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Molecules (Basel, Switzerland) Feb 2023Bioconversion of biosynthetic heterocyclic compounds has been utilized to produce new semisynthetic pharmaceuticals and study the metabolites of bioactive drugs used...
Bioconversion of biosynthetic heterocyclic compounds has been utilized to produce new semisynthetic pharmaceuticals and study the metabolites of bioactive drugs used systemically. In this investigation, the biotransformation of natural heterocyclic alkaloid papaverine via filamentous fungi was explored. Molecular docking simulations, using protein tyrosine phosphatase 1B (PTP1B), α-glucosidase and pancreatic lipase (PL) as target enzymes, were performed to investigate the antidiabetic potential of papaverine and its metabolites in silico. The metabolites were isolated from biotransformation of papaverine with NRRL 2310, NRRL y1592, ATCC 10002 and NRRL 1369 via reduction, demethylation, -oxidation, oxidation and hydroxylation reactions. Seven metabolites were isolated: namely, 3,4-dihydropapaverine (metabolite ), papaveroline (metabolite ), 7-demethyl papaverine (metabolite ), 6,4'-didemethyl papaverine (metabolite ), papaverine-3-ol (metabolite ), papaverinol (metabolite ) and papaverinol N-oxide (metabolite ). The structural elucidation of the metabolites was investigated with 1D and 2D NMR and mass spectroscopy (EI and ESI). The molecular docking studies showed that metabolite exhibited better binding interactions with the target enzymes PTP1B, α-glucosidase and PL than did papaverine. Furthermore, papaverinol--oxide () also displayed inhibition of α-glucosidase and lipase enzymes comparable to that of their ligands (acarbose and orlistat, respectively), as unveiled with an in silico ADMET profile, molecular docking and molecular dynamics studies. In conclusion, this study provides evidence for enhanced inhibition of PTP1B, α-glucosidase and PL via some papaverine fungal transformation products and, therefore, potentially better antidiabetic and antiobesity effects than those of papaverine and other known therapeutic agents.
Topics: Hypoglycemic Agents; Papaverine; Molecular Docking Simulation; alpha-Glucosidases; Biotransformation; Lipase; Oxides
PubMed: 36838572
DOI: 10.3390/molecules28041583 -
Andrology Jan 2017Cyclic adenosine monophosphate (cAMP) plays a crucial role as a signaling molecule for capacitation, motility, and acrosome reaction in mammalian spermatozoa. It is...
Cyclic adenosine monophosphate (cAMP) plays a crucial role as a signaling molecule for capacitation, motility, and acrosome reaction in mammalian spermatozoa. It is well-known that cAMP degradation by phosphodiesterase (PDE) enzyme has a major impact on sperm functions. This study was undertaken to characterize cAMP-PDE activity in bovine spermatozoa. Total cAMP-PDE activity in cauda epididymal and ejaculated spermatozoa was 543.2 ± 49.5 and 1252.6 ± 86.5 fmoles/min/10 spermatozoa, respectively. Using different family-specific PDE inhibitors, we showed that in cauda epididymal and ejaculated spermatozoa, the major cAMP-PDE activity was papaverine-sensitive (44.5% and 57.5%, respectively, at 400 nm, papaverine is a specific inhibitor of the PDE10 family). These data are supporting the functional presence of PDE10 in bovine spermatozoa and were further confirmed by western blot to be PDE10A. Using immunocytochemistry, we showed immunoreactive signal for PDE10A present on the post-acrosomal region of the head and on the flagella of ejaculated spermatozoa. Using papaverine, we showed that it promotes tyrosine phosphorylation of sperm proteins, phosphorylation of Erk1 and Erk2, and Ca release from Ca store. These results suggest that PDE10 is functionally present in bovine spermatozoa and is affecting different molecular events involved in capacitation, most probably by cAMP local regulation.
Topics: Acrosome Reaction; Animals; Calcium; Cattle; Epididymis; Male; Papaverine; Phosphoric Diester Hydrolases; Phosphorylation; Signal Transduction; Spermatozoa
PubMed: 27860455
DOI: 10.1111/andr.12290 -
Molecules (Basel, Switzerland) Nov 2020Cancer is one of the leading causes of death worldwide. Although several potential therapeutic agents have been developed to efficiently treat cancer, some side effects...
