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1.
Int Immunopharmacol ; 110: 108984, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35780642

RESUMO

The centrally acting antitussive opiate derivative, noscapine, has been claimed to be a non-competitive bradykinin B2 receptor antagonist. Raloxifene, a selective estrogen receptor modulator, was predicted to bind the bradykinin B2 receptor and to exert a partial agonist activity. These intriguing claims suggest that new molecular scaffolds ("chemotypes") may be identified for small molecule ligands of kinin receptors and that some off-target effects of noscapine or raloxifene may be mediated by bradykinin B2 receptors. An established contractile bioassay for ligands of the bradykinin B2 receptor, the isolated human umbilical vein, was exploited to characterize the inhibitory effect of noscapine and raloxifene on the B2 receptor-mediated contractile response to bradykinin. Observed effects were compared with those of the peptide antagonist icatibant, a potent, selective and competitive B2 receptor antagonist. Our results indicate that neither noscapine (2.5 µM) nor raloxifene (20 µM) behave as B2 receptor antagonists in concentrations that vastly exceeded an effective concentration of the control antagonist, icatibant; further, none of these drugs had direct contractile effects. It is suggested that the previously reported B2 receptor inhibitory effect of noscapine, a putative sigma-receptor agonist, might result from an indirect physiological antagonism, while raloxifene did not appear to have any significant affinity for the B2 receptors.


Assuntos
Noscapina , Receptores da Bradicinina , Bioensaio , Bradicinina/metabolismo , Antagonistas dos Receptores da Bradicinina , Humanos , Noscapina/farmacologia , Cloridrato de Raloxifeno/farmacologia , Receptor B1 da Bradicinina , Receptor B2 da Bradicinina , Receptores da Bradicinina/metabolismo , Veias Umbilicais/metabolismo
2.
Chirality ; 34(10): 1371-1382, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35778873

RESUMO

Noscapine is an isolated compound from the opium poppy, with distinctive chiral structure and chemistry, interacts with other compounds due to having multiple π-acceptors, hydrogen bond acceptors, and ionic sites. Therefore, it has promising applicability for the enantioselective separation of a wide range of polar, acidic, basic, and neutral compounds. A new noscapine derivative chiral stationary phase (ND-CSP) has been synthesized by consecutive N-demethylation, reduction, and N-propargylation of noscapine followed by attachment of a solid epoxy-functionalized silica bed through the 1,3-dipolar Huisgen cycloaddition. The noscapine derivative-based stationary phase provides a considerable surface coverage, which is greater than some commercial CSPs and can validate better enantioresolution performance. The major advantages inherent to this chiral selector are stability, reproducibility after more than 200 tests, and substantial loading capacity. The characterization by Fourier transform infrared (FTIR) spectroscopy and elemental analysis indicated successful functionalization of the silica surface. Chromatographic method conditions like flow rate and mobile phase composition for enantioseparation of various compounds such as warfarin, propranolol, mandelic acid, and a sulfanilamide derivative were optimized. Comparing the experimental results with docking data revealed a clear correlation between the calculated binding energy of ND-CSP and each enantiomer with the resolution of enantiomer peaks.


Assuntos
Noscapina , Cromatografia Líquida de Alta Pressão/métodos , Reprodutibilidade dos Testes , Dióxido de Silício/química , Estereoisomerismo
3.
Appl Biochem Biotechnol ; 194(10): 4292-4318, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35366187

RESUMO

Epidermal growth factor receptor tyrosine kinase domain (EGFR-TKD) plays a pivotal role in cellular signaling, growth, and metabolism. The EGFR-TKD is highly expressed in cancer cells and was endorsed as a therapeutic target for cancer management to overcome metastasis, cell proliferation, and angiogenesis. The novel thiazolo-[2,3-b]quinazolinones series were strategically developed by microwave-assisted organic synthesis and multi dominos reactions aimed to identify the potent thiazolo-[2,3-b]quinazolinone inhibitor against EGFR-TKD. This study explores the binding stability and binding strength of newly developed series via molecular docking, molecular dynamics simulation, and MM/PBSA and MM/GBSA calculations. The binding interaction was observed to be through the functional groups on aryl substituents at positions 3 and 5 of the thiazolo-[2, 3-b]quinazolinone scaffold. The methyl substituents at position 8 of the ligands had prominent hydrophobic interactions corroborating their bindings similar to the reference FDA-approved drug erlotinib in the active site. ADMET predictions reveal that derivatives 5ab, 5aq, and 5bq are drug-like and may be effective in in vitro study. Molecular dynamics simulation for 100 ns of docked complexes revealed their stability at the atomistic level. The ΔGbinding of thiazolo-[2,3-b]quinazolinone was found to be 5ab - 22.45, 5aq - 22.23, and 5bq - 20.76 similar to standard drug, and erlotinib - 24.11 kcal/mol was determined by MM/GBSA method. Furthermore, the anti-proliferative activity of leads of thiazolo-[2,3-b]quinazolinones (n = 3) was studied against breast cancer cell line (MCF-7) and non-small lung carcinoma cell line (H-1299). The highest inhibitions in cell proliferation were shown by 5bq derivatives, and the IC50 was found to be 6.5 ± 0.67 µM against MCF-7 and 14.8 µM against H-1299. The noscapine was also taken as a positive control and showed IC50 at higher concentrations 37 ± 1 against MCF-7 and 46.5 ± 1.2 against H-1299.


