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1.
Chem Commun (Camb) ; 56(14): 2194-2197, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-31971170

RESUMO

An Ugi, novel pseudo-Knoevenagel, ring expansion cascade reaction was discovered and utilized for the synthesis of aziridinyl succinimides in one-pot. Subsequently, densely functionalized aziridines and maleimides have been designed and synthesized through similar cascade reactions. The target compounds were prepared by means of a mild reaction and a simple operation procedure, which could be applicable to a broad scope of starting materials. This series of novel cascade reactions generates opportunities for the tailored synthesis of a wide range of biologically active scaffolds through tuneable Ugi inputs. Discovery of compound 8i with comparable potency to sorafenib in liver cancer cell lines could provide a new avenue for liver cancer drug discovery.


Assuntos
Antineoplásicos/farmacologia , Aziridinas/farmacologia , Maleimidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Aziridinas/síntese química , Aziridinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Maleimidas/síntese química , Maleimidas/química , Estrutura Molecular
2.
Chem Biodivers ; 16(11): e1900375, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31512351

RESUMO

New aziridine 2-phosphonic acids were prepared by monohydrolysis of the aziridine 2-phosphonates that were obtained by the modified Gabriel-Cromwell reaction of vinyl phosphonate or α-tosylvinyl phosphonate with a primary amine or a chiral amine. The cellular cytotoxicity of these compounds was tested against the HCT-116 colorectal cancer cell lines and the CCD-18Co normal colon fibroblast lines using the MTT assay. Three of the synthesized phosphonic acid derivatives 2e (ethyl hydrogen {(2S)-1-[(1S)-1-(naphthalen-2-yl)ethyl]aziridin-2-yl}phosphonate), 2h (ethyl hydrogen (1-benzylaziridin-2-yl)phosphonate), and 2i (ethyl hydrogen (1-cyclohexylaziridin-2-yl)phosphonate) showed higher cytotoxicity than the reference cancer treatment agent etoposide. Cell death was through a robust induction of apoptosis even more effectively than etoposide, a well-known apoptosis inducing agent.


Assuntos
Antineoplásicos/farmacologia , Aziridinas/farmacologia , Ácidos Fosforosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Aziridinas/síntese química , Aziridinas/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Ácidos Fosforosos/síntese química , Ácidos Fosforosos/química
3.
Int J Mol Sci ; 20(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096565

RESUMO

Many medicinal plant species are currently threatened in their natural habitats because of the growing demand for phytochemicals worldwide. A sustainable alternative for the production of bioactive plant compounds are plant biofactories based on cell cultures and organs. In addition, plant extracts from biofactories have significant advantages over those obtained from plants, since they are free of contamination by microorganisms, herbicides and pesticides, and they provide more stable levels of active ingredients. In this context, we report the establishment of Satureja khuzistanica cell cultures able to produce high amounts of rosmarinic acid (RA). The production of this phytopharmaceutical was increased when the cultures were elicited with coronatine and scaled up to a benchtop bioreactor. S. khuzistanica extracts enriched in RA were found to reduce the viability of cancer cell lines, increasing the sub-G0/G1 cell population and the activity of caspase-8 in MCF-7 cells, which suggest that S. khuzistanica extracts can induce apoptosis of MCF-7 cells through activation of the extrinsic pathway. In addition, our findings indicate that other compounds in S. khuzistanica extracts may act synergistically to potentiate the anticancer activity of RA.


Assuntos
Aziridinas/farmacologia , Cinamatos/metabolismo , Cinamatos/farmacologia , Cicloexenos/farmacologia , Depsídeos/metabolismo , Depsídeos/farmacologia , Espécies em Perigo de Extinção , Extratos Vegetais/farmacologia , Satureja/metabolismo , Adenocarcinoma/tratamento farmacológico , Reatores Biológicos , Caspase 8/metabolismo , Caspases/metabolismo , Técnicas de Cultura de Células , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2/efeitos dos fármacos , Humanos , Células MCF-7 , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química , Satureja/crescimento & desenvolvimento
4.
Arch Pharm Res ; 42(9): 815-823, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30879173

