Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
Eur J Med Chem ; 208: 112841, 2020 Dec 15.
Article in English | MEDLINE | ID: mdl-32998089

ABSTRACT

In this study, (S)-naproxen thiosemicarbazides (3a-d), 1,2,4-triazoles (4a-c), triazole-thioether hybride compounds (5a-p) were synthesized and their structures (3a, 3d, 4a and 5a-p) were confirmed by FT-IR, 1H NMR,13C NMR, HR-Mass spectra and elemental analysis. These compounds are designed to inhibit methionine amino peptidase-2 (MetAP2) enzyme in prostate cancer. These compounds (3d, 5a-p) evaluated against androgen-independent prostate adenocarcinoma (PC-3, DU-145) and androgen-dependent prostate adenocarcinoma (LNCaP) cell lines by using MTS method. Compounds 5a, 5b, 5d and 5e showed 14.2, 5.8, 10.8 and 8.4 µM anticancer activity against PC-3 cell lines, compounds 5e, 5g and 5n presented anticancer activity against DU-145 cell lines 18.8, 12.25 and 10.2 µM, and compounds 5g, 5m and 5n exhibited anticancer activity against LNCaP cell lines 12.25, 22.76 and 2.21 µM, respectively. Consequently, of these results, compounds 5e and 5n showed the highest activities against androgen dependent and independent prostate cancer cell lines, so these compounds could be potent small molecules against prostate cancer. Furthermore, mitogen-activated protein kinase (MAPK) pathway activation, AKT (protein kinase B) phosphorylation and androgen receptor activation of compound 5n (SGK636) were investigated in LNCaP cells by using Western blot method. Compound 5n (SGK636) was also tested against mRNA expression analysis of the Bax, Bcl-2, Caspase 3, Caspase 9 by using real-time PCR analysis. Compound 5n was given to nude male mice with cancer in comparison to the control group. Compound 5n was found to reverse the malignant phenotype in the nude male mice, whereas the prostate cancer progressed in the control group. Analysis of some blood parameters in the study showed that they were within the normal values with respect to the control. The blood values of the animals treated according to the control group also exhibited compliance with the blood limit values. Molecular docking and dynamics simulation of compound 5n binding to Methionine Aminopeptidase 2 (MetAP2) enzyme rationalized its potential activity. In addition, inhibition assay MetAP2 enzyme of compound 5n was evaluated. Taken together, we suggest compound 5n to be a potential candidate for prostate cancer therapy.


Subject(s)
Antineoplastic Agents/therapeutic use , Naproxen/analogs & derivatives , Naproxen/therapeutic use , Prostatic Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Apoptosis/drug effects , Cell Line, Tumor , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/therapeutic use , Humans , Male , Methionyl Aminopeptidases/antagonists & inhibitors , Methionyl Aminopeptidases/metabolism , Mice, Nude , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Naproxen/metabolism , Protein Binding , Stereoisomerism , Structure-Activity Relationship
2.
Med Chem ; 16(6): 735-749, 2020.
Article in English | MEDLINE | ID: mdl-31203805

ABSTRACT

BACKGROUND: Prostate cancer is still one of the serious causes of mortality and morbidity in men. Despite recent advances in anticancer therapy, there is a still need of novel agents with more efficacy and specificity in the treatment of prostate cancer. Because of its function on angiogenesis and overexpression in the prostate cancer, methionine aminopeptidase-2 (MetAP-2) has been a potential target for novel drug design recently. OBJECTIVE: A novel series of Flurbiprofen derivatives N-(substituted)-2-(2-(2-fluoro-[1,1'- biphenyl]-4-il)propanoyl)hydrazinocarbothioamide (3a-c), 4-substituted-3-(1-(2-fluoro-[1,1'-biphenyl]- 4-yl)ethyl)-1H-1,2,4-triazole-5(4H)-thione (4a-d), 3-(substitutedthio)-4-(substituted-phenyl)- 5-(1-(2-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-4H-1,2,4-triazole (5a-y) were synthesized. The purpose of the research was to evaluate these derivatives against MetAP-2 in vitro and in silico to obtain novel specific and effective anticancer agents against prostate cancer. METHODS: The chemical structures and purities of the compounds were defined by spectral methods (1H-NMR, 13C-NMR, HR-MS and FT-IR) and elemental analysis. Anticancer activities of the compounds were evaluated in vitro by using MTS method against PC-3 and DU-143 (androgenindependent human prostate cancer cell lines) and LNCaP (androgen-sensitive human prostate adenocarcinoma) prostate cancer cell lines. Cisplatin was used as a positive sensitivity reference standard. RESULTS: Compounds 5b and 5u; 3c, 5b and 5y; 4d and 5o showed the most potent biological activity against PC3 cancer cell line (IC50= 27.1 µM, and 5.12 µM, respectively), DU-145 cancer cell line (IC50= 11.55 µM, 6.9 µM and 9.54 µM, respectively) and LNCaP cancer cell line (IC50= 11.45 µM and 26.91 µM, respectively). Some compounds were evaluated for their apoptotic caspases protein expression (EGFR/PI3K/AKT pathway) by Western blot analysis in androgen independent- PC3 cells. BAX, caspase 9, caspsase 3 and anti-apoptotic BcL-2 mRNA levels of some compounds were also investigated. In addition, molecular modeling studies of the compounds on MetAP-2 enzyme active site were evaluated in order to get insight into binding mode and energy. CONCLUSION: A series of Flurbiprofen-thioether derivatives were synthesized. This study presented that some of the synthesized compounds have remarkable anticancer and apoptotic activities against prostate cancer cells. Also, molecular modeling studies exhibited that there is a correlation between molecular modeling and anticancer activity results.


