Protein Tyrosine Phosphatase 1B (PTP1B): A Comprehensive Review of Its Role in Pathogenesis of Human Diseases.

Overexpression of protein tyrosine phosphatase 1B (PTP1B) disrupts signaling pathways and results in numerous human diseases. In particular, its involvement has been well documented in the pathogenesis of metabolic disorders (diabetes mellitus type I and type II, fatty liver disease, and obesity); neurodegenerative diseases (Alzheimer's disease, Parkinson's disease); major depressive disorder; calcific aortic valve disease; as well as several cancer types. Given this multitude of therapeutic applications, shortly after identification of PTP1B and its role, the pursuit to introduce safe and selective enzyme inhibitors began. Regrettably, efforts undertaken so far have proved unsuccessful, since all proposed PTP1B inhibitors failed, or are yet to complete, clinical trials. Intending to aid introduction of the new generation of PTP1B inhibitors, this work collects and organizes the current state of the art. In particular, this review intends to elucidate intricate relations between numerous diseases associated with the overexpression of PTP1B, as we believe that it is of the utmost significance to establish and follow a brand-new holistic approach in the treatment of interconnected conditions. With this in mind, this comprehensive review aims to validate the PTP1B enzyme as a promising molecular target, and to reinforce future research in this direction.

Thalidomide derivatives as nanomolar human neutrophil elastase inhibitors: Rational design, synthesis, antiproliferative activity and mechanism of action.

Here, we rationally designed a human neutrophil elastase (HNE) inhibitors 4a-4f derived from thalidomide. The HNE inhibition assay showed that synthesized compounds 4a, 4b, 4e and 4f demonstrated strong HNE inhibiton properties with IC50 values of 21.78-42.30 nM. Compounds 4a, 4c, 4d and 4f showed a competitive mode of action. The most potent compound 4f shows almost the same HNE inhibition as sivelestat. The molecular docking analysis revealed that the strongest interactions occur between the azetidine-2,4-dione group and the following three aminoacids: Ser195, Arg217 and His57. A high correlation between the binding energies and the experimentally determined IC50 values was also demonstrated. The study of antiproliferative activity against human T47D (breast carcinoma), RPMI 8226 (multiple myeloma), and A549 (non-small-cell lung carcinoma) revealed that designed compounds were more active compared to thalidomide, pomalidomide and lenalidomide used as the standard drugs. Additionally, the most active compound 4f derived from lenalidomide induces cell cycle arrest at the G2/M phase and apoptosis in T47D cells.

Coumarin-Based Compounds as Inhibitors of Tyrosinase/Tyrosine Hydroxylase: Synthesis, Kinetic Studies, and In Silico Approaches.

Cancer represents the main cause of morbidity and mortality worldwide, constituting a serious health problem. In this context, melanoma represents the most aggressive and fatal type of skin cancer, with death rates increasing every year. Scientific efforts have been addressed to the development of inhibitors targeting the tyrosinase enzyme as potential anti-melanoma agents due to the importance of this enzyme in melanogenesis biosynthesis. Coumarin-based compounds have shown potential activity as anti-melanoma agents and tyrosinase inhibitors. In this study, coumarin-based derivatives were designed, synthesized, and experimentally evaluated upon tyrosinase. Compound FN-19, a coumarin-thiosemicarbazone analog, exhibited potent anti-tyrosinase activity, with an IC50 value of 42.16 ± 5.16 µM, being more active than ascorbic acid and kojic acid, both reference inhibitors. The kinetic study showed that FN-19 acts as a mixed inhibitor. Still, for this compound, molecular dynamics (MD) simulations were performed to determine the stability of the complex with tyrosinase, generating RMSD, RMSF, and interaction plots. Additionally, docking studies were performed to elucidate the binding pose at the tyrosinase, suggesting that the hydroxyl group of coumarin derivative performs coordinate bonds (bidentate) with the copper(II) ions at distances ranging from 2.09 to 2.61 Å. Then, MM/PBSA calculations revealed that van der Waals interactions are the most relevant intermolecular forces for complex stabilization. Furthermore, it was observed that FN-19 has a binding energy (ΔEMM) value similar to tropolone, a tyrosinase inhibitor. Therefore, the data obtained in this study will be useful for designing and developing novel coumarin-based analogs targeting the tyrosinase enzyme.