RESUMO

RH1 (2, 5-diaziridinyl-3-(hydroxymethy)-6-methyl-1, 4-benzoquinone) is a bioreductive anticancer drug. The mechanism underlying its therapeutic properties has not yet been elucidated. In this study, we aimed to determine whether RH1 exerts its anticancer effect via p53-mediated apoptosis and senescence in vitro and in vivo. RH1 displayed dose-dependent biphasic effects in vitro, i.e., it induced apoptosis at higher dose and senescence at lower dose accompanied by marked activation of p53. Thus, RH1 primarily induced cell death by apoptosis. The cytotoxicity of RH1 was inhibited in A549 cells treated with the p53-inhibitor pifithrin-α or transfected p53 siRNA and in human colon cancer HCT116 isogenic (p53-/-) cells. At sub-lethal doses of RH1, the cells survived and underwent senescence. The senescent cells showed flattened and enlarged morphology, and exhibited blue color in senescence-associated ß-galactosidase staining. These changes were found to be related to p53. RH1-induced senescence decreased in A549-E6 cells (suppressed p53 level) and HCT 116 p53-/- cells. The growth of A549 xenograft tumors in nude mice was significantly delayed by intraperitoneal injection of RH1, and senescent cells were observed in these xenograft tumors. These results suggest that the in vivo anticancer therapeutic effect of RH1 is mediated by senescence via p53 activation.


Assuntos
Antineoplásicos/farmacologia , Aziridinas/farmacologia , Benzoquinonas/farmacologia , Senescência Celular/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Células A549 , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/genética
5.
Eur J Med Chem ; 163: 736-746, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30576904

RESUMO

This work reports an efficient diastereoselective synthetic methodology for the preparation of phosphorus substituted cyanoaziridines through the nucleophilic addition of TMSCN, as cyanide source, to the C-N double bond of 2H-azirine derivatives. The aziridine ring, in these novel cyanoaziridines, can be activated by simple N-tosylation or N-acylation. In addition, the cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549) and human embryonic kidney (HEK293) was also screened. N-H and N-Substituted cyanoaziridines showed excellent activity against the A549 cell line in vitro. Moreover, selectivity towards cancer cell (A549) over (HEK293), and non-malignant cells (MCR-5) has been observed.


Assuntos
Aziridinas/farmacologia , Organofosfonatos/farmacologia , Óxidos/farmacologia , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Aziridinas/síntese química , Proliferação de Células/efeitos dos fármacos , Cianetos , Células HEK293 , Humanos , Organofosfonatos/síntese química , Óxidos/síntese química , Relação Estrutura-Atividade
6.
Biochem Pharmacol ; 158: 192-200, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30352235

RESUMO

Gene-directed enzyme-prodrug therapy (GDEPT) employs tumour-tropic vectors including viruses and bacteria to deliver a genetically-encoded prodrug-converting enzyme to the tumour environment, thereby sensitising the tumour to the prodrug. Nitroreductases, able to activate a range of promising nitroaromatic prodrugs to genotoxic metabolites, are of great interest for GDEPT. The bystander effect (cell-to-cell transfer of activated prodrug metabolites) has been quantified for some nitroaromatic prodrugs in mixed multilayer human cell cultures, however while these provide a good model for viral DEPT (VDEPT) they do not inform on the ability of these prodrug metabolites to exit bacterial vectors (relevant to bacterial-DEPT (BDEPT)). To investigate this we grew two Escherichia coli strains in co-culture; an activator strain expressing the nitroreductase E. coli NfsA and a recipient strain containing an SOS-GFP DNA damage responsive gene construct. In this system, induction of GFP by reduced prodrug metabolites can only occur following their transfer from the activator to the recipient cells. We used this to investigate five clinically relevant prodrugs: metronidazole, CB1954, nitro-CBI-DEI, and two dinitrobenzamide mustard prodrug analogues, PR-104A and SN27686. Consistent with the bystander efficiencies previously measured in human cell multilayers, reduced metronidazole exhibited little bacterial cell-to-cell transfer, whereas nitro-CBI-DEI was passed very efficiently from activator to recipient cells post-reduction. However, in contrast with observations in human cell multilayers, the nitrogen mustard prodrug metabolites were not effectively passed between the two bacterial strains, whereas reduced CB1954 was transferred efficiently. Using nitroreductase enzymes that exhibit different biases for the 2- versus 4-nitro substituents of CB1954, we further showed that the 2-nitro reduction products exhibit substantially higher levels of bacterial cell-to-cell transfer than the 4-nitro reduction products, consistent with their relative bystander efficiencies in human cell culture. Overall, our data suggest that prodrugs may differ in their suitability for VDEPT versus BDEPT applications and emphasise the importance of evaluating an enzyme-prodrug partnership in an appropriate context for the intended vector.


