring hematopoietic progenitor cells in leukapheresis products (AP-HPCs) using a Sysmex XN-series analyzer could resolve this problem. Methods We retrospectively compared the absolute AP-HPC value per body weight with the CD34+ (AP-CD34+) count in 96 first-day leukapheresis product samples obtained between September 2013 and January 2021. Comparisons were also conducted according to regimen: granulocyte colony-stimulating factor (G-CSF) monotherapy, chemotherapy plus G-CSF, or plerixafor mobilization. Results AP-CD34+ and AP-HPC counts correlated strongly (rs=0.846) overall and, in particular, under chemotherapy plus G-CSF (rs=0.92) but correlated mildly under G-CSF monotherapy (rs=0.655). AP-HPCs could not completely be dichotomized based on an AP-CD34+ threshold of 2×106/kg for any stimulation procedure. In most cases with AP-HPCs >6×106/kg, the AP-CD34+ count exceeded 2.0×106/kg, but in 5.7% of these cases, the AP-CD34+ count was <2.0×106/kg. A cut-off of AP-HPCs >4.843×106/kg yielded a sensitivity of 71% and specificity of 96% for predicting AP-CD34+≥2×106/kg. Conclusion AP-HPCs can identify cases in which sufficient stem cells have been collected.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Compostos Heterocíclicos , Transplante de Células-Tronco de Sangue Periférico , Células-Tronco de Sangue Periférico , Humanos , Leucaférese , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco de Sangue Periférico/metabolismo , Estudos Retrospectivos , Transplante Autólogo , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Antígenos CD34/metabolismo , Fator Estimulador de Colônias de Granulócitos/metabolismoRESUMO
Heterocyclic amines (HCAs) are mutagenic compounds found in cooked meat. Recent epidemiological studies reported significant associations between dietary HCA exposure and insulin resistance and type II diabetes, and we recently reported that HCAs induce insulin resistance and glucose production in human hepatocytes. It is well known that HCAs require hepatic bioactivation by cytochrome P450 1A2 (CYP1A2) and N-acetyltransferase 2 (NAT2). NAT2 expresses a well-defined genetic polymorphism in humans that, depending on the combination of NAT2 alleles, correlates to rapid, intermediate, or slow acetylator phenotype that exhibits differential metabolism of aromatic amines and HCAs. No previous studies have examined the role of NAT2 genetic polymorphism in the context of HCA-mediated induction of glucose production. In the present study, we assessed the effect of three HCAs commonly found in cooked meat (2-amino-3,4-dimethylimidazo[4,5-f]quinoline [MeIQ], 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline [MeIQx], and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine [PhIP]) on glucose production in cryopreserved human hepatocytes with slow, intermediate, or rapid NAT2 acetylator phenotype. HCA treatment did not affect glucose production in slow NAT2 acetylator hepatocytes, while a slight increase in glucose production was observed in intermediate NAT2 acetylators treated with MeIQ or MeIQx. However, significant increases in glucose production were observed in rapid NAT2 acetylators following each HCA. The current findings suggest that individuals who are rapid NAT2 acetylators may be at a greater risk of developing hyperglycemia and insulin resistance following dietary exposure to HCAs.
