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1.
Curr Top Med Chem ; 19(9): 691-712, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30931858

RESUMO

Nitrogen mustards, a family of DNA alkylating agents, marked the start of cancer pharmacotherapy. While traditionally characterized by their dose-limiting toxic effects, nitrogen mustards have been the subject of intense research efforts, which have led to safer and more effective agents. Even though the alkylating prodrug mustards were first developed decades ago, active research on ways to improve their selectivity and cytotoxic efficacy is a currently active topic of research. This review addresses the historical development of the nitrogen mustards, outlining their mechanism of action, and discussing the improvements on their therapeutic profile made through rational structure modifications. A special emphasis is made on discussing the nitrogen mustard prodrug category, with Cyclophosphamide (CPA) serving as the main highlight. Selected insights on the latest developments on nitrogen mustards are then provided, limiting such information to agents that preserve the original nitrogen mustard mechanism as their primary mode of action. Additionally, future trends that might follow in the quest to optimize these invaluable chemotherapeutic medications are succinctly suggested.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Compostos de Mostarda Nitrogenada/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Humanos , Estrutura Molecular , Neoplasias/patologia , Compostos de Mostarda Nitrogenada/síntese química , Compostos de Mostarda Nitrogenada/química
2.
Anticancer Agents Med Chem ; 19(9): 1080-1102, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30834842

RESUMO

BACKGROUND & OBJECTIVE: Nitrogen mustard derivatives form one of the major classes of anti-cancer agents in USFDA approved drugs list. These are polyfunctional alkylating agents which are distinguished by a unique mechanism of adduct formation with DNA involving cross-linking between guanine N-7 of one strand of DNA with the other. The generated cross-linking is irreversible and leads to cell apoptosis. Hence it is of great interest to explore this class of anticancer alkylating agents. METHODS: An exhaustive list of reviews, research articles, patents, books, patient information leaflets, and orange book is presented and the contents related to nitrogen mustard anti-cancer agents have been reviewed. Attempts are made to present synthesis schemes in a simplified manner. The mechanism of action of the drugs and their side effects are also systematically elaborated. RESULTS: This review provides a platform for understanding all aspects of such drugs right from synthesis to their mechanism of action and side effects, and lists USFDA approved ANDA players among alkylating anticancer agents in the current market. CONCLUSION: Perusing this article, generic scientists will be able to access literature information in this domain easily to gain insight into the nitrogen mustard alkylating agents for further ANDA development. It will help the scientific and research community to continue their pursuit for the design of newer and novel heterocyclic alkylating agents of this class in the coming future.


Assuntos
Alquilantes/farmacologia , Antineoplásicos Alquilantes/farmacologia , Neoplasias/tratamento farmacológico , Compostos de Mostarda Nitrogenada/farmacologia , Alquilantes/síntese química , Alquilantes/química , Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/química , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias/patologia , Compostos de Mostarda Nitrogenada/síntese química , Compostos de Mostarda Nitrogenada/química , Estados Unidos , United States Food and Drug Administration
3.
Mov Disord ; 34(6): 832-844, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30759320

RESUMO

OBJECTIVE: Spreading depolarization (SD) is a transient self-propagating wave of neuronal and glial depolarization coupled with large membrane ionic changes and a subsequent depression of neuronal activity. Spreading depolarization in the cortex is implicated in migraine, stroke, and epilepsy. Conversely, spreading depolarization in the striatum, a brain structure deeply involved in motor control and in Parkinson's disease (PD) pathophysiology, has been poorly investigated. METHODS: We characterized the participation of glutamatergic and dopaminergic transmission in the induction of striatal spreading depolarization by using a novel approach combining optical imaging, measurements of endogenous DA levels, and pharmacological and molecular analyses. RESULTS: We found that striatal spreading depolarization requires the concomitant activation of D1-like DA and N-methyl-d-aspartate receptors, and it is reduced in experimental PD. Chronic l-dopa treatment, inducing dyskinesia in the parkinsonian condition, increases the occurrence and speed of propagation of striatal spreading depolarization, which has a direct impact on one of the signaling pathways downstream from the activation of D1 receptors. CONCLUSION: Striatal spreading depolarization might contribute to abnormal basal ganglia activity in the dyskinetic condition and represents a possible therapeutic target. © 2019 International Parkinson and Movement Disorder Society.