Assuntos
Escherichia coli/metabolismo , Terapia Genética/métodos , Vetores Genéticos/metabolismo , Nitrorredutases/metabolismo , Pró-Fármacos/metabolismo , Aziridinas/metabolismo , Aziridinas/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Escherichia coli/efeitos dos fármacos , Vetores Genéticos/farmacologia , Humanos , Pró-Fármacos/farmacologia
7.
J Pharm Pharmacol ; 70(12): 1700-1712, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30229910

RESUMO

OBJECTIVES: This work describes the synthesis, the bioactivity and the structure-activity relationship of new derivatives from a natural coumarin. METHODS: (-)-Deltoin 1 and the corresponding isoxazolines and aziridines were characterized by spectroscopic means. The cytotoxic (HTC-116, IGROV-1 and OVCAR-3 cancer cell lines) and 5-lipoxygenase activity of (-)-deltoin 1 and its structural analogues have been evaluated. KEY FINDINGS: The phytochemical investigation of the ethyl acetate extract of the flowers of Ferula lutea (Poir.) Maire has led to the isolation of (-)-deltoin 1. A series of new isoxazoline 2a,a'-2f,f' and aziridine 3a,a'-3e,e' derivatives have been prepared by 1,3-dipolar cycloaddition. It has been found that the derivatives 2a (IC50 = 3.3 ± 0.1 µm), 3a,a' (IC50 = 5.9 ± 0.1 µm), 3b,b' (IC50 = 6.1 ± 0.7 µm) and 3c,c' (IC50 = 7.3 ± 0.9 µm) bearing a phenyl isoxazoline, a phenylaziridine, a 4-methlphenylaziridine and a 4-methoxyphenylaziridine, respectively, are more cytotoxic than (-)-deltoin 1 (IC50 = 14.3 ± 0.2 µm). The diastereoisomers in mixture (2f,f') with a 6-chloropyridin-2-yl system have shown the best anti-5-lipoxygenase activity (% inhibition = 53.1 ± 4.8% at 200 µm). CONCLUSIONS: Some analogues have been found more bioactive than deltoin 1. Their activity has been related to the nature of the added heterocycles. It would be interesting to evaluate their in-vivo activity.


Assuntos
Antineoplásicos/farmacologia , Aziridinas/farmacologia , Furocumarinas/química , Isoxazóis/farmacologia , Extratos Vegetais/farmacologia , Antineoplásicos/química , Araquidonato 5-Lipoxigenase/efeitos dos fármacos , Aziridinas/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Flores , Furocumarinas/farmacologia , Humanos , Isoxazóis/química , Extratos Vegetais/química , Relação Estrutura-Atividade
8.
Eur J Med Chem ; 157: 657-664, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30125724

RESUMO

It is known that aziridines and nitrogen mustards exert their biological activities, especially in chemotherapy, via DNA alkylation. The studied scaffold, 2-phenyl-1-aziridine, provides a distinct conformation compared to commonly used aziridines, and therefore, leads to a change in high-strained ring reactivity towards biological nucleophiles, such as DNA. The above series of compounds was tested in three breast cell lines: MCF-10, a healthy cell; MCF-7, a hormone responsive cancer cell; and MDA-MB-231, a triple negative breast cancer cell. Both aziridines and their precursors, ß-amino alcohols, showed activity towards these cells, and some of the compounds showed higher selectivity index than cisplatin, the drug used as control. When the type of cell death was investigated, the synthesized compounds demonstrated higher apoptosis and lower necrosis rates than cisplatin, and when the mechanism of action was studied, the compounds were shown to interact with DNA via its minor groove instead of alkylation or intercalation.


Assuntos
Amino Álcoois/farmacologia , Antineoplásicos/farmacologia , Aziridinas/farmacologia , DNA/efeitos dos fármacos , Alquilação/efeitos dos fármacos , Amino Álcoois/química , Antineoplásicos/química , Aziridinas/química , Linhagem Celular , Cisplatino/química , Cisplatino/farmacologia , DNA/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
9.
World J Microbiol Biotechnol ; 34(8): 121, 2018 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-30039311