Assuntos
Aminas , Arilamina N-Acetiltransferase , Diabetes Mellitus Tipo 2 , Compostos Heterocíclicos , Resistência à Insulina , Humanos , Acetiltransferases/genética , Acetiltransferases/metabolismo , Aminas/toxicidade , Aminas/metabolismo , Arilamina N-Acetiltransferase/genética , Arilamina N-Acetiltransferase/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Hepatócitos/metabolismo , Compostos Heterocíclicos/metabolismo , Polimorfismo GenéticoRESUMO
Microbial consortia HY3 and JY3 with high degradation efficiency of 2-Diethylamino-4-hydroxy-6-methylpyrimidine (DHMP) were isolated from aerobic and parthenogenic ponds of DHMP-containing pharmaceutical wastewater, respectively. Both consortia were enriched and reached stable degradation performance with a DHMP concentration of 1500 mg L-1. The DHMP degradation efficiencies of HY3 and JY3 were 95.66% ± 0.24% and 92.16% ± 2.34% under the condition of shaking at 180 r·min-1 and the temperature of 30 °C for 72 h. And the removal efficiencies of chemical oxygen demand were 89.14% ± 4.78% and 80.30% ± 11.74%, respectively. High-throughput sequencing results indicated that three bacterial phyla of Proteobacteria, Bacteroidetes, and Actinobacteria were dominant in both HY3 and JY3, but their dominances varied. At the genus level, the richness of Unclassified Comamonadaceae (34.23%), Paracoccus (14.75%), and Brevundimonas (13.94%) ranked top three in HY3 whereas Unclassified Comamonadaceae (40.80%), Unclassified Burkholderiales (13.81%) and Delftia (13.11%) were dominant in JY3. The metabolites of DHMP degradation by HY3 and JY3 were analyzed in detail. Two pathways for cleavage of the nitrogenous heterocyclic ring were speculated, one of which was identified for the first time in this study.
Assuntos
Compostos Heterocíclicos , Águas Residuárias , Consórcios Microbianos , Bactérias , Compostos Heterocíclicos/metabolismo , Preparações Farmacêuticas/metabolismo , Reatores Biológicos/microbiologiaRESUMO
BACKGROUND: The unpredictable and unstable tissue retention rate of autologous fat grafting remains an obstacle faced by plastic surgeons. The authors' previous study using a fat grafting mouse model with donor sites showed that adipose-derived stem cell (ASC) infiltration in the recipient site was delayed, leading to poor regeneration and lower retention. Thus, the mechanism behind the differential infiltration of ASCs needed to be explored. METHODS: First, the authors locally injected C-X-C chemokine ligand 12 (CXCL12) or C-X-C motif chemokine receptor 4 (CXCR4) inhibitor AMD3100 in the recipient or donor site, respectively (CXCL12 + AMD3100 - , CXCL12 - AMD3100 + , and CXCL12 + AMD3100 + groups). The authors compared the migration of ASCs, adipose regeneration, and long-term retention. Next, the authors explored the role of angiogenesis using a normal/ischemic mice model in which the authors test the expression of CXCL12/CXCR4, migration of ASCs, and adipose regeneration. RESULTS: Blocking CXCL12 in the donor site using AMD3100 (CXCL12 - AMD3100 + and CXCL12+AMD3100+ groups) could accelerate ASC infiltration and promote adipose regeneration and long-term retention ( P < 0.05) compared with the other groups. CXCL12 and its receptor CXCR4 were more highly expressed in normal than in ischemic adipose tissue; consistently, there were more ASCs infiltrating normal than ischemic adipose tissue early after surgery ( P < 0.05). CONCLUSION: Early angiogenesis is essential for CXCL12 in promoting ASC infiltration, improving adipose tissue repair in the recipient site, and potentiating the long-term fat retention rate. CLINICAL RELEVANCE STATEMENT: The authors provide a proof-of-concept way to improve the outcomes of fat grafting by locally injecting AMD3100, also known as plerixafor, to the donor site.