Assuntos
Antineoplásicos , Noscapina , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/farmacologia , Cloridrato de Erlotinib/farmacologia , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Noscapina/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinonas/química , Quinazolinonas/farmacologia , Relação Estrutura-Atividade , Tirosina
4.
J Photochem Photobiol B ; 229: 112415, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35231758

RESUMO

Noscapine (NSC) is a benzyl-isoquinoline alkaloid discovered in 1930 as an antitussive agent. Recently, NSC has also been reported to exhibit antitumor activity and, according to computational studies, it is able to attack the protease enzyme of Coronavirus (COVID-19) and thus could be used as antiviral for COVID-19 pandemic. Therefore, an increasing use of this drug could be envisaged in the coming years. NSC is readily metabolized with a half-life of 4.5 h giving rise to cotarnine, hydrocotarnine, and meconine, arising from the oxidative breaking of the CC bond between isoquinoline and phthalide moieties. Because of its potentially increasing use, high concentrations of NSC but also its metabolites will be delivered in the environment and potentially affect natural ecosystems. Thus, the aim of this work is to investigate the degradation of NSC in the presence of naturally occurring photocatalysts. As a matter of fact, the present contribution has demonstrated that NSC can be efficiently degraded in the presence of a derivative of the natural organic dye Riboflavin (RFTA) upon exposure to visible light. Indeed, a detailed study of the mechanism involved in the photodegradation revealed the similarities between the biomimetic and the photocatalyzed processes. In fact, the main photoproducts of NSC were identified as cotarnine and opianic acid based on a careful UPLC-MS2 analysis compared to the independently synthesized standards. The former is coincident with one of the main metabolites obtained in humans, whereas the latter is related to meconine, a second major metabolite of NSC. Photophysical experiments demonstrated that the observed oxidative cleavage is mediated mainly by singlet oxygen in a medium in which the lifetime of 1O2 is long enough, or by electron transfer to the triplet excited state of RFTA if the photodegradation occurs in aqueous media, where the 1O2 lifetime is very short.


Assuntos
COVID-19 , Recuperação e Remediação Ambiental , Noscapina , Biomimética , Cromatografia Líquida , Corantes , Ecossistema , Humanos , Luz , Pandemias , Fotólise , Riboflavina/química , Espectrometria de Massas em Tandem , Água/química
5.
Naunyn Schmiedebergs Arch Pharmacol ; 395(2): 167-185, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34988596

RESUMO

Ischemic stroke presents multifaceted pathological outcomes with overlapping mechanisms of cerebral injury. High mortality and disability with stroke warrant a novel multi-targeted therapeutic approach. The neuroprotection with progesterone (PG) and noscapine (NOS) on cerebral ischemia-reperfusion (I-R) injury was demonstrated individually, but the outcome of combination treatment to alleviate cerebral damage is still unexplored. Randomly divided groups of rats (n = 6) were Sham-operated, I-R, PG (8 mg/kg), NOS (10 mg/kg), and PG + NOS (8 mg/kg + 10 mg/kg). The rats were exposed to bilateral common carotid artery occlusion, except Sham-operated, to investigate the therapeutic outcome of PG and NOS alone and in combination on I-R injury. Besides the alterations in cognitive and motor abilities, we estimated infarct area, oxidative stress, blood-brain barrier (BBB) permeability, and histology after treatment. Pharmacokinetic parameters like Cmax, Tmax, half-life, and AUC0-t were estimated in biological samples to substantiate the therapeutic outcomes of the combination treatment. We report PG and NOS prevent loss of motor ability and improve spatial memory after cerebral I-R injury. Combination treatment significantly reduced inflammation and restricted infarction; it attenuated oxidative stress and BBB damage and improved grip strength. Histopathological analysis demonstrated a significant reduction in leukocyte infiltration with the most profound effect in the combination group. Simultaneous analysis of PG and NOS in plasma revealed enhanced peak drug concentration, improved AUC, and prolonged half-life; the drug levels in the brain have increased significantly for both. We conclude that PG and NOS have beneficial effects against brain damage and the co-administration further reinforced neuroprotection in the cerebral ischemia-reperfusion injury.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Noscapina/administração & dosagem , Progesterona/administração & dosagem , Animais , Área Sob a Curva , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Meia-Vida , AVC Isquêmico/tratamento farmacológico , Masculino , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/farmacologia , Noscapina/farmacocinética , Noscapina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Progesterona/farmacocinética , Progesterona/farmacologia , Ratos , Ratos Wistar , Traumatismo por Reperfusão/tratamento farmacológico
6.
Br J Clin Pharmacol ; 88(4): 1713-1721, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34427950