RESUMO

L-valine is an essential branched-amino acid that is widely used in multiple areas such as pharmaceuticals and special dietary products and its use is increasing. As the world market for L-valine grows rapidly, there is an increasing interest to develop an efficient L-valine-producing strain. In this study, a simple, sensitive, efficient, and consistent screening procedure termed 96 well plate-PC-HPLC (96-PH) was developed for the rapid identification of high-yield L-valine strains to replace the traditional L-valine assay. L-valine production by Brevibacterium flavum MDV1 was increased by genome shuffling. The starting strains were obtained using ultraviolet (UV) irradiation and binary ethylenimine treatment followed by preparation of protoplasts, UV irradiation inactivation, multi-cell fusion, and fusion of the inactivated protoplasts to produce positive colonies. After two rounds of genome shuffling and the 96-PH method, six L-valine high-yielding mutants were selected. One genetically stable mutant (MDVR2-21) showed an L-valine yield of 30.1 g/L during shake flask fermentation, 6.8-fold higher than that of MDV1. Under fed-batch conditions in a 30 L automated fermentor, MDVR2-21 accumulated 70.1 g/L of L-valine (0.598 mol L-valine per mole of glucose; 38.9% glucose conversion rate). During large-scale fermentation using a 120 m3 fermentor, this strain produced > 66.8 g/L L-valine (36.5% glucose conversion rate), reflecting a very productive and stable industrial enrichment fermentation effect. Genome shuffling is an efficient technique to improve production of L-valine by B. flavum MDV1. Screening using 96-PH is very economical, rapid, efficient, and well-suited for high-throughput screening.


Assuntos
Brevibacterium flavum/genética , Brevibacterium flavum/metabolismo , Embaralhamento de DNA/métodos , Ensaios de Triagem em Larga Escala/métodos , Valina/biossíntese , Valina/genética , Aziridinas/farmacologia , Técnicas de Cultura Celular por Lotes , Biomassa , Reatores Biológicos/microbiologia , Brevibacterium flavum/efeitos dos fármacos , Brevibacterium flavum/efeitos da radiação , Fermentação , Genoma Bacteriano , Instabilidade Genômica , Glucose/metabolismo , Microbiologia Industrial , Fusão de Membrana , Mutagênese , Mutação/genética , Protoplastos/efeitos dos fármacos , Protoplastos/efeitos da radiação , Fatores de Tempo , Raios Ultravioleta
10.
Eur J Med Chem ; 156: 587-597, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30029081

RESUMO

In the present work a series of aziridine-2,3-dicarboxylate inhibitors of papain-like cysteine proteases was designed, synthesized and tested. The compounds displayed selectivity for the parasitic protozoon Leishmania mexicana cathepsin L-like cysteine protease LmCPB2.8. The computational methods of homology modelling and molecular docking predicted some significant differences in the S2 pocket of LmCPB2.8 and cruzain, a related enzyme from Trypanosoma cruzi. Due to the presence of Tyr209 in LmCPB2.8 rather than Glu208 in cruzain sterically demanding, lipophilic ester groups (inhibitor 7d, 9d, 12d and 14d) are predicted to occupy the S2 pocket of the Leishmania protease, but do not form favorable interactions in cruzain, which is in common with our experimental results. Further, inhibitor 18 bearing a free carboxylic acid attached to the aziridine moiety showed a time-dependent inhibition of LmCPB2.8 (Ki = 0.41 µM; k2nd = 190,569 M-1 min-1). Docking results suggested a strong ionic interaction with the positively charged His163 of the active site. Biological and theoretical data confirm that the novel selective aziridine-based inhibitors are promising candidates for further optimization as LmCPB2.8 inhibitors.


Assuntos
Aziridinas/química , Aziridinas/farmacologia , Catepsina L/antagonistas & inibidores , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacologia , Leishmania/enzimologia , Antiparasitários/química , Antiparasitários/farmacologia , Catepsina L/metabolismo , Descoberta de Drogas , Humanos , Leishmania/efeitos dos fármacos , Leishmania mexicana/efeitos dos fármacos , Leishmania mexicana/enzimologia , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologia , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Simulação de Acoplamento Molecular
11.
Nanomedicine (Lond) ; 13(9): 1051-1066, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29790803

RESUMO

AIM: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype. Since no targeted therapy is available, gene-directed enzyme prodrug therapy (GDEPT) could be an attractive strategy for treating TNBC. MATERIALS & METHODS: Polyethylene glycol (PEG)ylated-poly(lactic-co-glycolic acid)/polyethyleneimine nanoparticles (PLGA/PEI NPs) were synthesized and complexed with TK-NTR fusion gene. Ultrasound (US) and microbubble (MB) mediated sonoporation was used for efficient delivery of the TK-NTR-DNA-NP complex to TNBC tumor in vivo for cancer therapy. Therapeutic effect was evaluated by treating TNBC cells in vitro and tumor xenograft in vivo by using prodrugs ganciclovir (GCV) and CB1954. RESULTS: TNBC cells treated with GCV/CB1954 prodrugs after transfection of TK-NTR-DNA by PEGylated-PLGA/PEI NP resulted in high apoptotic-index. US-MB image-guided delivery of TK-NTR-DNA-NP complex displayed significant expression level of TK-NTR protein and showed tumor reduction when treated with GCV/CB1954 prodrugs in TNBC xenograft in vivo. CONCLUSION: US-MB image-guided delivery of TK-NTR gene by PEGylated-PLGA/PEI NPs could be a potential prodrug therapy for TNBC in the clinic.