Assuntos
Mobilização de Células-Tronco Hematopoéticas , Compostos Heterocíclicos , Animais , Camundongos , Tecido Adiposo/metabolismo , Quimiocina CXCL12/metabolismo , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/metabolismo , Ligantes , Células-Tronco/metabolismoRESUMO
INTRODUCTION: Although plerixafor in association with granulocyte colony-stimulating factor (G-CSF) can improve mobilization and collection of hematopoietic stem cells (HSC) by leukapheresis, cost may limit its clinical application. The present study systematically reviews economic evaluations of plerixafor plus G-CSF usage compared to G-CSF alone and compares different strategies of plerixafor utilization in multiple myeloma and lymphoma patients eligible for autologous HSC transplantation. AREAS COVERED: Relevant economic evaluations, partial or complete, were searched on PubMed, Embase, LILACS, and Cochrane Central Register of Controlled Trials for a period ending 30 June 2021. This systematic review was reported following the PRISMA Statement. Six economic evaluations were included, considering the use of upfront or just-in-time plerixafor compared to G-CSF alone or other plerixafor strategies. Most comparisons showed both increased cost and health benefits with the addition of plerixafor. Most analyses favored just-in-time plerixafor compared to upfront plerixafor, with a probable preference for broader cutoffs for just-in-time plerixafor initiation. EXPERT OPINION: Plerixafor is a potentially cost-effective technology in the mobilization of HSC in patients with multiple myeloma and lymphomas eligible for autologous HSC transplantation. There is a decreased number of leukapheresis sessions and remobilizations and a higher yield of CD34+ cells.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Compostos Heterocíclicos , Linfoma , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/terapia , Mobilização de Células-Tronco Hematopoéticas , Leucaférese , Análise Custo-Benefício , Transplante Autólogo , Compostos Heterocíclicos/metabolismo , Linfoma/terapia , Linfoma/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Fator Estimulador de Colônias de Granulócitos , Benzilaminas/metabolismoRESUMO
Covering: 2015 to 2020Nitrogen heterocyclic natural products (NHNPs) are primary or secondary metabolites containing nitrogen heterocyclic (N-heterocyclic) skeletons. Due to the existence of the N-heterocyclic structure, NHNPs exhibit various bioactivities such as anticancer and antibacterial, which makes them widely used in medicines, pesticides, and food additives. However, the low content of these NHNPs in native organisms severely restricts their commercial application. Although a variety of NHNPs have been produced through extraction or chemical synthesis strategies, these methods suffer from several problems. The development of biotechnology provides new options for the production of NHNPs. This review introduces the recent progress of two strategies for the biosynthesis of NHNPs: enzymatic biosynthesis and microbial cell factory. In the enzymatic biosynthesis part, the recent progress in the mining of enzymes that synthesize N-heterocyclic skeletons (e.g., pyrrole, piperidine, diketopiperazine, and isoquinoline), the engineering of tailoring enzymes, and enzyme cascades constructed to synthesize NHNPs are discussed. In the microbial cell factory part, with tropane alkaloids (TAs) and tetrahydroisoquinoline (THIQ) alkaloids as the representative compounds, the strategies of unraveling unknown natural biosynthesis pathways of NHNPs in plants are summarized, and various metabolic engineering strategies to enhance their production in microbes are introduced. Ultimately, future perspectives for accelerating the biosynthesis of NHNPs are discussed.
Assuntos
Compostos Heterocíclicos/metabolismo , Engenharia Metabólica/métodos , Compostos de Nitrogênio/metabolismo , Redes e Vias MetabólicasRESUMO
The pandemic infectious disease (Covid-19) caused by the coronavirus (SARS-CoV2) is spreading rapidly around the world. Covid-19 does an irreparable harm to the health and life of people. It also has a negative financial impact on the economies of most countries of the world. In this regard, the issue of creating drugs aimed at combating this disease is especially acute. In this work, molecular docking was used to study the docking of 23 compounds with QRF3a SARS-CoV2. The performed in silico modeling made it possible to identify leading compounds capable of exerting a potential inhibitory and virucidal effect. The leading compounds include chlorin (a drug used in PDT), iron(III)protoporphyrin (endogenous porphyrin), and tetraanthraquinone porphyrazine (an exogenous substance). Having taken into consideration the localization of ligands in the QRF3a SARS-CoV2, we have made an assumption about their influence on the pathogenesis of Covid-19. The interaction of chlorin, iron(III)protoporphyrin and protoporphyrin with the viral protein ORF3a were studied by fluorescence and UV-Vis spectroscopy. The obtained experimental results confirm the data of molecular docking. The results showed that a viral protein binds to endogenous porphyrins and chlorins, moreover, chlorin is a competitive ligand for endogenous porphyrins. Chlorin should be considered as a promising drug for repurposing.