Assuntos
Corpo Estriado/fisiopatologia , Neurônios Dopaminérgicos/fisiologia , Discinesia Induzida por Medicamentos/fisiopatologia , Levodopa/farmacologia , Neurônios/fisiologia , Transtornos Parkinsonianos/fisiopatologia , Transmissão Sináptica/fisiologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Antiparkinsonianos/farmacologia , Corpo Estriado/efeitos dos fármacos , Compostos de Mostarda Nitrogenada/metabolismo , Prednisolona/metabolismo , Procarbazina/metabolismo , Ratos , Ratos Wistar , Vincristina/metabolismo
4.
Dalton Trans ; 48(4): 1144-1160, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30629051

RESUMO

The alkylating agents bearing the -N(CH2CH2Cl)2 moiety, commonly known as 'the nitrogen mustards,' are among the first chemotherapeutic agents against cancer. They form covalent alkyl linkages due to reaction with nucleophilic entities viz. N7 of guanine in DNA. The reactivity of nitrogen mustards may be controlled in various ways, which include metabolic activation, reductive or hypoxic activation and metal complexation. This review discusses how the metal complexation of nitrogen mustards affects their reactivity and mechanistic pathways. The discussion encompasses those transition metal complexes for which the structure has been well characterized and cytotoxicity studies have been performed. This review discusses how the binding of the metal centre along with its oxidation state helps to control the reactivity of the nitrogen mustards. The discussion emphasizes the effect of the reduction potential of the coordinated metal center on the reactivity of the respective mustard under specific conditions, the dependence of efficiency and specificity on the stability of the reduced species and the importance of steric hindrance around the metal center. The insight into the mechanism of action is expected to provide a better understanding to overcome the existing lacunae and design better molecules of this class which have excellent potential, given the ever growing need for therapeutics against cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Complexos de Coordenação/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos de Mostarda Nitrogenada/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/química , Complexos de Coordenação/química , Humanos , Estrutura Molecular , Compostos de Mostarda Nitrogenada/química
5.
Invest New Drugs ; 37(5): 984-993, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30645699

RESUMO

1,3,5-triazine is an important heterocyclic skeleton for mono, two or three 2-chloroethylamine groups. The study presented here provides novel information on cellular effects of 1,3,5-triazine with mono, two or three 2-chloroethylamine groups in glioblastoma LBC3, LN-18 and LN-229 cell lines. In our study, the most cytotoxic effect was observed in 1,3,5-triazine with three 2-chloroethylamine groups (12f compound). It has been demonstrated that 12f induce time- and dose-dependent cytotoxicity in all investigated glioma cell lines. Apart from that in glioblastoma cells, treated with 12f compound, we noticed strong induction of apoptosis. In conclusion, this research provides novel information concerning cellular effects of apoptosis in LBC3, LN-18 and LN-229 cell lines. Moreover, we suggest that 12f compound may be a candidate for further evaluation as an effective chemotherapeutic agent for human glioblastoma cells.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glioblastoma/patologia , Compostos de Mostarda Nitrogenada/farmacologia , Triazinas/farmacologia , Glioblastoma/tratamento farmacológico , Humanos , Necrose , Triazinas/química , Células Tumorais Cultivadas
6.
J Med Chem ; 61(20): 9132-9145, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-30247905

RESUMO

We describe several new aromatic nitrogen mustards with various aromatic substituents and boronic esters that can be activated with H2O2 to efficiently cross-link DNA. In vitro studies demonstrated the anticancer potential of these compounds at lower concentrations than those of other clinically used chemotherapeutics, such as melphalan and chlorambucil. In particular, compound 10, bearing an amino acid ester chain, is selectively cytotoxic toward breast cancer and leukemia cells that have inherently high levels of reactive oxygen species. Importantly, 10 was 10-14-fold more efficacious than melphalan and chlorambucil for triple-negative breast-cancer (TNBC) cells. Similarly, 10 is more toxic toward primary chronic-lymphocytic-leukemia cells than either chlorambucil or the lead compound, 9. The introduction of an amino acid side chain improved the solubility and permeability of 10. Furthermore, 10 inhibited the growth of TNBC tumors in xenografted mice without obvious signs of general toxicity, making this compound an ideal drug candidate for clinical development.