Subject(s)
Aminopeptidases/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Flurbiprofen/analogs & derivatives , Metalloendopeptidases/antagonists & inhibitors , Prostatic Neoplasms/drug therapy , Sulfides/chemistry , Cell Line, Tumor , Drug Delivery Systems , Flurbiprofen/chemistry , Flurbiprofen/pharmacology , Humans , Male , Molecular Structure , Structure-Activity Relationship
3.
Arch Pharm (Weinheim) ; 352(6): e1800365, 2019 Jun.
Article in English | MEDLINE | ID: mdl-31115928

ABSTRACT

A new series of 1,2,4-triazole containing hydrazide-hydrazones derived from (S)-naproxen ( 7a-m) was synthesized in this study. The structures of these compounds were characterized by spectral (Fourier-transform infrared spectroscopy, 1 H-nuclear magnetic resonance (NMR), 13 C-NMR, and high-resolution electron ionization mass spectrometry) methods. Furthermore, molecular modeling of these compounds was studied on human methionine aminopeptidase-2. All synthesized compounds were screened for anticancer activity against three prostate cancer cell lines (PC3, DU-145, and LNCaP) using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium colorimetric method. Compound 7a showed the best activity against the PC3, DU-145 and LNCaP cancer cell lines with IC50 values of 26.0, 34.5, and 48.8 µM, respectively. Compounds 7b, 7k, and 7m showed anticancer activity against cancer cell lines PC3 and DU-145 with IC50 values of 43.0, 36.5, 29.3 µM and 49.8, 49.1, 31.6 µM, respectively. Compounds 7f and 7g showed anticancer activity against PC3 cells with IC50 values of 43.4 and 34.5 µM, respectively. To assess the biodistribution in mice of IRDye800, dye-labeled compound 7a or 100 µM of free dye was injected intravenously into the mice's tail. In vivo images were taken with in vivo imaging system spectrum device at 60, 120, 180, 240, 300, and 360 min after injection. At the end of 360 min, ex vivo studies were carried out to determine in which organs the dye was accumulated in the urogenital system. Ex vivo studies showed that the accumulation of compound 7a in the prostate is greater than that of the free dye, and it is concluded that compound 7a may be promising for the treatment of prostate cancer.


Subject(s)
Antineoplastic Agents/chemical synthesis , Hydrazones/chemical synthesis , Naproxen/analogs & derivatives , Triazoles/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Hydrazones/chemistry , Hydrazones/pharmacology , Mice , Molecular Docking Simulation , Xenograft Model Antitumor Assays
4.
J Enzyme Inhib Med Chem ; 28(5): 885-93, 2013 Oct.
Article in English | MEDLINE | ID: mdl-22803669

ABSTRACT

Xanthene intermediates 4a and 4b were obtained from the reduction of nitro xanthene derivatives 3a and 3b which were synthesized via condensation of dimedone with m-nitrobenzaldehyde and p-nitrobenzaldehyde, respectively. Then xanthene sulfonamide 6a-n, and xanthene carboxamide derivatives 8a-h were synthesized by reaction of amino xanthene 4a, 4b with sulfonyl chlorides 5a-g and acyl chlorides 7a-d. Structures of the novel amino xanthene compounds and xanthene sulfonamide/carboxamide derivatives were established by their spectral data and elemental analyses. Furthermore, all the synthesized compounds were tested in vitro for their antimicrobial activity. The results were compared with reference standard antibiotics, erythromycin and nystatin. 6c, 6f, 6m and 8b Compounds were found to display most effective antimicrobial activity against a series of bacteria and fungi.


Subject(s)
Amides/pharmacology , Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Bacteria/drug effects , Fungi/drug effects , Xanthenes/pharmacology , Amides/chemical synthesis , Amides/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacology , Xanthenes/chemical synthesis , Xanthenes/chemistry
SELECTION OF CITATIONS
SEARCH DETAIL
...