Assuntos
Antivirais/química , Antivirais/metabolismo , Compostos Heterocíclicos/química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/metabolismo , Proteínas Viroporinas/química , Proteínas Viroporinas/metabolismo , Sítios de Ligação , Reposicionamento de Medicamentos , Compostos Heterocíclicos/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Porfirinas/química , Porfirinas/metabolismo , Protoporfirinas/química , Protoporfirinas/metabolismo , SARS-CoV-2/efeitos dos fármacos , Proteínas Viroporinas/antagonistas & inibidores , Tratamento Farmacológico da COVID-19RESUMO
Heterocyclic aromatic amines (HAAs) including PhIP and MeIQx are potential carcinogens found mainly in well-done meat. Consuming brassica vegetables was shown to promote metabolisms of HAAs due to the action of isothiocyanates. Previous in vivo studies showed that phenethyl isothiocyanate (PEITC) was a potent stimulator of phase II detoxification enzymes. Nevertheless, the clinical effect of PEITC-rich vegetables on detoxification of HAAs in grilled meat was unknown. This research aimed to investigate the effect of a PEITC-rich vegetable sauce on the detoxification of HAAs in healthy people consuming grilled meat. A randomized crossover placebo-controlled trial was conducted in twenty-one healthy participants. They were randomly assigned into three groups. The participants consumed a single meal of grilled beef with 100 g of the placebo sauce and 100 g and 50 g of the vegetable sauce. All participants consumed all sauces in an alternating random sequence. After de-conjugation with ß-glucuronidase, the HAA metabolites in urine were measured by using LC/MS-MS. Compared to the placebo sauce, consuming grilled beef with 100 g of the vegetable sauce increased the urinary excretion of both PhIP and MeIQx glucuronide metabolites (p-value <0.0001), while consuming 50 g of the sauce significantly increased only MeIQx metabolites (p-value <0.05). The findings of this study suggested that consuming grilled meat with 100 g of the PEITC-rich vegetable sauce could increase the urinary excretion of PhIP and MeIQx glucuronide metabolites. Since meat eaters usually consume a low amount of vegetables, the PEITC-rich vegetable sauce could be an alternative approach to provide detoxification benefits from vegetable-derived compounds.
Assuntos
Brassica/metabolismo , Culinária/métodos , Compostos Heterocíclicos/metabolismo , Isotiocianatos/farmacologia , Carne , Verduras/metabolismo , Adulto , Estudos Cross-Over , Feminino , Humanos , Isotiocianatos/metabolismo , Masculino , Pessoa de Meia-Idade , Valores de Referência , Método Simples-Cego , Adulto JovemRESUMO
Toll-like receptors (TLRs) are members of a large family of evolutionarily conserved pattern recognition receptors (PRRs), which serve as key components of the innate immune system by playing a pivotal role in sensing "nonself" ligands. Endosomal TLRs (TLR3, TLR7, TLR8, and TLR9) can recognize pathogen-derived nucleic acid and initiate an innate immune response because they react against both self- and non-self-origin nucleic acid molecules. Accordingly, both receptor agonists and antagonists are potentially useful in disparate clinical contexts and thus are globally sought after. Recent research has revealed that agonists and antagonists share an overlapping binding region. This Perspective highlights rational medicinal chemistry approaches to elucidate the structural attributes of small molecules capable of agonism or antagonism or of elegantly switching between the two. The structural evolution of different chemotypes can provide the framework for the future development of endosomal TLR agonists and antagonists.