Assuntos
Antineoplásicos Alquilantes/metabolismo , Antineoplásicos Alquilantes/farmacologia , Desenho de Fármacos , Peróxido de Hidrogênio/metabolismo , Compostos de Mostarda Nitrogenada/metabolismo , Compostos de Mostarda Nitrogenada/farmacologia , Antineoplásicos Alquilantes/química , Ácidos Borônicos/química , Linhagem Celular Tumoral , Ésteres/química , Humanos , Compostos de Mostarda Nitrogenada/química
7.
Anticancer Drugs ; 29(7): 613-615, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29738337

RESUMO

The biochemicals and reactions involved in the present mechanism of degradation of tumour cells during chemotherapy are reconsidered and limitations noted. Alternative mechanisms and treatment methods are detailed.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Compostos de Mostarda Nitrogenada/farmacologia , Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Química Farmacêutica , Humanos , Peróxido de Hidrogênio/metabolismo , Hidroxilamina/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Compostos de Mostarda Nitrogenada/uso terapêutico
8.
Behav Brain Res ; 350: 1-5, 2018 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-29753726

RESUMO

Increasing evidence has revealed that genetic variants in Reelin (RELN) gene, especially single-nucleotide polymorphisms (SNPs), correlate with autistic spectrum disorders (ASD) risk; however, no consensus have been reached. This study aimed to provide additional evidence for the association between two SNPs of RELN (i.e., rs736707, rs2229864) and ASD risk, as well as the relationship between RELN gene and symptom-based and developmental deficits of ASD patients in Chinese Han children and adolescents. 157 ASD subjects and 256 typical development (TD) controls were genotyped by TaqMan® genotyping assay. ASD patients were assessed by Childhood Autism Rating Scale (CARS), Autism Behavior Checklist (ABC), and Early Childhood Development Questionnaire (ECDQ). We found that SNP rs2229864 was associated with the genetic predisposition of ASD, whereas a negative association between SNP rs2229864 and symptom-based and developmental features was detected. In contrast, RELN rs736707 correlated with the sensory subscale of the ABC, the relating subscale of the ABC and the total score of ABC, although we did not detect a significant association between SNP rs736707 and ASD risk. Furthermore, a significant rs736707-rs2229864 haplotype was detected. Individuals with a CC haplotype were more likely to have ASD, but individuals with a CT haplotype had more chance be TD controls. Further studies using more samples and including more gene variants in RELN are warranted to confirm our results.


Assuntos
Transtorno do Espectro Autista/genética , Moléculas de Adesão Celular Neuronais/genética , Proteínas da Matriz Extracelular/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Serina Endopeptidases/genética , Adolescente , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , China , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Compostos de Mostarda Nitrogenada
9.
Biochem Pharmacol ; 154: 64-74, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29630868

RESUMO

PR-104A is a clinical-stage nitrogen mustard prodrug that is activated for DNA alkylation by reduction of a nitro group to the corresponding hydroxylamine (PR-104H) or amine (PR-104M). Metabolic reduction is catalysed by flavoreductases such as cytochrome P450 oxidoreductase (POR) under hypoxia, or by aldo-ketoreductase 1C3 (AKR1C3) independently of hypoxia. The unstable reduced metabolites are challenging to measure in biological samples, and biomarkers of the metabolic activation of PR-104A have not been used in the clinical evaluation of PR-104 to date. Here, we employ a selected reaction monitoring mass spectrometry assay for DNA crosslinks to assess the capacity of human cancer cells to bioactivate PR-104A. We also test whether the more abundant DNA monoadducts could be used for the same purpose. DNA monoadducts and crosslinks from PR-104A itself, and from its reduced metabolites, accumulated over 4 h in AKR1C3-expressing TF1 erythroleukaemia cells under hypoxia, whereas intracellular concentrations of unstable PR-104H and PR-104M reached steady state within 1 h. We then varied rates of PR-104A reduction by manipulating hypoxia or reductase expression in a panel of cell lines, in which AKR1C3 and POR were quantified by targeted proteomics. Hypoxia or reductase overexpression induced large increases in PR-104A sensitivity (inhibition of proliferation), DNA damage response (γH2AX formation), steady-state concentrations of PR-104H/M and formation of reduced drug-DNA adducts but not DNA adducts retaining the dinitro groups of PR-104A. The fold-change in the sum of PR-104H and PR-104M correlated with the fold-change in reduced crosslinks or monoadducts (R2 = 0.87 for both), demonstrating their potential for assessing the capacity of cancer cells to bioactivate PR-104A.