Cancer is one of the leading causes of death worldwide. Although several potential therapeutic agents have been developed to efficiently treat cancer, some side effects can occur simultaneously. Papaverine, a non-narcotic opium alkaloid, is a potential anticancer drug that showed selective antitumor activity in various tumor cells. Recent studies have demonstrated that metal complexes improve the biological activity of the parent bioactive ligands. Based on those facts, herein we describe the synthesis of novel papaverine-vanadium(III), ruthenium(III) and gold(III) metal complexes aiming at enhancing the biological activity of papaverine drug. The structures of the synthesized complexes were characterized by various spectroscopic methods (IR, UV-Vis, NMR, TGA, XRD, SEM). The anticancer activity of synthesized metal complexes was evaluated in vitro against two types of cancer cell lines: human breast cancer MCF-7 cells and hepatocellular carcinoma HepG-2 cells. The results revealed that papaverine-Au(III) complex, among the synthesized complexes, possess potential antimicrobial and anticancer activities. Interestingly, the anticancer activity of papaverine-Au(III) complex against the examined cancer cell lines was higher than that of the papaverine alone, which indicates that Au-metal complexation improved the anticancer activity of the parent drug. Additionally, the Au complex showed anticancer activity against the breast cancer MCF-7 cells better than that of cisplatin. The biocompatibility experiments showed that Au complex is less toxic than the papaverine drug alone with IC ≈ 111 µg/mL. These results indicate that papaverine-Au(III) complex is a promising anticancer complex-drug which would make it a suitable candidate for further in vivo investigations.
Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Chemistry Techniques, Synthetic; Coordination Complexes; Humans; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Molecular Structure; Nanostructures; Papaverine; Structure-Activity Relationship
PubMed: 33233775
DOI: 10.3390/molecules25225447 -
Non-addictive opium alkaloids selectively induce apoptosis in cancer cells compared to normal cells.Daru : Journal of Faculty of Pharmacy,... Feb 2015Cytotoxic effects of some of the members of papaveraceae family have been reported in Iranian folk medicine. Recent reports has indicated that alkaloids fraction of...
BACKGROUND
Cytotoxic effects of some of the members of papaveraceae family have been reported in Iranian folk medicine. Recent reports has indicated that alkaloids fraction of opium may be responsible for its cytotoxic effect; however, the mechanism of this effect is not fully understood. This study has been designed to investigate the selective cytotoxic, genotoxic and also apoptosis induction effects of noscapine, papaverine and narceine, three non-addictable opium alkaloids, on HT29, T47D and HT1080 cancer cell lines. Mouse NIH3T3 cell line was chosen to present non-cancerous cells and Doxorubicin was selected as the positive control.
METHODS
Cells were treated by different concentrations of Noscapine, Papaverine, Narceine and doxorubicin; viability was assessed by MTT assay. The genotoxicity and apoptosis induction were tested with comet assay and Annexin-V affinity when the concentration of each these drugs is less than its IC50. In addition, the DNA damage and caspase activity of the T47D cells were examined and the results were compared.
RESULTS
This study noted the cytotoxicity and genotoxicity of noscapine and papaverine, specifically on cancerous cell lines. Furthermore, papaverine induces apoptosis in all studied cancer cell lines and noscapine showed this effect in T47D and HT29 cells but not in NIH-3 T3 cells as noncancerous cell line. narceine also showed genototoxicity in the studied cell lines at its IC50 concentration.
CONCLUSIONS
This experiment suggests that noscapine and papaverine may be of use in cancer treatment due to their specific cytotoxicity and genotoxicity. However, further in vivo studies are needed to confirm its usefulness in cancer treatment.
Topics: Animals; Antineoplastic Agents; Apoptosis; Benzodioxoles; Cell Line, Tumor; Cell Proliferation; DNA, Neoplasm; Doxorubicin; HT29 Cells; Humans; Indole Alkaloids; Mice; NIH 3T3 Cells; Neoplasms; Noscapine; Opiate Alkaloids; Papaverine
PubMed: 25890335
DOI: 10.1186/s40199-015-0101-1 -
Molecules (Basel, Switzerland) Oct 2019The reaction of papaverine with a series of Baran Diversinates is reported. Although the yields were low, it was possible to synthesize a small biodiscovery library...