RESUMO

AIMS: The French Ministry of Health scheduled opioid cough suppressants as prescription-only drugs on 12 July 2017. The present study assessed the impact of this regulation on the diversion modalities of the concerned drugs and the related drug pholcodine by analysing the national OSIAP (Ordonnances Suspectes Indicateur d'Abus Possible) database. METHODS: Medical prescriptions with at least 1 mention of codeine, dextromethorphan, ethylmorphine, noscapine or pholcodine for cough suppression recorded in 2013-2019 were extracted from OSIAP. Annual mentioning rates were estimated by dividing numbers of mentions over those of prescriptions recorded the year considered. A descriptive analysis compared the characteristics of prescriptions before and after 12 July 2017. RESULTS: Overall, 832 mentions of the requested drugs were retrieved on 827 prescription forms. Codeine was the most frequent (n = 809, 8.7%) with 6 additional mentions of codeine/ethylmorphine combination, followed by dextromethorphan (n = 11, 0.1%) and pholcodine (n = 6, 0.1%). There was no mention of noscapine. Annual mentioning rates varied between 0 and 0.3% for all drugs except codeine. Codeine mentioning rates ranged between 0.3% (n = 2) and 0.7% (n = 9) before 12 July 2017 and increased to 10.1% (n = 61) thereafter in 2017, 16.1% (n = 314) in 2018, and 19.8% (n = 414) in 2019. The profile of subjects evolved accordingly with an increased male/female ratio (10.0 vs. 1.5 before) and decreased age (23 vs. 40 y before, P < .001). DISCUSSION: The sharp increase of recourse to falsified prescription forms indicates that codeine diversion continues despite restricted access, whereas the other drugs studied do not seem to have been impacted.


Assuntos
Antitussígenos , Noscapina , Analgésicos Opioides/uso terapêutico , Codeína , Tosse/tratamento farmacológico , Dextrometorfano , Etilmorfina , Feminino , Humanos , Masculino , Medicamentos sem Prescrição/uso terapêutico , Prescrições
7.
J Biomol Struct Dyn ; 40(6): 2600-2620, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-33140690

RESUMO

First case of the present epidemic, coronavirus disease (COVID-19) is reported in the Wuhan, a city of the China and all the countries throughout the world are being affected. COVID-19 is named by World Health Organization and it stands for coronavirus disease-19. As on 27th October, 2020, 73,776,588 people around the world are infected. It is also known as SARS-CoV-2 infection. Till date, there is no promising drug or vaccine available in market to cure from this lethal infection. As the literature reported that noscapine a promising candidate to cure from malaria as well reported to be cough suppressant and anti-cancerous. In our previous work, a derivative of noscapine has shown potential behavior against the main protease of novel coronavirus or SARS-CoV-2. Based on the previous study, hybrid molecules based on noscapine and repurposing (antiviral) drugs were designed to target the main protease of novel coronavirus and falcipan-2 using molecular docking. It is proposed that the designed hydrids or conjugates may have promising antiviral property i.e. against the main protease of novel coronavirus and falcipan-2. The designed molecules were thoroughly studied by DFT and different thermodynamic parameters were determined. Further, infrared and Raman spectra of the designed hybrid molecules were determined and studied. Communicated by Ramaswamy H. Sarma.