Assuntos
Adutos de DNA/metabolismo , Dano ao DNA/fisiologia , Compostos de Mostarda Nitrogenada/metabolismo , Pró-Fármacos/metabolismo , Biomarcadores/metabolismo , Dano ao DNA/efeitos dos fármacos , Células HCT116 , Humanos , Compostos de Mostarda Nitrogenada/farmacologia , Pró-Fármacos/farmacologia
10.
Eur J Med Chem ; 151: 401-433, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29649739

RESUMO

Cancer is considered as one of the most serious health problems today. The discovery of nitrogen mustard as an alkylating agent in 1942, opened a new era in the cancer chemotherapy. This valuable class of alkylating agent exerts its biological activity by binding to DNA, cross linking two strands, preventing DNA replication and ultimate cell death. At the molecular level, nitrogen lone pairs of nitrogen mustard generate a strained intermediate "aziridinium ion" which is very reactive towards DNA of tumor cell as well as normal cell resulting in various adverse side effects alogwith therapeutic implications. Over the last 75 years, due to its high reactivity and peripheral cytotoxicity, numerous modifications have been made in the area of nitrogen mustard to improve its efficacy as well as enhancing drug delivery specifically to tumor cells. This review mainly discusses the medicinal chemistry aspects in the development of various classes of nitrogen mustards (mechlorethamine, chlorambucil, melphalan, cyclophosphamide and steroidal based nitrogen mustards). The literature collection includes the historical and the latest developments in these areas. This comprehensive review also attempted to showcase the recent progress in the targeted delivery of nitrogen mustards that includes DNA directed nitrogen mustards, antibody directed enzyme prodrug therapy (ADEPT), gene directed enzyme prodrug therapy (GDEPT), nitrogen mustard activated by glutathione transferase, peptide based nitrogen mustards and CNS targeted nitrogen mustards.


Assuntos
Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos de Mostarda Nitrogenada/química , Compostos de Mostarda Nitrogenada/uso terapêutico , Animais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Humanos , Compostos de Mostarda Nitrogenada/administração & dosagem , Compostos de Mostarda Nitrogenada/farmacologia
11.
Transfusion ; 58(4): 905-916, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29498049

RESUMO

BACKGROUND: Nucleic acid-targeted pathogen inactivation technology using amustaline (S-303) and glutathione (GSH) was developed to reduce the risk of transfusion-transmitted infectious disease and transfusion-associated graft-versus-host disease with red blood cell (RBC) transfusion. STUDY DESIGN AND METHODS: A randomized, double-blind, controlled study was performed to assess the in vitro characteristics of amustaline-treated RBCs (test) compared with conventional (control) RBCs and to evaluate safety and efficacy of transfusion during and after cardiac surgery. The primary device efficacy endpoint was the postproduction hemoglobin (Hb) content of RBCs. Exploratory clinical outcomes included renal and hepatic failure, the 6-minute walk test (a surrogate for cardiopulmonary function), adverse events (AEs), and the immune response to amustaline-treated RBCs. RESULTS: A total of 774 RBC unis were produced. Mean treatment difference in Hb content was -2.27 g/unit (95% confidence interval, -2.61 to -1.92 g/unit), within the prespecified equivalence margins (±5 g/unit) to declare noninferiority. Amustaline-treated RBCs met European guidelines for Hb content, hematocrit, and hemolysis. Fifty-one (25 test and 26 control) patients received study RBCs. There were no significant differences in RBC usage or other clinical outcomes. Observed AEs were within the spectrum expected for patients of similar age undergoing cardiovascular surgery requiring RBCs transfusion. No patients exhibited an immune response specific to amustaline-treated RBCs. CONCLUSION: Amustaline-treated RBCs demonstrated equivalence to control RBCs for Hb content, have appropriate characteristics for transfusion, and were well tolerated when transfused in support of acute anemia. Renal impairment was characterized as a potential efficacy endpoint for pivotal studies of RBC transfusion in cardiac surgery.