The reaction of papaverine with a series of Baran Diversinates is reported. Although the yields were low, it was possible to synthesize a small biodiscovery library using this plant alkaloid as a scaffold for late-stage C-H functionalization. Ten papaverine analogues (-), including seven new compounds, were synthesized. An unexpected radical-induced exchange reaction is reported where the dimethoxybenzyl group of papaverine was replaced by an alkyl group. This side reaction enabled the synthesis of additional novel fragments based on the isoquinoline scaffold, which is present in numerous natural products. Possible reasons for the poor yields in the Diversinate reactions with this particular scaffold are discussed.
Topics: Carbon-13 Magnetic Resonance Spectroscopy; Electrons; Models, Molecular; Papaverine; Proton Magnetic Resonance Spectroscopy; Sulfinic Acids
PubMed: 31683610
DOI: 10.3390/molecules24213938 -
Journal of Cardiothoracic Surgery Dec 2021Internal thoracic arteries (ITAs) are the gold standard conduits for coronary revascularization because of their long-term patency and anti-atherosclerotic properties.... (Review)
Review
Internal thoracic arteries (ITAs) are the gold standard conduits for coronary revascularization because of their long-term patency and anti-atherosclerotic properties. Harvesting and preparation of ITAs for revascularization is a technically demanding procedure with multiple challenges. Over the last few decades, various methods and techniques for ITAs harvesting have been introduced by different surgeons and applied in clinical practice with different results. Harvesting of ITAs in pedicled or skeletonized fashion, with electrocautery or harmonic scalpel, with open or intact pleura, with clipping the end or keeping it perfused; papaverine delivery with intraluminal injection, perivascular injection, injecting into endothoracic fascia, and papaverine topical spray are the different techniques introduced by the number of researchers. At the same time, access to the ITAs for harvesting has also been studied. Access and harvesting through median sternotomy, mini anterolateral thoracotomy, thoracoscopic, and robotic-assisted harvesting of ITAs are the different techniques used in clinical practice. However, the single standard method for harvesting and preparation of ITAs has yet to be determined. In this review article, we aimed to discuss and analyze all these techniques of harvesting and preparing ITAs with the help of literature to find the best way for ITAs harvesting and preparation for myocardial revascularization.
Topics: Humans; Mammary Arteries; Myocardial Revascularization; Papaverine; Thoracotomy; Tissue and Organ Harvesting
PubMed: 34961523
DOI: 10.1186/s13019-021-01733-2 -
Annals of Cardiac Anaesthesia 2020In this study, we aimed at a comparative quantitative estimation of the difference in LIMA blood flow between LIMAs treated with topical papaverine alone and LIMAs...
OBJECTIVE
In this study, we aimed at a comparative quantitative estimation of the difference in LIMA blood flow between LIMAs treated with topical papaverine alone and LIMAs treated with a combination of topical papaverine plus an intraluminal cocktail of papaverine, nitroglycerine, and milrinone.
METHODS
Nearly 50 consecutive patients with similar demographics undergoing elective on-pump CABG were recruited for the study. After pedicled LIMA harvest, topical papaverine was sprayed on the pedicle and kept enveloped in papaverine soaked gauze. LIMA flow was then estimated. Later, intraluminal vasodilator solution of papaverine, NTG, milrinone, and heparinized blood were instilled in LIMA, and LIMA flows were estimated.
RESULTS
The mean LIMA flows with topical papaverine alone was 47.19 mL/min whereas the mean LIMA flows with topical papaverine plus intraluminal cocktail was 104 mL/min. There was a significant difference between the two flows as their mean was 56.815 mL/min and the paired t-test for significance had a P value of 0.0001.
CONCLUSION
There was a significant difference in the LIMA flow when the LIMA had been treated with the intraluminal instillation of the vasodilator cocktail in addition to the topical application of papaverine solution. Therefore, intraluminal vasodilator cocktail of milrinone, NTG, and papaverine mixed with heparinized blood in addition to topical papaverine is a simple and effective method for LIMA preparation in CABG.
Topics: Coronary Artery Bypass; Humans; Male; Mammary Arteries; Nitroglycerin; Papaverine; Regional Blood Flow; Vasodilator Agents
PubMed: 33109796
DOI: 10.4103/aca.ACA_164_19 -
International Journal of Molecular... Apr 2022Papaverine (PPV) is a benzylisoquinoline alkaloid isolated from that exerts antiproliferative activity. However, several questions remain regarding the biochemical...