Assuntos
COVID-19 , Proteases 3C de Coronavírus/antagonistas & inibidores , Noscapina , Inibidores de Proteases , SARS-CoV-2/efeitos dos fármacos , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Noscapina/farmacologia , Inibidores de Proteases/farmacologia
8.
Drug Dev Res ; 83(3): 605-614, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34612529

RESUMO

Noscapine is a phthalide isoquinoline alkaloid present in the latex of Papaver somniferum and has demonstrated potent antitumor activity in various cancer models. Structural changes in the core molecule of noscapine architecture have produced a number of potent analogs. We have recently synthesized the novel noscapine analogs (3, 4, and 5) with different functional groups appended at ninth position of natural noscapine. The anticancer activity of these compounds has been investigated using various human cancer cell lines such as HeLa (cervical cancer), DU-145 (prostate cancer), MCF-7 (breast cancer), and IMR-32 (neuroblastoma). One of the compounds in this series, 9-ethynyl noscapine (5), has demonstrated good anticancer activity against HeLa cells. Biological studies demonstrated that compound 5 decreased cell viability and colony formation in HeLa cells in a concentration dependent manner. To further uncover the mechanism in detail, we evaluated compound 5 effect on cell cycle progression, microtubule dynamics, and apoptosis. Cell cycle and western blotting analysis revealed that 9-ethynyl noscapine treatment resulted in cell cycle arrest at G2/M and decreased CDK1 and cyclinB1 protein expression. We also observed that 9-ethynyl noscapine (5) treatment leads to disruption in tubulin polymerization and induction of apoptosis by decreasing expression of bcl2, pro-caspase 3, and activation of cytochrome C. Taken together, our results indicate that 9-ethynyl noscapine (5) effectively supresses the growth of cervical cancer cells (HeLa) by disrupting tubulin polymerization, cell cycle progression leading to apoptosis.


Assuntos
Antineoplásicos , Noscapina , Neoplasias do Colo do Útero , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular , Células HeLa , Humanos , Masculino , Noscapina/farmacologia , Polimerização , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Tubulina (Proteína)/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
9.
J Biomol Struct Dyn ; 40(1): 101-116, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32815796

RESUMO

Coronavirus pandemic has caused a vast number of deaths worldwide. Thus creating an urgent need to develop effective counteragents against novel coronavirus disease (COVID-19). Many antiviral drugs have been repurposed for treatment but implicated minimal recovery, which further advanced the need for clearer insights and innovation to derive effective therapeutics. Strategically, Noscapine, an approved antitussive drug with positive effects on lung linings may show favorable outcomes synergistically with antiviral drugs in trials. Hence, we have theoretically examined the combinatorial drug therapy by culminating the existing experimental results with in silico analyses. We employed the antitussive noscapine in conjugation with antiviral drugs (Chloroquine, Umifenovir, Hydroxychloroquine, Favlplravir and Galidesivir). We found that Noscapine-Hydroxychloroquine (Nos-Hcq) conjugate has strong binding affinity for the main protease (Mpro) of SARS-CoV-2, which performs key biological function in virus infection and progression. Nos-Hcq was analyzed through molecular dynamics simulation. The MD simulation for 100 ns affirmed the stable binding of conjugation unprecedentedly through RMSD and radius of gyration plots along with critical reaction coordinate binding free energy profile. Also, dynamical residue cross-correlation map with principal component analysis depicted the stable binding of Nos-Hcq conjugate to Mpro domains with optimal secondary structure statistics of complex dynamics. Also, we reveal the drugs with stable binding to major domains of Mpro can significantly improve the work profile of reaction coordinates, drug accession and inhibitory regulation of Mpro. The designed combinatorial therapy paves way for further prioritized in vitro and in vivo investigations for drug with robust binding against Mpro of SARS-CoV-2.


Assuntos
Antitussígenos , COVID-19 , Noscapina , Antivirais/uso terapêutico , Quimioinformática , Humanos , Simulação de Acoplamento Molecular , Inibidores de Proteases , SARS-CoV-2
10.
Chem Biol Interact ; 352: 109794, 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-34963564

RESUMO

Noscapine is a phthalide isoquinoline alkaloid with antitussive activity. Noscapine protects oligodendroglia from ischemic and chemical injury, binds to bitter taste receptors, antagonizes the bradykinin and histaminergic systems, which may be of benefit in treatment of multiple sclerosis. Noscapine normalizes axonal transport and exerts significant therapeutic efficacy in animal models of Parkinson's Disease and Amyotrophic Lateral Sclerosis. Noscapine exerts neuroprotective effects on oxygen- and glucose-deprived fetal cortical neuronal cells and reduces ischemic brain damage in neonatal rat pups. Pilot clinical studies indicated some beneficial effects of noscapine in stroke. Noscapine harbours anxiolytic activity and methyl-noscapine blocks small conductance SK channels, which is beneficial in alleviating anxiety and depression. Noscapine exerts anticholinesterase activity and acts inhibitory on the inflammatory transcription factor NF-κB, which may be harnessed in treatment of Alzheimer's Disease. With its blood-brain barrier traversing features and versatile actions, noscapine may be a promising agent in the armamentarium against neurodegenerative and psychiatric diseases.