Assuntos
Lactatos/química , Nanopartículas/química , Nitrorredutases/genética , Polietilenoglicóis/química , Timidina Quinase/genética , Neoplasias de Mama Triplo Negativas/terapia , Ondas Ultrassônicas , Animais , Apoptose/efeitos dos fármacos , Aziridinas/farmacologia , Linhagem Celular Tumoral , Feminino , Citometria de Fluxo , Humanos , Camundongos , Camundongos Nus , Transfecção , Neoplasias de Mama Triplo Negativas/genética
12.
Cancer Lett ; 424: 97-108, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29580806

RESUMO

Metastasis is a major cause of breast cancer-associated mortality. Natural products extracted from herbs provide rich bioactive compounds with anticancer efficacy but may have limited or moderate potency and considerable toxicity. We developed a novel aziridonin, YD0514, by aziridinating oridonin, a natural product of the medicinal herb Rabdosia rubescens. In this study, we found that YD0514 significantly inhibited proliferation, motility, and adhesion of metastatic breast cancer cell lines MDA-MB-231, GI101, GILM2, and GILM3. YD0514 also decreased the protein expression of matrix metalloproteinases 2 and 9 (MMP2 and MMP9), focal adhesion kinase (FAK), and integrin family members. Importantly, YD0514 suppressed the growth of metastatic breast cancer xenograft tumors and significantly inhibited lung metastasis in vivo. Lastly, we showed that YD0514's anti-metastatic effect on highly aggressive breast cancer is mediated via regulating the NRF-2/RHOA/ROCK signaling pathway. These results demonstrate that YD0514, the first active analog based on an oridonin D-ring modification, has the potential to be developed as an anti-metastasis therapy for patients with metastatic cancers.


Assuntos
Aziridinas/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Transdução de Sinais/efeitos dos fármacos , Animais , Aziridinas/farmacologia , Neoplasias da Mama/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
13.
J Lipid Res ; 59(5): 830-842, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29563219

RESUMO

apoE is the primary lipid carrier within the CNS and the strongest genetic risk factor for late onset Alzheimer's disease (AD). apoE is primarily lipidated via ABCA1, and both are under transcriptional regulation by the nuclear liver X receptor (LXR). Considerable evidence from genetic (using ABCA1 overexpression) and pharmacological (using synthetic LXR agonists) studies in AD mouse models suggests that increased levels of lipidated apoE can improve cognitive performance and, in some strains, can reduce amyloid burden. However, direct synthetic LXR ligands have hepatotoxic side effects that limit their clinical use. Here, we describe a set of small molecules, previously annotated as antagonists of the purinergic receptor, P2X7, which enhance ABCA1 expression and activity as well as apoE secretion, and are not direct LXR ligands. Furthermore, P2X7 is not required for these molecules to induce ABCA1 upregulation and apoE secretion, demonstrating that the ABCA1 and apoE effects are mechanistically independent of P2X7 inhibition. Hence, we have identified novel dual activity compounds that upregulate ABCA1 across multiple CNS cell types, including human astrocytes, pericytes, and microglia, through an indirect LXR mechanism and that also independently inhibit P2X7 receptor activity.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/agonistas , Apolipoproteínas E/agonistas , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X7/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Adamantano/análogos & derivados , Adamantano/química , Adamantano/farmacologia , Animais , Apolipoproteínas E/metabolismo , Aziridinas/química , Aziridinas/farmacologia , Benzamidas/química , Benzamidas/farmacologia , Células Cultivadas , Humanos , Camundongos , Camundongos Knockout , Estrutura Molecular , Naftoquinonas/química , Naftoquinonas/farmacologia , Antagonistas do Receptor Purinérgico P2X/química , Receptores Purinérgicos P2X7/deficiência , Bibliotecas de Moléculas Pequenas/química , Sulfonamidas/química , Sulfonamidas/farmacologia , Regulação para Cima/efeitos dos fármacos
14.
Med Chem ; 14(5): 495-507, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29189173