Discovery of New 3,3-Diethylazetidine-2,4-dione Based Thiazoles as Nanomolar Human Neutrophil Elastase Inhibitors with Broad-Spectrum Antiproliferative Activity.

A series of 3,3-diethylazetidine-2,4-dione based thiazoles 3a-3j were designed and synthesized as new human neutrophil elastase (HNE) inhibitors in nanomolar range. The representative compounds 3c, 3e, and 3h exhibit high HNE inhibitory activity with IC50 values of 35.02-44.59 nM, with mixed mechanism of action. Additionally, the most active compounds 3c and 3e demonstrate high stability under physiological conditions. The molecular docking study showed good correlation of the binding energies with the IC50 values, suggesting that the inhibition properties are largely dependent on the stage of ligand alignment in the binding cavity. The inhibition properties are correlated with the energy level of substrates of the reaction of ligand with Ser195. Moreover, most compounds showed high and broad-spectrum antiproliferative activity against human leukemia (MV4-11), human lung carcinoma (A549), human breast adenocarcinoma (MDA-MB-231), and urinary bladder carcinoma (UMUC-3), with IC50 values of 4.59-9.86 µM. Additionally, compounds 3c and 3e can induce cell cycle arrest at the G2/M phase and apoptosis via caspase-3 activation, leading to inhibition of A549 cell proliferation. These findings suggest that these new types of drugs could be used to treat cancer and other diseases in which immunoreactive HNE is produced.

New Borane-Protected Derivatives of α-Aminophosphonous Acid as Anti-Osteosarcoma Agents: ADME Analysis and Molecular Modeling, In Vitro Studies on Anti-Cancer Activities, and NEP Inhibition as a Possible Mechanism of Anti-Proliferative Activity.

Many organophosphorus compounds (OPs), especially various α-aminophosphonates, exhibit anti-cancer activities. They act, among others, as inhibitors of the proteases implicated in cancerogenesis. Thesetypes of inhibitors weredescribed, e.g., for neutral endopeptidase (NEP) expressed in different cancer cells, including osteosarcoma (OS). The aim of the present study isto evaluate new borane-protected derivatives of phosphonous acid (compounds 1-7) in terms of their drug-likeness properties, anti-osteosarcoma activities in vitro (against HOS and Saos-2 cells), and use as potential NEP inhibitors. The results revealed that all tested compounds exhibited the physicochemical and ADME properties typical for small-molecule drugs. However, compound 4 did not show capability of blood-brain barrier penetration (Lipinski and Veber rules;SwissAdme tool). Moreover, the α-aminophosphonite-boranes (compounds 4-7) exhibited stronger anti-proliferative activity against OS cells than the other phosphonous acid-borane derivatives (compounds 1-3),especially regarding HOS cells (MTT assay). The most promising compounds 4 and 6 induced apoptosis through the activation of caspase 3 and/or cell cycle arrest at the G2 phase (flow cytometry). Compound 4 inhibited the migration and invasiveness of highly aggressive HOS cells (wound/transwell and BME-coated transwell assays, respectively). Additionally, compound 4 and, to a lesser extent, compound 6 inhibited NEP activity (fluorometric assay). This activity of compound 4 was involved in its anti-proliferative potential (BrdU assay). The present study shows that compound 4 can be considered a potential anti-osteosarcoma agent and a scaffold for the development of new NEP inhibitors.

Spectrofluorimetric and Computational Investigation of New Phthalimide Derivatives towards Human Neutrophil Elastase Inhibition and Antiproliferative Activity.