Assuntos
Compostos Heterocíclicos/química , Receptores Toll-Like/agonistas , Receptores Toll-Like/antagonistas & inibidores , Animais , Endossomos/química , Células HEK293 , Compostos Heterocíclicos/metabolismo , Compostos Heterocíclicos/farmacologia , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Receptores Toll-Like/metabolismoRESUMO
Aldehyde oxidase (AOX) is a soluble, cytosolic enzyme that metabolizes various N-heterocyclic compounds and organic aldehydes. It has wide tissue distribution with highest levels found in liver, kidney, and lung. Human clearance projections of AOX substrates by in vitro assessments in isolated liver fractions (cytosol, S9) and even hepatocytes have been largely underpredictive of clinical outcomes. Various hypotheses have been suggested as to why this is the case. One explanation is that extrahepatic AOX expression contributes measurably to AOX clearance and is at least partially responsible for the often observed underpredictions. Although AOX expression has been confirmed in several extrahepatic tissues, activities therein and potential contribution to overall human clearance have not been thoroughly studied. In this work, the AOX enzyme activity using the S9 fractions of select extrahepatic human tissues (kidney, lung, vasculature, and intestine) were measured using carbazeran as a probe substrate. Measured activities were scaled to a whole-body clearance using best-available parameters and compared with liver S9 fractions. Here, the combined scaled AOX clearance obtained from the kidney, lung, vasculature, and intestine is very low and amounted to <1% of liver. This work suggests that AOX metabolism from extrahepatic sources plays little role in the underprediction of activity in human. One of the notable outcomes of this work has been the first direct demonstration of AOX activity in human vasculature. SIGNIFICANCE STATEMENT: This work demonstrates aldehyde oxidase (AOX) activity is measurable in a variety of extrahepatic human tissues, including vasculature, yet activities and potential contributions to human clearance are relatively low and insignificant when compared with the liver. Additionally, the modeling of the tissue-specific in vitro kinetic data suggests that AOX may be influenced by the tissue it resides in and thus show different affinity, activity, and modified activity over time.
Assuntos
Aldeído Oxidase/metabolismo , Vasos Sanguíneos/enzimologia , Intestinos/enzimologia , Rim/enzimologia , Pulmão/enzimologia , Aldeídos/metabolismo , Correlação de Dados , Ensaios Enzimáticos/métodos , Compostos Heterocíclicos/metabolismo , Humanos , Fígado/enzimologia , Taxa de Depuração Metabólica , Distribuição Tecidual/fisiologiaRESUMO
Screening of a library of small polar molecules against Mycobacterium tuberculosis (Mtb) led to the identification of a potent benzoheterocyclic oxime carbamate hit series. This series was subjected to medicinal chemistry progression underpinned by structure-activity relationship studies toward identifying a compound for proof-of-concept studies and defining a lead optimization strategy. Carbamate and free oxime frontrunner compounds with good stability in liver microsomes and no hERG channel inhibition liability were identified and evaluated in vivo for pharmacokinetic properties. Mtb-mediated permeation and metabolism studies revealed that the carbamates were acting as prodrugs. Toward mechanism of action elucidation, selected compounds were tested in biology triage assays to assess their activity against known promiscuous targets. Taken together, these data suggest a novel yet unknown mode of action for these antitubercular hits.
Assuntos
Antituberculosos/farmacologia , Carbamatos/farmacologia , Compostos Heterocíclicos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Oximas/farmacologia , Antituberculosos/química , Antituberculosos/metabolismo , Carbamatos/química , Carbamatos/metabolismo , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/química , Compostos Heterocíclicos/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/metabolismo , Oximas/química , Oximas/metabolismo , Relação Estrutura-AtividadeRESUMO
Breast cancer, emerging malignancy is common among women due to overexpression of estrogen. Estrogens are biosynthesized from androgens by aromatase, a cytochrome P450 enzyme complex, and play a pivotal role in stimulating cell proliferation. Therefore, deprivation of estrogen by blocking aromatase is considered as the effective way for the inhibition and treatment of breast cancer. In recent years, various non-steroidal heterocyclic functionalities have been extensively developed and studied for their aromatase inhibition activity. This review provides information about the structural-activity relationship of heterocycles (Type II) towards aromatase. This aids the medicinal chemist around the significance of different heterocyclic moieties and helps to design potent aromatase inhibitors.