RESUMO

BACKGROUND: Directed Enzyme Prodrugs Therapy (DEPT) as an alternative method against conventional cancer treatments, in which the non-toxic prodrugs is converted to highly cytotoxic derivative, has attracted an ample attention in recent years for cancer therapy studies. OBJECTIVE: The metabolite profile, cell cytotoxicity and molecular modeling interactions of a series of nitro benzamides with Ssap-NtrB were investigated in this study. METHOD: A series of nitro-substituted benzamide prodrugs (1-4) were synthesized and firstly investigated their enzymatic reduction by Ssap-NtrB (S. saprophyticus Nitroreductase B) using HPLC analysis. Resulting metabolites were analyzed by LC-MS/MS. Molecular docking studies were performed with the aim of investigating the relationship between nitro benzamide structures (prodrugs 1-4) and Ssap-NtrB at the molecular level. Cell viability assay was conducted on two cancer cell lines, hepatoma (Hep3B) and colon (HT-29) cancer models and healthy cell model HUVEC. Upon reduction of benzamide prodrugs by Ssap-NtrB, the corresponding amine effectors were tested in a cell line panel comprising PC-3, Hep3B and HUVEC cells and were compared with the established NTR substrates, CB1954 (an aziridinyl dinitrobenzamide). RESULTS: Cell viability assay resulted in while prodrugs 1, 2 and 3 had no remarkable cytotoxic effects, prodrug 4 showed the differential effect, showing moderate cytotoxicity with Hep3B and HUVEC. The metabolites that obtained from the reduction of nitro benzamide prodrugs (1-4) by Ssap-NtrB, showed differential cytotoxic effects, with none toxic for HUVEC cells, moderate toxic for Hep3B cells, but highly toxic for PC3 cells. CONCLUSION: Amongst all metabolites of prodrugs after Ssap-NtrB reduction, N-(2,4- dinitrophenyl)-4-nitrobenzamide (3) was efficient and toxic in PC3 cells as comparable as CB1954. Kinetic parameters, molecular docking and HPLC results also confirm that prodrug 3 is better for Ssap-NtrB than 1, 2 and 4 or known cancer prodrugs of CB1954 and SN23862, demonstrating that prodrug 3 is an efficient candidate for NTR based cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Nitrobenzenos/farmacologia , Nitrorredutases/metabolismo , Pró-Fármacos/farmacologia , Mostarda de Anilina/análogos & derivados , Mostarda de Anilina/farmacologia , Antineoplásicos/metabolismo , Antineoplásicos/toxicidade , Aziridinas/farmacologia , Benzamidas/metabolismo , Benzamidas/toxicidade , Linhagem Celular Tumoral , Células Endoteliais da Veia Umbilical Humana , Humanos , Cinética , Simulação de Acoplamento Molecular , Nitrobenzenos/metabolismo , Nitrobenzenos/toxicidade , Nitrorredutases/química , Pró-Fármacos/metabolismo , Pró-Fármacos/toxicidade , Staphylococcus saprophyticus/enzimologia
15.
Int Immunol ; 29(8): 385-390, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28992076

RESUMO

Autoimmune and inflammatory conditions are frequent complications in patients with reduced numbers of T cells. Here, we describe a mouse model of thymic stromal dysplasia resulting in peripheral T-cell lymphopenia. In Foxn1:CFP-NTR transgenic mice, the bacterial nitroreductase enzyme is expressed in thymic epithelial cells and converts the prodrug CB1954 into a cytotoxic agent. This strategy enables titratable and durable destruction of thymopoietic tissue in early embryogenesis. Our results indicate that the resulting low levels of thymic capacity for T-cell production create a predisposition for the development of a complex autoimmune syndrome, chiefly characterized by inflammatory bowel disease and lymphocytic organ infiltrations. We conclude that the Foxn1:CFP-NTR transgenic mouse strain represents a suitable animal model to optimize established clinical protocols, such as thymus transplantation, to correct various forms of thymic dysplasia and to explore novel treatment options.