Papaverine (PPV) is a benzylisoquinoline alkaloid isolated from that exerts antiproliferative activity. However, several questions remain regarding the biochemical pathways affected by PPV in tumourigenic cells. In this study, the influence of PPV on cell migration (light microscopy), expression of vascular endothelial growth factor (VEGF) B, VEGF R1, VEGF R2, and phosphorylated focal adhesion kinase (pFAK) were investigated using spectrophotometry in MDA-MB-231-, A549- and DU145 cell lines. The migration assay revealed that, after 48 h, PPV (100 µM) reduced cell migration to 81%, 91%, and 71% in MDA-MB-231-, A549-, and DU145 cells, respectively. VEGF B expression was reduced to 0.79-, 0.71-, and 0.73-fold after 48 h of exposure to PPV in MDA-MB-231-, A549- and DU145 cells, while PPV exposure of 48 h increased VEGF R1 expression in MDA-MB-231- and DU145 cells to 1.38 and 1.46. A fold decrease in VEGF R1 expression was observed in A549 cells to 0.90 after exposure to 150 µM. No statistically significant effects were observed on VEGF R2- and FAK expression after exposure to PPV. This study contributes to the understanding of the effects of a phytomedicinal alkaloid compound in cancer cells and may provide novel approaches to the application of non-addictive alkaloids.
Topics: Antineoplastic Agents; Cell Line; Cell Movement; Humans; Neoplasms; Papaverine; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 35563045
DOI: 10.3390/ijms23094654 -
AJNR. American Journal of Neuroradiology Apr 1994Five cases of ipsilateral pupillary dilatation that developed during local intraarterial infusion of papaverine are reported. All patients were being treated for...
Five cases of ipsilateral pupillary dilatation that developed during local intraarterial infusion of papaverine are reported. All patients were being treated for symptomatic vasospasm secondary to subarachnoid hemorrhage. In each case, the tip of the infusion catheter was positioned in the internal carotid artery in close proximity to the ostium of the ophthalmic artery. Pupillary dilatation in all patients readily resolved after termination of the infusion.
Topics: Adult; Aged; Carotid Artery, Internal; Female; Humans; Infusions, Intra-Arterial; Ischemic Attack, Transient; Male; Middle Aged; Mydriasis; Ophthalmic Artery; Papaverine; Subarachnoid Hemorrhage
PubMed: 8010274
DOI: No ID Found -
Journal of Biochemistry Jul 2019Cytochrome P450 monooxygenases (P450s) play crucial roles in the cell metabolism and provide an unsurpassed diversity of catalysed reactions. Here, we report the...
Cytochrome P450 monooxygenases (P450s) play crucial roles in the cell metabolism and provide an unsurpassed diversity of catalysed reactions. Here, we report the identification and biochemical characterization of two P450s from Arthrobacter sp., a Gram-positive organism known to degrade the opium alkaloid papaverine. Combining phylogenetic and genomic analysis suggested physiological roles for P450s in metabolism and revealed potential gene clusters with redox partners facilitating the reconstitution of the P450 activities in vitro. CYP1232F1 catalyses the para demethylation of 3,4-dimethoxyphenylacetic acid to homovanillic acid while CYP1232A24 continues demethylation to 3,4-dihydroxyphenylacetic acid. Interestingly, the latter enzyme is also able to perform both demethylation steps with preference for the meta position. The crystal structure of CYP1232A24, which shares only 29% identity to previous published structures of P450s helped to rationalize the preferred demethylation specificity for the meta position and also the broader substrate specificity profile. In addition to the detailed characterization of the two P450s using their physiological redox partners, we report the construction of a highly active whole-cell Escherichia coli biocatalyst expressing CYP1232A24, which formed up to 1.77 g l-1 3,4-dihydroxyphenylacetic acid. Our results revealed the P450s' role in the metabolic pathway of papaverine enabling further investigation and application of these biocatalysts.
Topics: Arthrobacter; Biocatalysis; Cytochrome P-450 Enzyme System; Molecular Structure; Oxidation-Reduction; Papaverine
PubMed: 30759214
DOI: 10.1093/jb/mvz010