Assuntos
Acridinas/farmacologia , Bacteriemia/prevenção & controle , Segurança do Sangue/métodos , Patógenos Transmitidos pelo Sangue , Procedimentos Cirúrgicos Cardíacos , Transfusão de Eritrócitos , Eritrócitos/efeitos dos fármacos , Compostos de Mostarda Nitrogenada/farmacologia , Viremia/prevenção & controle , Lesão Renal Aguda/etiologia , Idoso , Idoso de 80 Anos ou mais , Bacteriemia/transmissão , Patógenos Transmitidos pelo Sangue/efeitos dos fármacos , Método Duplo-Cego , Transfusão de Eritrócitos/efeitos adversos , Feminino , Glutationa/farmacologia , Doença Enxerto-Hospedeiro/prevenção & controle , Testes de Função Cardíaca , Hemoglobinas/análise , Humanos , Falência Hepática/etiologia , Masculino , Complicações Pós-Operatórias/etiologia , Reação Transfusional/prevenção & controle , Viremia/transmissão , Inativação de Vírus
12.
Colloids Surf B Biointerfaces ; 164: 134-143, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29413590

RESUMO

C60 fullerene is reported to directly interact with biomolecules, such as aromatic mutagens or anticancer drugs. Therefore, it is extensively studied for its potential application in the fields of drug delivery and chemoprevention. Understanding the nature of fullerene-drugs interactions might contribute to optimization and modification of the existing chemotherapy systems. Possible interactions between ICR-191, a model acridine mutagen, with well-established biophysical properties and mutagenic activity, and C60 fullerene aqueous solution were investigated by broad range of biophysical methods, such as Dynamic Light Scattering, Isothermal Titration Calorimetry, and Atomic Force Microscopy. Additionally, to determine biological activity of ICR-191-C60 fullerene mixtures, Ames mutagenicity test was employed. It was demonstrated that C60 fullerene interacts non-covalently with ICR-191 and has strong affinity to bacterial membranes. The obtained results provide practical insight into C60 fullerene interactions with aromatic compounds.


Assuntos
Fulerenos/química , Hidrocarbonetos Aromáticos/metabolismo , Aminacrina/análogos & derivados , Aminacrina/metabolismo , Transporte Biológico , Fenômenos Biofísicos , Microscopia de Força Atômica , Modelos Moleculares , Mutagênicos/toxicidade , Compostos de Mostarda Nitrogenada/metabolismo , Salmonella typhimurium/efeitos dos fármacos
13.
Vox Sang ; 113(3): 232-241, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29314033

RESUMO

BACKGROUND AND OBJECTIVES: Chikungunya virus (CHIKV) infections have been reported in all continents, and the potential risk for CHIKV transfusion-transmitted infections (TTIs) was demonstrated by the detection of CHIKV RNA-positive donations in several countries. TTIs can be reduced by pathogen inactivation (PI) of blood products. In this study, we evaluated the efficacy of amustaline and glutathione (S-303/GSH) to inactivate CHIKV in red-blood-cell concentrates (RBCs). MATERIAL AND METHODS: Red-blood-cells were spiked with high level of CHIKV. Infectious titres and RNA loads were measured before and after PI treatment. Residual CHIKV infectivity was also assessed after five successive cell culture passages. RESULTS: The mean CHIKV titres in RBCs before inactivation was 5·81 ± 0·18 log10 50% tissue culture infectious dose (TCID50 )/mL, and the mean viral RNA load was 10·49 ± 0·15 log10 genome equivalent (GEq)/mL. No CHIKV TCID was detected after S-303 treatment nor was replicative CHIKV particles and viral RNA present after five cell culture passages of samples obtained immediately after S-303 treatment. CONCLUSION: Chikungunya virus was previously shown to be inactivated by the PI technology using amotosalen and ultraviolet A light for the treatment of plasma and platelets. This new study demonstrates that S-303/GSH can inactivate high titres of CHIKV in RBCs.