Assuntos
Doenças Inflamatórias Intestinais/imunologia , Linfócitos T/fisiologia , Timo/patologia , Anaplasia , Animais , Antineoplásicos/farmacologia , Apoptose , Autoimunidade , Aziridinas/farmacologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Humanos , Linfopenia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
16.
Med Oncol ; 34(10): 176, 2017 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-28879492

RESUMO

Potential drug target identification and mechanism of action is an important step in drug discovery process, which can be achieved by biochemical methods, genetic interactions or computational conjectures. Sometimes more than one approach is implemented to mine out the potential drug target and characterize the on-target or off-target effects. A novel anticancer agent RH1 is designed as pro-drug to be activated by NQO1, an enzyme overexpressed in many types of tumors. However, increasing data show that RH1 can affect cells in NQO1-independent fashion. Here, we implemented the bioinformatics approach of modeling and molecular docking for search of RH1 targets among protein kinase species. We have examined 129 protein kinases in total where 96 protein kinases are in complexes with their inhibitor, 11 kinases were in the unbound state with any ligand and for 22 protein kinases 3D structure were modeled. Comparison of calculated free energy of binding of RH1 with indigenous kinase inhibitors binding efficiency as well as alignment of their pharmacophoric maps let us predict and ranked protein kinases such as KIT, CDK2, CDK6, MAPK1, NEK2 and others as the most prominent off-targets of RH1. Our finding opens new avenues in search of protein targets that might be responsible for curing cancer by new promising drug RH1 in NQO1-independent way.


Assuntos
Antineoplásicos/farmacologia , Aziridinas/farmacologia , Benzoquinonas/farmacologia , Proteínas Quinases/química , Domínio Catalítico , Biologia Computacional/métodos , Descoberta de Drogas/métodos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Simulação de Acoplamento Molecular , NAD(P)H Desidrogenase (Quinona)/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo
17.
Artigo em Inglês | MEDLINE | ID: mdl-28784676

RESUMO

The mammalian and microbial cell selectivity of synthetic and biosynthetic cationic polymers has been investigated. Among the polymers with peptide backbones, polymers containing amino side chains display greater antimicrobial activity than those with guanidine side chains, whereas ethylenimines display superior activity over allylamines. The biosynthetic polymer ε-polylysine (εPL) is noncytotoxic to primary human dermal fibroblasts at concentrations of up to 2,000 µg/ml, suggesting that the presence of an isopeptide backbone has greater cell selectivity than the presence of α-peptide backbones. Both εPL and linear polyethylenimine (LPEI) exhibit bactericidal properties by depolarizing the cytoplasmic membrane and disrupt preformed biofilms. εPL displays broad-spectrum antimicrobial properties against antibiotic-resistant Gram-negative and Gram-positive strains and fungi. εPL elicits rapid bactericidal activity against both Gram-negative and Gram-positive bacteria, and its biocompatibility index is superior to those of cationic antiseptic agents and LPEI. εPL does not interfere with the wound closure of injured rabbit corneas. In a rabbit model of bacterial keratitis, the topical application of εPL (0.3%, wt/vol) decreases the bacterial burden and severity of infections caused by Pseudomonas aeruginosa and Staphylococcus aureus strains. In vivo imaging studies confirm that εPL-treated corneas appeared transparent and nonedematous compared to untreated infected corneas. Taken together, our results highlight the potential of εPL in resolving topical microbial infections.


Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Candida albicans/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Alilamina/farmacologia , Animais , Aziridinas/farmacologia , Candidíase/tratamento farmacológico , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Humanos , Ceratite/tratamento farmacológico , Ceratite/microbiologia , Testes de Sensibilidade Microbiana , Polietilenoimina/farmacologia , Polilisina/farmacologia , Polímeros/química , Infecções por Pseudomonas/tratamento farmacológico , Coelhos , Infecções Estafilocócicas/tratamento farmacológico
18.
Biochemistry ; 56(25): 3178-3183, 2017 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-28621541

RESUMO

There is growing interest in reversible and irreversible covalent inhibitors that target noncatalytic amino acids in target proteins. With a goal of targeting oncogenic K-Ras variants (e.g., G12D) by expanding the types of amino acids that can be targeted by covalent inhibitors, we survey a set of electrophiles for their ability to label carboxylates. We functionalized an optimized ligand for the K-Ras switch II pocket with a set of electrophiles previously reported to react with carboxylates and characterized the ability of these compounds to react with model nucleophiles and oncogenic K-Ras proteins. Here, we report that aziridines and stabilized diazo groups preferentially react with free carboxylates over thiols. Although we did not identify a warhead that potently labels K-Ras G12D, we were able to study the interactions of many electrophiles with K-Ras, as most of the electrophiles rapidly label K-Ras G12C. We characterized the resulting complexes by crystallography, hydrogen/deuterium exchange, and differential scanning fluorimetry. Our results both demonstrate the ability of a noncatalytic cysteine to react with a diverse set of electrophiles and emphasize the importance of proper spatial arrangements between a covalent inhibitor and its intended nucleophile. We hope that these results can expand the range of electrophiles and nucleophiles of use in covalent protein modulation.