Herein, nine phthalimide-based thiazoles (4a-4i) were synthesized and investigated as new human neutrophil elastase (HNE) inhibitors using spectrofluorimetric and computational methods. The most active compounds containing 4-trifluoromethyl (4c), 4-naphthyl (4e) and 2,4,6-trichloro (4h) substituents in the phenyl ring exhibited high HNE inhibitory activity with IC50 values of 12.98-16.62 µM. Additionally, compound 4c exhibited mixed mechanism of action. Computational investigation provided a consistent picture of the ligand-receptor pattern of inter-actions, common for the whole considered group of compounds. Moreover, compounds 4b, 4c, 4d and 4f showed high antiproliferative activity against human cancer cells lines MV4-11, and A549 with IC50 values of 8.21 to 25.57 µM. Additionally, compound 4g showed high activity against MDA-MB-231 and UMUC-3 with IC50 values of 9.66 and 19.81 µM, respectively. Spectrophotometric analysis showed that the most active compound 4c demonstrated high stability under physiological conditions.

The newly synthesized thiazole derivatives as potential antifungal compounds against Candida albicans.

Recently, the occurrence of candidiasis has increased dramatically, especially in immunocompromised patients. Additionally, their treatment is often ineffective due to the resistance of yeasts to antimycotics. Therefore, there is a need to search for new antifungals. A series of nine newly synthesized thiazole derivatives containing the cyclopropane system, showing promising activity against Candida spp., has been further investigated. We decided to verify their antifungal activity towards clinical Candida albicans isolated from the oral cavity of patients with hematological malignancies and investigate the mode of action on fungal cell, the effect of combination with the selected antimycotics, toxicity to erythrocytes, and lipophilicity. These studies were performed by the broth microdilution method, test with sorbitol and ergosterol, checkerboard technique, erythrocyte lysis assay, and reversed phase thin-layer chromatography, respectively. All derivatives showed very strong activity (similar and even higher than nystatin) against all C. albicans isolates with minimal inhibitory concentration (MIC) = 0.008-7.81 µg/mL Their mechanism of action may be related to action within the fungal cell wall structure and/or within the cell membrane. The interactions between the derivatives and the selected antimycotics (nystatin, chlorhexidine, and thymol) showed additive effect only in the case of combination some of them and thymol. The erythrocyte lysis assay confirmed the low cytotoxicity of these compounds as compared to nystatin. The high lipophilicity of the derivatives was related with their high antifungal activity. The present studies confirm that the studied thiazole derivatives containing the cyclopropane system appear to be a very promising group of compounds in treatment of infections caused by C. albicans. However, this requires further studies in vivo. KEY POINTS: • The newly thiazoles showed high antifungal activity and some of them - additive effect in combination with thymol. • Their mode of action may be related with the influence on the structure of the fungal cell wall and/or the cell membrane. • The low cytotoxicity against erythrocytes and high lipophilicity of these derivatives are their additional good properties.

Effect of the dichloro-substitution on antiproliferative activity of phthalimide-thiazole derivatives. Rational design, synthesis, elastase, caspase 3/7, and EGFR tyrosine kinase activity and molecular modeling study.

Phthalimide derivatives are a promising group of anticancer drugs, while aminothiazoles have great potential as elastase inhibitors. In these context fourteen phthalimido-thiazoles containing a dichloro-substituted phenyl ring with high antiproliferative activity against various cancer cell lines were designed and synthesized. Among the screened derivatives, compounds 5a-5e and 6a-6f showed high activity against human leukemia (MV4-11) cells with IC50 values in the range of 5.56-16.10 µM. The phthalimide-thiazoles 5a, 5b and 5d showed the highest selectivity index (SI) relative to MV4-11 with 11.92, 10.80 and 8.21 values, respectively. The antiproliferative activity of compounds 5e, 5f and 6e, 6f against human lung carcinoma (A549) cells is also very high, with IC50 values in the range of 6.69-10.41 µM. Lead compounds 6e and 6f showed elastase inhibition effect, with IC50 values about 32 µM with mixed mechanism of action. The molecular modeling studies showed that the binding energies calculated for all set of compounds are strongly correlated with the experimentally determined values of IC50. The lead compound 6e also increases almost 16 times caspase 3/7 activity in A549 cells compared to control. We have also demonstrated that compound 6f reduced EGFR tyrosine kinase levels in A549 cells by approximately 31%. These results clearly suggest that 3,4-dichloro-derivative 6e and 3,5-dichloro-derivative 6f could constitute lead dual-targeted anticancer drug candidates.