Assuntos
Inibidores da Aromatase/química , Aromatase/metabolismo , Compostos Heterocíclicos/química , Aromatase/química , Inibidores da Aromatase/metabolismo , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Desenho de Fármacos , Estrogênios/metabolismo , Feminino , Compostos Heterocíclicos/metabolismo , Compostos Heterocíclicos/uso terapêutico , Humanos , Relação Estrutura-AtividadeRESUMO
Aromatic and heteroaromatic amines (ArNH2) are activated by cytochrome P450 monooxygenases, primarily CYP1A2, into reactive N-arylhydroxylamines that can lead to covalent adducts with DNA nucleobases. Hereby, we give hands-on mechanism-based guidelines to design mutagenicity-free ArNH2. The mechanism of N-hydroxylation of ArNH2 by CYP1A2 is investigated by density functional theory (DFT) calculations. Two putative pathways are considered, the radicaloid route that goes via the classical ferryl-oxo oxidant and an alternative anionic pathway through Fenton-like oxidation by ferriheme-bound H2O2. Results suggest that bioactivation of ArNH2 follows the anionic pathway. We demonstrate that H-bonding and/or geometric fit of ArNH2 to CYP1A2 as well as feasibility of both proton abstraction by the ferriheme-peroxo base and heterolytic cleavage of arylhydroxylamines render molecules mutagenic. Mutagenicity of ArNH2 can be removed by structural alterations that disrupt geometric and/or electrostatic fit to CYP1A2, decrease the acidity of the NH2 group, destabilize arylnitrenium ions, or disrupt their pre-covalent transition states with guanine.
Assuntos
Aminas/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Compostos Heterocíclicos/metabolismo , Hidrocarbonetos Aromáticos/metabolismo , Mutagênicos/metabolismo , Aminas/química , Domínio Catalítico , Cristalografia por Raios X , Citocromo P-450 CYP1A2/química , Teoria da Densidade Funcional , Análise Discriminante , Compostos Heterocíclicos/química , Humanos , Hidrocarbonetos Aromáticos/química , Hidroxilação , Análise dos Mínimos Quadrados , Modelos Químicos , Estrutura Molecular , Mutagênicos/química , Ligação ProteicaRESUMO
Linear nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) template the modular biosynthesis of numerous nonribosomal peptides, polyketides and their hybrids through assembly line chemistry. This chemistry can be complex and highly varied, and thus challenges our understanding in NRPS and PKS-programmed, diverse biosynthetic processes using amino acid and carboxylate building blocks. Here, we report that caerulomycin and collismycin peptide-polyketide hybrid antibiotics share an assembly line that involves unusual NRPS activity to engage a trans-acting flavoprotein in C-C bond formation and heterocyclization during 2,2'-bipyridine formation. Simultaneously, this assembly line provides dethiolated and thiolated 2,2'-bipyridine intermediates through differential treatment of the sulfhydryl group arising from L-cysteine incorporation. Subsequent L-leucine extension, which does not contribute any atoms to either caerulomycins or collismycins, plays a key role in sulfur fate determination by selectively advancing one of the two 2,2'-bipyridine intermediates down a path to the final products with or without sulfur decoration. These findings further the appreciation of assembly line chemistry and will facilitate the development of related molecules using synthetic biology approaches.
Assuntos
2,2'-Dipiridil/análogos & derivados , 2,2'-Dipiridil/química , Flavoproteínas/química , 2,2'-Dipiridil/síntese química , 2,2'-Dipiridil/metabolismo , Antibacterianos/química , Antibacterianos/metabolismo , Cisteína/química , Cisteína/metabolismo , Flavoproteínas/metabolismo , Compostos Heterocíclicos/química , Compostos Heterocíclicos/metabolismo , Modelos Químicos , Estrutura Molecular , Peptídeo Sintases/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Policetídeo Sintases/metabolismo , Policetídeos/química , Policetídeos/metabolismo , Compostos de Sulfidrila/química , Compostos de Sulfidrila/metabolismoRESUMO
Natural [4 + 2]-cyclases catalyze concerted cycloaddition during biosynthesis of over 400 natural products reported. Microbial [4 + 2]-cyclases are structurally diverse with a broad range of substrates. Thus far, about 52 putative microbial [4 + 2]-cyclases of 13 different types have been characterized, with over 20 crystal structures. However, how these cyclases have evolved during natural product biosynthesis remains elusive. Structural and phylogenetic analyses suggest that these different types of [4 + 2]-cyclases might have diverse evolutionary origins, such as reductases, dehydratases, methyltransferases, oxidases, etc. Divergent evolution of enzyme function might have occurred in these different families. Understanding the independent evolutionary history of these cyclases would provide new insights into their catalysis mechanisms and the biocatalyst design.