Assuntos
Aziridinas/farmacologia , Ácidos Carboxílicos/metabolismo , Oncogenes , Proteínas Proto-Oncogênicas p21(ras)/química , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Compostos de Sulfidrila/metabolismo , Humanos , Conformação Proteica
19.
Microb Pathog ; 110: 140-151, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28648622

RESUMO

In the present study, we prepared fucoidan coated Au-NPs (Fu-AuNPs), and examined its antimicrobial activity against Aeromonas hydrophila. The green synthesized Fu-AuNPs were bio-physically characterized by Ultraviolet-visible (UV-Vis) spectroscopy, X-ray Diffraction (XRD), Fourier Transform Infrared spectroscopy (FTIR), Higher Transmission Electron Microscopy (HR-TEM), Zeta potential analysis and Energy Dispersive X-ray spectroscopy (EDX). Fu-AuNPs were crystalline in nature, spherical to triangular in shape, with particle size ranging within 10-100 nm. The synthesized Fu-AuNPs at 100 µg mL-1 showed inhibition zone against A. hydrophila (23.2 mm) which is much higher than that of commercial antibiotic chloramphenicol (17.3 mm). The biofilm inhibitory activity of Fu-AuNPs against Gram negative (Aeromonas hydrophila) was higher. Light and confocal laser scanning microscopic observations showed that the Fu-AuNPs at 100 µg mL-1 inhibited the biofilm of A. hydrophila. The cytotoxicity study indicated that Fu-AuNPs were effective in inhibiting the viability of human cervical cancer cells (HeLa) at 100 µg mL-1. In another experiment, the antibacterial effect of Fu-AuNPs on tilapia, Oreochromis mossambicus were evaluated in vivo. The mortality rate of O. mossambicus infected by A. hydrophila was much higher (90%), whereas, the mortality of O. mossambicus that received Fu-AuNPs followed by challenge with A. hydrophia was reduced to 30%. This study concludes that Fu-AUNPs are effective in the control of A. hydrophila infections in O. mossambicus.


Assuntos
Aeromonas hydrophila/efeitos dos fármacos , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Ouro/química , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Nanopartículas Metálicas/química , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/uso terapêutico , Aquicultura , Aziridinas/farmacologia , Biofilmes/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cloranfenicol/farmacologia , Cicloexenos/farmacologia , Doenças dos Peixes/tratamento farmacológico , Doenças dos Peixes/microbiologia , Química Verde , Células HeLa/efeitos dos fármacos , Humanos , Índia , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/ultraestrutura , Testes de Sensibilidade Microbiana , Microscopia Confocal/métodos , Microscopia Eletrônica de Transmissão/métodos , Mortalidade , Tamanho da Partícula , Extratos Vegetais/química , Polissacarídeos/química , Espectrometria por Raios X/métodos , Espectrofotometria Ultravioleta/métodos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Tilápia/microbiologia , Difração de Raios X/métodos
20.
Expert Opin Drug Metab Toxicol ; 13(7): 783-791, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28637373

RESUMO

INTRODUCTION: Apaziquone (also known as EO9 and QapzolaTM) is a prodrug that is activated to DNA damaging species by oxidoreductases (particularly NQO1) and has the ability to kill aerobic and/or hypoxic cancer cells. Areas covered: Whilst its poor pharmacokinetic properties contributed to its failure in phase II clinical trials when administered intravenously, these properties were ideal for loco-regional therapies. Apaziquone demonstrated good anti-cancer activity against non-muscle invasive bladder cancer (NMIBC) when administered intravesically to marker lesions and was well tolerated with no systemic side effects. However, phase III clinical trials did not reach statistical significance for the primary endpoint of 2-year recurrence in apaziquone over placebo although improvements were observed. Post-hoc analysis of the combined study data did indicate a significant benefit for patients treated with apaziquone, especially when the instillation of apaziquone was given 30 min or more after surgery. A further phase III study is ongoing to test the hypotheses generated in the unsuccessful phase III studies conducted to date. Expert opinion: Because of its specific pharmacological properties, Apaziquone is excellently suited for local therapy such as NMIBC. Future studies should include proper biomarkers.


Assuntos
Antineoplásicos/administração & dosagem , Aziridinas/administração & dosagem , Indolquinonas/administração & dosagem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Aziridinas/farmacocinética , Aziridinas/farmacologia , Humanos , Indolquinonas/farmacocinética , Indolquinonas/farmacologia , Invasividade Neoplásica , Recidiva Local de Neoplasia , Neoplasias da Bexiga Urinária/patologia
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