Tropinone-Derived Alkaloids as Potent Anticancer Agents: Synthesis, Tyrosinase Inhibition, Mechanism of Action, DFT Calculation, and Molecular Docking Studies.

A new series of hybrid compounds with tropinone and thiazole rings in the structure was designed and synthesized as potential anticancer agents. They were tested against human multiple myeloma (RPMI 8226), lung carcinoma (A549), breast adenocarcinoma (MDA-MB-231), and mouse skin melanoma (B16-F10) cell lines. Toxicity was tested on human normal skin fibroblasts (HSF) and normal colon fibroblasts (CCD-18Co). The growth inhibition mechanism of the most active derivative was analyzed through investigation of its effect on the distribution of cell cycle phases and ability to induce apoptosis and necrosis in RPMI 8226 and A549 cancer cells. The tyrosinase inhibitory potential was assessed, followed by molecular docking studies. Compounds 3a-3h show high anticancer activity against MDA-MB-231 and B16-F10 cell lines with IC50 values of 1.51-3.03 µM. Moreover, the cytotoxic activity of the investigated compounds against HSF and CCD-18Co cells was 8-70 times lower than against the cancer cells or no toxicity was shown in our tests, with derivative 3a being particularly successful. The mechanism of action of compound 3a in RPMI 8226 cell was shown to be through induction of cell death through apoptosis. The derivatives show ability to inhibit the tyrosinase activity with a mixed mechanism of inhibition. The final molecular docking results showed for IC50 distinct correlation with experiment.

Towards understanding the interaction of (S)-thalidomide with nucleobases.

Interaction of (S)-thalidomide molecule with four nucleobases: adenine, guanine, cytosine and thymine, is investigated in details employing density functional theory methods. Different mutual positions of the molecules are considered, with the starting geometries enabling hydrogen bond interactions between the monomers. Optimization of geometrical parameters is carried out within the B3LYP/6-311G** approximation and followed by evaluation of vibrational frequencies. Binding and interaction energies are calculated employing exchange-correlation functionals including long-range corrections and properly diffuse basis sets. The strongest interaction exists within the (S)-thalidomide-guanine complex. Interestingly, in one of the investigated (S)-thalidomide-guanine complexes two bifurcated hydrogen bonds are observed. The two hydrogens involved in one of them are bonded to a carbon atom in the α position relative to carbonyl group. The present study can be useful in the design of new anticancer and antiviral drugs interacting selectively with DNA or RNA.

Discovery of tropinone-thiazole derivatives as potent caspase 3/7 activators, and noncompetitive tyrosinase inhibitors with high antiproliferative activity: Rational design, one-pot tricomponent synthesis, and lipophilicity determination.

We have designed novel tropinone-thiazole derivatives that showed high antiproliferative activity against a variety of cancer cell lines via caspase 3/7 activation mechanism. Among the derivatives, compounds 3b-3h were found to exhibit high activity against human leukemia (MV4-11), human lung carcinoma (A549), human breast carcinoma (MCF-7), and skin melanoma (B16-F10) cancer cell lines, with IC50 values of 5.43-11.06 µM. The lead compound 3g increases caspase 3/7 activity in A549 cells 25 times more than the control, and 2 times more than reference drug camptothecin. We have also found that tropinone-thiazole derivatives exhibit high tyrosinase inhibitory activity. The lead compounds 3g and 3h showed tyrosinase inhibition effect, with IC50 values 3.22 and 3.51 µM, respectively. These inhibitory activities are 22 times higher than the activity of kojic acid (IC50 72.27 µM) and 120 times higher than activity of ascorbic acid (IC50 386.5 µM). For compounds 3g and 3h, the experimentally determined lipophilicity correlates very well with their enzymatic activities. These data suggest that presented compounds could constitute lead anticancer drug candidates.

Triazene salts: Design, synthesis, ctDNA interaction, lipophilicity determination, DFT calculation, and antiproliferative activity against human cancer cell lines.