Assuntos
Acridinas/uso terapêutico , Antivirais/uso terapêutico , Segurança do Sangue/métodos , Febre de Chikungunya/prevenção & controle , Compostos de Mostarda Nitrogenada/uso terapêutico , Inativação de Vírus , Acridinas/farmacologia , Antivirais/farmacologia , Febre de Chikungunya/sangue , Vírus Chikungunya/efeitos dos fármacos , Eritrócitos/virologia , Humanos , Compostos de Mostarda Nitrogenada/farmacologia , Carga Viral
14.
ChemMedChem ; 13(1): 30-36, 2018 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-29205945

RESUMO

Herein we report the first exploration of a dual-targeting drug design strategy to improve the efficacy of small-molecule cancer immunotherapy. New hybrids of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors and DNA alkylating nitrogen mustards that respectively target IDO1 and DNA were rationally designed. As the first-in-class examples of such molecules, they were found to exhibit significantly enhanced anticancer activity in vitro and in vivo with low toxicity. This proof-of-concept study has established a critical step toward the development of a novel and effective immunotherapy for the treatment of cancers.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , DNA/metabolismo , Inibidores Enzimáticos/uso terapêutico , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , DNA/química , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Dinâmica Molecular , Neoplasias/patologia , Compostos de Mostarda Nitrogenada/química , Compostos de Mostarda Nitrogenada/farmacologia , Compostos de Mostarda Nitrogenada/uso terapêutico , Oximas/química , Oximas/metabolismo , Oximas/uso terapêutico , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico
15.
Transfusion ; 57(12): 2888-2896, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28921542

RESUMO

BACKGROUND: Dengue virus (DENV) is an arbovirus primarily transmitted through mosquito bite; however, DENV transfusion-transmitted infections (TTIs) have been reported and asymptomatic DENV RNA-positive blood donors have been identified in endemic countries. DENV is considered a high-risk pathogen for blood safety. One of the mitigation strategies to prevent arbovirus TTIs is pathogen inactivation. In this study we demonstrate that the amustaline and glutathione (S-303/GSH) treatment previously found effective against Zika virus in red blood cells (RBCs) is also effective in inactivating DENV. STUDY DESIGN AND METHODS: Red blood cells were spiked with high levels of DENV. Viral RNA loads and infectious titers were measured in the untreated control and before and after pathogen inactivation treatment of RBC samples. DENV infectivity was also assessed over five successive cell culture passages to detect any potential residual replicative virus. RESULTS: The mean ± SD DENV titer in RBCs before inactivation was 6.61 ± 0.19 log 50% tissue culture infectious dose (TCID50 )/mL and the mean viral RNA load was 8.42 log genome equivalents/mL. No replicative DENV was detected either immediately after completion of treatment using S-303/GSH or after cell culture passages. CONCLUSION: Treatment using S-303/GSH inactivated high levels of DENV in RBCs to the limit of detection. In combination with previous studies showing the effective inactivation of DENV in plasma and platelets using the licensed amotosalen/UVA system, this study demonstrates that high levels of DENV can be inactivated in all blood components.