Assuntos
/farmacologia , Fármacos Neuroprotetores/farmacologia , Noscapina/farmacologia , Doença de Alzheimer/tratamento farmacológico , Esclerose Amiotrófica Lateral/tratamento farmacológico , Animais , Bradicinina/metabolismo , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Canais Iônicos/efeitos dos fármacos , Transtornos Mentais/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Noscapina/administração & dosagem , Noscapina/sangue , Oligodendroglia/efeitos dos fármacos , Transtornos Parkinsonianos/tratamento farmacológico , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico
11.
Comput Biol Med ; 139: 104996, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34753081

RESUMO

To strategically design and frame the novel 9-Br-Trimethoxybenzyl noscapine (BTN) with rigorous binding affinity with tubulin, the structure of noscapine (an antitussive plant alkaloid) was amended with a 3,4,5-trimethoxybenzyl group linked at the seventh position on the lower isobenzofuran unit. Molecular modelling and cellular studies were used to assess the single and combined effects of BTN and docetaxel (DOX). Based on MM-GBSA, the individual calculated free energies of binding (ΔGbind, pred) for BTN and DOX with tubulin was found to be -25.69 and -38.17 kcal/mol, respectively, and -29.11 and -36.60 kcal/mol based on MM-PBSA. Furthermore, the ΔGbind,pred of BTN was dramatically reduced (-30.02 and -33.54 kcal/mol using MM-GBSA and MM-PBSA) in presence of DOX on its binding pocket. Parenthetically, the ΔGbind,pred of DOX was substantially decreased (-39.17 and -35.80 kcal/mol using MM-GBSA and MM-PBSA) in the presence of BTN on its binding pocket. The synergistic activity of both compounds on tubulin dimmer was also analysed using purified tubulin, where a combined regimen of BTN and DOX attenuated tubulin intensity to a higher value (50%) particularly in comparison to the single regimen. In comparison to the single regimen, the combination of BTN and DOX effectively prevents cell cycle progression during the G2/M phase and induces breast cancer cell death. Female athymic nude mice were xenografted with MCF-7 cells and the efficacy of (150 mg/kg/day), DOX (1.5 mg/kg/week, i.v.), or in combination (BTN 300 mg/kg/day + DOX 1.0 mg/kg/week, i.v) were evaluated.


Assuntos
Antineoplásicos , Neoplasias da Mama , Noscapina , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Docetaxel/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Noscapina/farmacologia , Tubulina (Proteína)
12.
Nat Commun ; 12(1): 6030, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34654815

RESUMO

For millions of years, plants evolve plenty of structurally diverse secondary metabolites (SM) to support their sessile lifestyles through continuous biochemical pathway innovation. While new genes commonly drive the evolution of plant SM pathway, how a full biosynthetic pathway evolves remains poorly understood. The evolution of pathway involves recruiting new genes along the reaction cascade forwardly, backwardly, or in a patchwork manner. With three chromosome-scale Papaver genome assemblies, we here reveal whole-genome duplications (WGDs) apparently accelerate chromosomal rearrangements with a nonrandom distribution towards SM optimization. A burst of structural variants involving fusions, translocations and duplications within 7.7 million years have assembled nine genes into the benzylisoquinoline alkaloids gene cluster, following a punctuated patchwork model. Biosynthetic gene copies and their total expression matter to morphinan production. Our results demonstrate how new genes have been recruited from a WGD-induced repertoire of unregulated enzymes with promiscuous reactivities to innovate efficient metabolic pathways with spatiotemporal constraint.