Synthesis, characterization and investigation of antiproliferative activity of nine triazene salts against human cancer cells lines (MV-4-11, MCF-7, JURKAT, HT-29, Hep-G2, HeLa, Du-145 and DAUDI), and normal human mammary epithelial cell line (MCF7-10A) is presented. The structures of novel compounds were determined using 1H and 13C NMR, and GC-APCI-MS analyses. Among the derivatives, compound 2c, 2d, 2e and 2f has very strong activity against biphenotypic B myelomonocytic leukemia MV4-11, with IC50 values from 5.42 to 7.69 µg/ml. The cytotoxic activity of compounds 2c-2f against normal human mammary gland epithelial cells MCF-10A is 6-11 times lower than against cancer cell lines. Our results also show that compounds 2c and 2f have very strong activity against DAUDI and HT-29 with IC50 4.91 µg/ml and 5.59 µg/ml, respectively. Their lipophilicity was determined using reversed-phase ultra-performance liquid chromatography and correlated with antiproliferative activity. Our UV-Vis spectroscopic results indicate also that triazene salts tends to interact with negatively charged DNA phosphate chain. To support the experiment, theoretical calculations of the 1H NMR shifts were carried out within the Density Functional Theory.

Synthesis, molecular docking, ctDNA interaction, DFT calculation and evaluation of antiproliferative and anti-Toxoplasma gondii activities of 2,4-diaminotriazine-thiazole derivatives.

Synthesis, characterization, and investigation of antiproliferative activities against human cancer cell lines (MV4-11, MCF-7, and A549) and Toxoplasma gondii parasite of twelve novel 2,4-diaminotriazine-thiazoles are presented. The toxicity of the compounds was studied at three different cell types, normal mouse fibroblast (Balb/3T3), mouse fibroblast (L929), and human VERO cells. The structures of novel compounds were determined using 1H and 13C NMR, FAB(+)-MS, and elemental analyses. Among the derivatives, 4a-k showed very high activity against MV4-11 cell line with IC50 values between 1.13 and 3.21 µg/ml. Additionally, the cytotoxic activity of compounds 4a-k against normal mouse fibroblast Balb/3T3 cells is about 20-100 times lower than against cancer cell lines. According to our results, compounds 4a, 4b, 4d, and 4i have very strong activity against human breast carcinoma MCF-7, with IC50 values from 3.18 to 4.28 µg/ml. Moreover, diaminotriazines 4a-l showed significant anti-Toxoplasma gondii activity, with IC50 values 9-68 times lower than those observed for sulfadiazine. Molecular docking studies indicated DNA-binding site of hTopoI and hTopoII as possible anticancer targets and purine nucleoside phosphorylase as possible anti-toxoplasmosis target. Our UV-Vis spectroscopic results indicate also that diaminotriazine-thiazoles tends to interact with DNA by intercalation. Additionally, the structure and the interaction and binding energies of a model complex formed by compound 4a and two thymine molecules are investigated using quantum mechanical methods.

Synthesis and in vitro antiproliferative activity of thiazole-based nitrogen mustards: the hydrogen bonding interaction between model systems and nucleobases.

Synthesis, characterization and investigation of antiproliferative activity of eight thiazole-based nitrogen mustard against human cancer cells lines (MV4-11, A549, HCT116 and MCF-7) and normal mouse fibroblast (BALB/3T3) are presented. Their structures were determined using NMR, FAB MS, HRMS and elemental analyses. Among the derivatives, 3a, 3b, 3e and 3h were found to exhibit high activity against human leukemia MV4-11 cells with IC50 values of 0.634-3.61 µg/ml. The cytotoxic activity of compound 3a against BALB/3T3 cells is up to 40 times lower than against cancer cell lines. Our data indicated also that compound 3e had very strong activity against MCF-7 and HCT116 with IC50 equal to 2.32 µg/ml and 2.81 µg/ml, respectively. Their activity was similar to the activity of cis-platin, which is clinically used as anticancer drug in the treatment of human solid tumours. We also perform quantum chemical calculation of interaction and binding energies in complexes of model systems and 3e with DNA bases. Interaction of real drug 3e with guanine is much stronger than with the remaining nucleobases, and the strongest among all investigated complexes. Computer simulations were performed with ATP-binding domain and DNA-binding site of hTopoII. Compounds 3a-h were recognized as potential inhibitors of hTopoII.