Assuntos
Proteínas de Bactérias/genética , Evolução Molecular , Compostos Heterocíclicos/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Sequência Conservada , Isomerases/química , Isomerases/genética , Isomerases/metabolismo , Ligases/química , Ligases/genética , Ligases/metabolismo , Oxirredutases/química , Oxirredutases/genética , Oxirredutases/metabolismo , Homologia de SequênciaAssuntos
Antivirais/química , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Cisteína Proteinase/química , SARS-CoV-2/química , Antivirais/metabolismo , Proteases 3C de Coronavírus/metabolismo , Inibidores de Cisteína Proteinase/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ensaios Enzimáticos , Compostos Heterocíclicos/química , Compostos Heterocíclicos/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismoRESUMO
The aim of this research was to investigate the effect of the number of freeze-thaw cycles (0, 1, 3, 5, and 7) on porcine longissimus protein and lipid oxidation, as well as changes in heterocyclic aromatic amines (HAAs) and advanced glycation end products (AGEs) and their precursors. We analyzed the relationship among HAAs, AGEs, oxidation, and precursors and found the following results after seven freeze-thaw cycles. The HAAs, Norharman and Harman, were 20.33% and 16.67% higher, respectively. The AGEs, Nε-carboxyethyllysine (CEL) and Nε-carboxymethyllysine (CML), were 11.81% and 14.02% higher, respectively. Glucose, creatine, and creatinine were reduced by 33.92%, 5.93%, and 1.12%, respectively after seven freeze-thaw cycles. Norharman was significantly correlated with thiobarbituric acid reactive substances (TBARS; r2 = 0.910) and glucose (r2 = -0.914). Harman was significantly correlated to TBARS (r2 = 0.951), carbonyl (r2 = 0.990), and glucose (r2 = -0.920). CEL was correlated to TBARS (r2 = 0.992) and carbonyl (r2 = 0.933). These changes suggest that oxidation and the Maillard reaction during freeze-thaw cycles promote HAA and AGE production in raw pork.
Assuntos
Tecido Adiposo/metabolismo , Aminas/metabolismo , Compostos Heterocíclicos/metabolismo , Proteínas/metabolismo , Aminas/química , Animais , Galinhas , Culinária , Congelamento/efeitos adversos , Compostos Heterocíclicos/química , Humanos , Reação de Maillard , Carne/análise , Oxirredução , Carne de Porco/análise , Suínos , Substâncias Reativas com Ácido Tiobarbitúrico/química , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Biodegradation of aromatic and heterocyclic compounds requires an oxidative ring cleavage enzymatic step. Extensive biochemical research has yielded mechanistic insights about catabolism of aromatic substrates; yet much less is known about the reaction mechanisms underlying the cleavage of heterocyclic compounds such as pyridine-ring-containing ones like 2,5-hydroxy-pyridine (DHP). 2,5-Dihydroxypyridine dioxygenase (NicX) from Pseudomonas putida KT2440 uses a mononuclear nonheme Fe(II) to catalyze the oxidative pyridine ring cleavage reaction by transforming DHP into N-formylmaleamic acid (NFM). Herein, we report a crystal structure for the resting form of NicX, as well as a complex structure wherein DHP and NFM are trapped in different subunits. The resting state structure displays an octahedral coordination for Fe(II) with two histidine residues (His265 and His318), a serine residue (Ser302), a carboxylate ligand (Asp320), and two water molecules. DHP does not bind as a ligand to Fe(II), yet its interactions with Leu104 and His105 function to guide and stabilize the substrate to the appropriate position to initiate the reaction. Additionally, combined structural and computational analyses lend support to an apical dioxygen catalytic mechanism. Our study thus deepens understanding of non-heme Fe(II) dioxygenases.