Assuntos
Vias Biossintéticas , Cromossomos/metabolismo , Morfinanos/metabolismo , Noscapina/metabolismo , Papaver/genética , Papaver/metabolismo , Alcaloides/química , Alcaloides/metabolismo , Benzilisoquinolinas/metabolismo , Vias Biossintéticas/genética , Evolução Molecular , Genoma , Genômica , Família Multigênica , Proteínas de Plantas/genética
13.
Biofactors ; 47(6): 975-991, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34534373

RESUMO

Noscapine has been mentioned as one of the effective drugs with potential therapeutic applications. With few side effects and amazing capabilities, noscapine can be considered different from other opioids-like structure compounds. Since 1930, extensive studies have been conducted in the field of pharmacological treatments from against malaria to control cough and cancer treatment. Furthermore, recent studies have shown that noscapine and some analogues, like 9-bromonoscapine, amino noscapine, and 9-nitronoscapine, can be used to treat polycystic ovaries syndrome, stroke, and other diseases. Given the numerous results presented in this field and the role of different receptors in the therapeutic effects of noscapine, we aimed to review the properties, therapeutic effects, and the role of receptors in the treatment of noscapine.


Assuntos
Anti-Inflamatórios/farmacologia , Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Antitussígenos/farmacologia , Noscapina/química , Noscapina/farmacologia , Animais , Anti-Inflamatórios/química , Antimaláricos/química , Antineoplásicos/química , Antitussígenos/química , Apoptose/efeitos dos fármacos , Feminino , Humanos , Camundongos , Noscapina/análogos & derivados
14.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361780

RESUMO

Parkinson's disease is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) and the resultant loss of dopamine in the striatum. Various studies have shown that oxidative stress and neuroinflammation plays a major role in PD progression. In addition, the autophagy lysosome pathway (ALP) plays an important role in the degradation of aggregated proteins, abnormal cytoplasmic organelles and proteins for intracellular homeostasis. Dysfunction of ALP results in the accumulation of α-synuclein and the loss of dopaminergic neurons in PD. Thus, modulating ALP is becoming an appealing therapeutic intervention. In our current study, we wanted to evaluate the neuroprotective potency of noscapine in a rotenone-induced PD rat model. Rats were administered rotenone injections (2.5 mg/kg, i.p.,) daily followed by noscapine (10 mg/kg, i.p.,) for four weeks. Noscapine, an iso-qinulinin alkaloid found naturally in the Papaveraceae family, has traditionally been used in the treatment of cancer, stroke and fibrosis. However, the neuroprotective potency of noscapine has not been analyzed. Our study showed that administration of noscapine decreased the upregulation of pro-inflammatory factors, oxidative stress, and α-synuclein expression with a significant increase in antioxidant enzymes. In addition, noscapine prevented rotenone-induced activation of microglia and astrocytes. These neuroprotective mechanisms resulted in a decrease in dopaminergic neuron loss in SNpc and neuronal fibers in the striatum. Further, noscapine administration enhanced the mTOR-mediated p70S6K pathway as well as inhibited apoptosis. In addition to these mechanisms, noscapine prevented a rotenone-mediated increase in lysosomal degradation, resulting in a decrease in α-synuclein aggregation. However, further studies are needed to further develop noscapine as a potential therapeutic candidate for PD treatment.


Assuntos
Autofagia/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Noscapina/farmacologia , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson Secundária/genética , Parte Compacta da Substância Negra/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Catalase/genética , Catalase/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia , Ratos , Ratos Wistar , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Rotenona/toxicidade , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , alfa-Sinucleína/antagonistas & inibidores , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
15.
Bioorg Chem ; 115: 105135, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34303039

RESUMO

Noscapine is a natural product first isolated from the opium poppy (Papaver somniferum L.) with anticancer properties. In this work, we report the synthesis and cellular screening of a noscapine-based library. A library of novel noscapine derivatives was synthesized with modifications in the isoquinoline and phthalide scaffolds. The so generated library, consisting of fifty-seven derivatives of the natural product noscapine, was tested against MDA-MB-231 breast cancer cells in a cellular proliferation assay (with a Z' > 0.7). The screening resulted in the identification of two novel noscapine derivatives as inhibitors of MDA cell growth with IC50 values of 5 µM and 1.5 µM, respectively. Both hit molecules have a five-fold and seventeen-fold higher potency, compared with that of lead compound noscapine (IC50 26 µM). The identified active derivatives retain the tubulin-binding ability of noscapine. Further testing of both hit molecules, alongside the natural product against additional cancer cell lines (HepG2, HeLa and PC3 cells) confirmed our initial findings. Both molecules have improved anti-proliferative properties when compared to the initial natural product, noscapine.