Assuntos
Acridinas/farmacologia , Vírus da Dengue/patogenicidade , Transfusão de Eritrócitos/efeitos adversos , Eritrócitos/virologia , Glutationa/farmacologia , Compostos de Mostarda Nitrogenada/farmacologia , Inativação de Vírus/efeitos dos fármacos , Células Cultivadas , Dengue/prevenção & controle , Dengue/transmissão , Vírus da Dengue/efeitos dos fármacos , Humanos , RNA Viral/sangue
17.
Cell Chem Biol ; 24(3): 391-403, 2017 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-28262557

RESUMO

Gene-directed enzyme-prodrug therapy (GDEPT) is a promising anti-cancer strategy. However, inadequate prodrugs, inefficient prodrug activation, and a lack of non-invasive imaging capabilities have hindered clinical progression. To address these issues, we used a high-throughput Escherichia coli platform to evolve the multifunctional nitroreductase E. coli NfsA for improved activation of a promising next-generation prodrug, PR-104A, as well as clinically relevant nitro-masked positron emission tomography-imaging probes EF5 and HX4, thereby addressing a critical and unmet need for non-invasive bioimaging in nitroreductase GDEPT. The evolved variant performed better in E. coli than in human cells, suggesting optimal usefulness in bacterial rather than viral GDEPT vectors, and highlighting the influence of intracellular environs on enzyme function and the shaping of promiscuous enzyme activities within the "black box" of in vivo evolution. We provide evidence that the dominant contribution to improved PR-104A activity was enhanced affinity for the prodrug over-competing intracellular substrates.


Assuntos
Proteínas de Escherichia coli/metabolismo , Neoplasias/terapia , Compostos de Mostarda Nitrogenada/metabolismo , Nitrorredutases/metabolismo , Pró-Fármacos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Etanidazol/análogos & derivados , Etanidazol/química , Etanidazol/metabolismo , Células HCT116 , Humanos , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/metabolismo , Imidazóis/química , Imidazóis/metabolismo , Concentração Inibidora 50 , Metronidazol/química , Metronidazol/metabolismo , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Neoplasias/diagnóstico , Neoplasias/patologia , Compostos de Mostarda Nitrogenada/química , Nitrorredutases/química , Nitrorredutases/genética , Tomografia por Emissão de Pósitrons , Pró-Fármacos/química , Estrutura Terciária de Proteína , Especificidade por Substrato , Triazóis/química , Triazóis/metabolismo
18.
Sci Rep ; 7: 41862, 2017 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-28139733

RESUMO

Targeting the autophagic pathway is currently regarded as an attractive strategy for cancer drug discovery. Our previous work showed that IMB-6G is a novel N-substituted sophoridinic acid derivative with potent cytotoxicity against tumor cells, yet the effect of IMB-6G on autophagy and pancreatic cancer cell death remains unknown. Here, we show that IMB-6G inhibits the growth of MiaPaCa-2 and HupT-3 pancreatic cancer cells and induces caspase-mediated apoptosis, which is correlated with an accumulation of autophagic vacuoles. IMB-6G promotes autophagosome accumulation from the early stage of treatment but blocks autophagic flux in the degradation stage, mainly through attenuation of lysosomal cathepsin activity in pancreatic cancer cells. Moreover, IMB-6G triggers lysosomal membrane permeabilization (LMP), followed by cathepsin B/CTSB and cathepsin D/CTSD release from lysosomes into the cytoplasm. Inhibition of autophagosome formation with siRNA against autophagy protein 5 (Atg5) attenuates IMB-6G-induced LMP and apoptosis. Furthermore, cathepsin inhibitors relieve IMB-6G-induced apoptosis as well. Altogether, our findings demonstrate that IMB-6G is a novel autophagy inhibitor, which induces autophagy-dependent apoptosis through autophagosomal-cathepsin axis in pancreatic cancer cells and indicate the potential value of IMB-6G as a novel antitumor drug candidate.


Assuntos
Antineoplásicos/farmacologia , Apoptose , Autofagia , Lisossomos/efeitos dos fármacos , Compostos de Mostarda Nitrogenada/farmacologia , Neoplasias Pancreáticas/metabolismo , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Catepsinas/metabolismo , Linhagem Celular Tumoral , Humanos , Lisossomos/metabolismo
19.
Chem Res Toxicol ; 30(3): 830-839, 2017 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-28140568