Assuntos
Antineoplásicos/síntese química , Noscapina/química , Bibliotecas de Moléculas Pequenas/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Benzofuranos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Humanos , Isoquinolinas/química , Papaver/química , Papaver/metabolismo , Ligação Proteica , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo
16.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069423

RESUMO

Endometrosis is a reproductive pathology that is responsible for mare infertility. Our recent studies have focused on the involvement of neutrophil extracellular traps enzymes, such as elastase (ELA), in the development of equine endometrosis. Noscapine (NOSC) is an alkaloid derived from poppy opium with anticough, antistroke, anticancer, and antifibrotic properties. The present work investigates the putative inhibitory in vitro effect of NOSC on collagen type I alpha 2 chain (COL1A2) mRNA and COL1 protein relative abundance induced by ELA in endometrial explants of mares in the follicular or mid-luteal phases at 24 or 48 h of treatment. The COL1A2 mRNA was evaluated by qPCR and COL1 protein relative abundance by Western blot. In equine endometrial explants, ELA increased COL 1 expression, while NOSC inhibited it at both estrous cycle phases and treatment times. These findings contribute to the future development of new endometrosis treatment approaches. Noscapine could be a drug capable of preventing collagen synthesis in mare's endometrium and facilitate the therapeutic approach.


Assuntos
Colágeno Tipo I/metabolismo , Endometriose/metabolismo , Noscapina/farmacologia , Animais , Colágeno/metabolismo , Colágeno Tipo I/efeitos dos fármacos , Colágeno Tipo I/genética , Endometriose/tratamento farmacológico , Endometriose/veterinária , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Ciclo Estral , Armadilhas Extracelulares/metabolismo , Feminino , Fibrose , Doenças dos Cavalos/patologia , Cavalos , Noscapina/metabolismo , Elastase Pancreática/metabolismo , Inibidores de Proteases/farmacologia
17.
Chem Biol Drug Des ; 98(3): 466-479, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34107169

RESUMO

Noscapine, an opium alkaloid, was discovered to bind tubulin, arrest dividing cells at mitosis, and selectively induce apoptosis to cancer cells. N-3-Br-Benzyl-Noscapine (Br-Bn-Nos), one of the derivatives of noscapine, was demonstrated to have improved anticancer potential compared with noscapine. We approached to evaluate the single and combined effect of Br-Bn-Nos and docetaxel (DOX) based on molecular modeling and cellular study. The individual predicted free energy of binding (∆Gbind,pred ) for Br-Bn-Nos and DOX with tubulin was found to be -28.89 and -36.07 kcal/mol based on molecular mechanics generalized Born solvation area (MM-GBSA) as well as -26.21 and -34.65 kcal/mol based on molecular mechanics Poisson Boltzmann solvation area (MM-PBSA), respectively. However, the ∆Gbind,pred of Br-Bn-Nos was significantly reduced (-33.02 and -30.24 kcal/mol using MM-GBSA and MM-PBSA) in the presence of DOX on its binding pocket. Parenthetically, the ∆Gbind,pred of DOX was significantly reduced (-37.17 and -32.80 kcal/mol using MM-GBSA and MM-PBSA) in the presence of Br-Bn-Nos on its binding pocket. The reduced ∆Gbind,pred in the presence of Br-Bn-Nos and DOX together indicated a combination effect of both the ligands. The combined interaction of both the agents onto tubulin dimmer was also determined experimentally using purified tubulin, in which a combination regimen of Br-Bn-Nos and DOX reduced the fluorescence intensity of tubulin to a higher value (68%) compared with the single regimen. Further, isobologram analysis revealed the synergistic effect of Br-Bn-Nos and DOX in antiproliferative activity using MCF-7 cell line at 48 hr (sum FIC = 0.49) and at 72 hr (sum FIC = 0.62). The combination dose regimen of Br-Bn-Nos and DOX blocks the cell cycle progression at the G2/M phase and induces apoptosis to cancer cells more effectively compared with the single regimen. Taken together, our study provides compelling evidence that the anticancer potential of noscapine derivatives may be substantially improved when it is used in a combined application with DOX for breast cancer.


Assuntos
Antineoplásicos/química , Docetaxel/química , Noscapina/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Docetaxel/metabolismo , Docetaxel/farmacologia , Sinergismo Farmacológico , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Noscapina/metabolismo , Noscapina/farmacologia , Termodinâmica , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo
18.
Chem Biol Drug Des ; 98(3): 445-465, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34051055

RESUMO

The scaffold structure of noscapine (an antitussive plant alkaloid) was modified by inducting N-aryl methyl pharmacophore at C-9 position of the isoquinoline ring to rationally design and screened three novel 9-(N-arylmethylamino) noscapinoids, 15-17 with robust binding affinity with tubulin. The selected 9-(N-arylmethylamino) noscapinoids revealed improved predicted binding energy of -6.694 kcal/mol for 15, -7.118 kcal/mol for 16 and -7.732 kcal/mol for 17, respectively in comparison to the lead molecule (-5.135 kcal/mol). These novel derivatives were chemically synthesized and validated their anticancer activity based on cellular studies using two human breast adenocarcinoma, MCF-7 and MDA-MB-231, as well as with a panel of primary breast tumor cells. These derivatives inhibited cellular proliferation in all the cancer cells that ranged between 3.2 and 32.2 µM, which is 11.9 to 1.8 fold lower than that of noscapine. These novel derivatives effectively arrest the cell cycle in the G2/M phase followed by apoptosis and appearance of apoptotic cells. Thus, we conclude that 9-(N-arylmethyl amino) noscapinoids, 15-17 have a high probability to be a novel therapeutic agent for breast cancers.


Assuntos
Aminas/química , Antineoplásicos/síntese química , Desenho de Fármacos , Noscapina/análogos & derivados , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Noscapina/metabolismo , Noscapina/farmacologia , Ligação Proteica , Relação Estrutura-Atividade , Termodinâmica , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo
19.
J Mol Graph Model ; 106: 107933, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33991960

RESUMO

We present a new class of derivatives of noscapine, 1,3-diynyl-noscapinoids of an antitussive plant alkaloid, noscapine based on our in silico efforts that binds tubulin and displays anticancer activity against a panel of breast cancer cells. Structure-activity analyses pointed the C-9 position of the isoquinoline ring which was modified by coupling of 1,3-diynyl structural motifs to rationally design and screened a series of novel 1,3-diynyl-noscapinoids (20-22) with robust binding affinity with tubulin. The selected 1,3-diynyl-noscapinoids, 20-22 revealed improved predicted binding energy of -6.568 kcal/mol for 20, -7.367 kcal/mol for 21 and -7.922 kcal/mol for 22, respectively in comparison to the lead molecule (-5.246 kcal/mol). These novel derivatives were chemically synthesized and validated their anticancer activity based on cellular studies using two human breast adenocarcinoma, MCF-7 and MDAMB-231, as well as with a panel of primary breast cancer cells isolated from patients. Interestingly, all these derivatives inhibited cellular proliferation in all the cancer cells that ranged between 6.2 to 38.9 µM, which is 6.7 to 1.5 fold lower than that of noscapine. Unlike previously reported derivatives of noscapine that arrests cells in the S-phase, these novel derivatives effectively inhibit proliferation of cancer cells, arrests cell cycle in the G2/M-phase followed by apoptosis and appearance of apoptotic cells. Thus, we conclude that 1,3-diynyl-noscapinoids have great potential to be a novel therapeutic agent for breast cancers.


Assuntos
Antineoplásicos , Noscapina , Antineoplásicos/farmacologia , Ciclo Celular , Linhagem Celular Tumoral , Humanos , Noscapina/farmacologia , Ligação Proteica , Tubulina (Proteína)/metabolismo
20.
Bioorg Med Chem Lett ; 43: 128055, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33892103

RESUMO

The antibacterial properties of close noscapine analogs have not been previously reported. We used our pDualrep2 double-reporter High Throughput Screening (HTS) platform to identify a series of noscapine derivatives with promising antibacterial activity. The platform is based on RPF (SOS-response/DNA damage) and Katushka2S (inhibition of translation) proteins and simultaneously provides information on antibacterial activity and the mechanism of action of small-molecule compounds against E. coli. The most potent compound exhibited an MIC of 13.5 µM(6.25 µg/ml) and a relatively low cytotoxicity against HEK293 cells (CC50 = 71 µM, selectivity index: ~5.5). Some compounds from this series induced average Katushka2S reporter signals, indicating inhibition of translation machinery in the bacteria; however, these compounds did not attenuate translation in vitro in a luciferase-based translation assay. The most effective compounds did not significantly arrest the mitotic cycle in HEK293 cells, in contrast to the parent compound in a flow cytometry assay. Several molecules showed activity against clinically relevant gram-negative and gram-positive bacterial strains. Compounds from the discovered series can be reasonably regarded as good templates for further development and evaluation.


Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Noscapina/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Noscapina/síntese química , Noscapina/química , Relação Estrutura-Atividade
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