RESUMO

PR104A is an experimental DNA-alkylating hypoxia-activated prodrug that can also be activated in an oxygen-independent manner by the two-electron aldo-keto reductase 1C3. Nitroreduction leads to the formation of cytotoxic hydroxylamine (PR104H) and amine (PR104M) metabolites, which induce DNA mono and cross-linked adducts in cells. PR104A-derived DNA adducts can be utilized as drug-specific biomarkers of efficacy and as a mechanistic tool to elucidate the cellular and molecular effects of PR104A. Toward this goal, a mass spectrometric bioanalysis approach based on a stable isotope-labeled adduct mixture (SILAM) and selected reaction monitoring (SRM) data acquisition for relative quantitation of PR104A-derived DNA adducts in cells was developed. Use of this SILAM-based approach supported simultaneous relative quantitation of 33 PR104A-derived DNA adducts in the same sample, which allowed testing of the hypothesis that the enhanced cytotoxicity, observed by preconditioning cells with the transcription-activating isothiocyanate sulforaphane, is induced by an increased level of DNA adducts induced by PR104H and PR104M, but not PR104A. By applying the new SILAM-SRM approach, we found a 2.4-fold increase in the level of DNA adducts induced by PR104H and PR104M in HT-29 cells preconditioned with sulforaphane and a corresponding 2.6-fold increase in cytotoxicity. These results suggest that DNA adduct levels correlate with drug potency and underly the possibility of monitoring PR104A-derived DNA adducts as biomarkers of efficacy.


Assuntos
Antineoplásicos/farmacologia , Adutos de DNA , Compostos de Mostarda Nitrogenada/farmacologia , Pró-Fármacos/farmacologia , Células HT29 , Humanos , Técnicas In Vitro
20.
Vox Sang ; 112(3): 210-218, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28220519

RESUMO

BACKGROUND AND OBJECTIVES: Pathogen reduction technology using amustaline (S-303) was developed to reduce the risk of transfusion-transmitted infection and adverse effects of residual leucocytes. In this study, the viability of red blood cells (RBCs) prepared with a second-generation process and stored for 35 days was evaluated in two different blood centres. MATERIALS AND METHODS: In a single-blind, randomized, controlled, two-period crossover study (n = 42 healthy subjects), amustaline-treated (Test) or Control RBCs were prepared in random sequence and stored for 35 days. On day 35, an aliquot of 51 Cr/99m Tc radiolabeled RBCs was transfused. In a subgroup of 26 evaluable subjects, 24-h RBC post-transfusion recovery, mean life span, median life span (T50 ) and life span area under the curve (AUC) were analysed. RESULTS: The mean 24-h post-transfusion recovery of Test and Control RBCs was comparable (83·2 ± 5·2 and 84·9 ± 5·9%, respectively; P = 0·06) and consistent with the US Food and Drug Administration (FDA) criteria for acceptable RBC viability. There were differences in the T50 between Test and Control RBCs (33·5 and 39·7 days, respectively; P < 0·001), however, these were within published reference ranges of 28-35 days. The AUC (per cent surviving × days) for Test and Control RBCs was similar (22·6 and 23·1 per cent surviving cells × days, respectively; P > 0·05). Following infusion of Test RBCs, there were no clinically relevant abnormal laboratory values or adverse events. CONCLUSION: RBCs prepared using amustaline pathogen reduction meet the FDA criteria for post-transfusion recovery and are metabolically and physiologically appropriate for transfusion following 35 days of storage.


Assuntos
Acridinas/farmacologia , Preservação de Sangue , Eritrócitos/efeitos dos fármacos , Compostos de Mostarda Nitrogenada/farmacologia , Acridinas/química , Adulto , Idoso , Área Sob a Curva , Sobrevivência Celular/efeitos dos fármacos , Isótopos do Cromo/química , Estudos Cross-Over , Contagem de Eritrócitos , Transfusão de Eritrócitos/efeitos adversos , Eritrócitos/química , Eritrócitos/citologia , Eritrócitos/metabolismo , Feminino , Meia-Vida , Hematoma/etiologia , Humanos , Marcação por Isótopo , Masculino , Viabilidade Microbiana/efeitos dos fármacos , Pessoa de Meia-Idade , Compostos de Mostarda Nitrogenada/química , Curva ROC , Método Simples-Cego , Tecnécio/química , Fatores de Tempo , Inativação de Vírus/efeitos dos fármacos , Adulto Jovem
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