Radiolabeled Peptides and Antibodies in Medicine.

Radiolabeled peptides are a relatively new, very specific radiotracer group, which is still expanding. This group is very diverse in terms of peptide size. It contains very small structures containing several amino acids and whole antibodies. Moreover, radiolabeled peptides are diverse in terms of the binding aim and therapeutic or diagnostic applications. The majority of this class of radiotracers is utilized in oncology, where the same structure can be used in therapy and diagnostic imaging by varying the radionuclide. In this study, we collected new reports of radiolabeled peptide applications in diagnosis and therapy in oncology and other fields of medicine. Radiolabeled peptides are also increasingly being used in rheumatology, cardiac imaging, or neurology. The studies collected in this review concern new therapeutic and diagnostic procedures in humans and new structures tested on animals. We also performed an analysis of clinical trials, which concerns application of radiolabeled peptides and antibodies that were reported in the clinicaltrials.gov database between 2008 and 2018.

An investigation into the pleiotropic activity of metformin. A glimpse of haemostasis.

The most characteristic features of type 2 diabetes mellitus (T2DM) are hyperglycaemia and insulin resistance, however, patients with T2DM are at higher risk of cardiovascular disease (CVD) and atherosclerosis. Diabetes, frequently related to metabolic and vascular impairments, is also associated with thrombosis, increased blood coagulation and an imbalance between coagulation and fibrinolysis. Metformin is the most often used oral glucose-lowering agent; its beneficial properties include lowering insulin resistance, weight reduction and cardioprotection. Available data suggest that the advantageous properties of metformin stem from its favourable effects on endothelium, and anti-oxidative and anti-inflammatory properties. This paper reviews the favourable impact of metformin on endothelial function, with particular emphasis on the release of endogenous molecules modulating the state of the vascular endothelium and coagulation. It also summarizes the present knowledge on the influence of metformin on platelet activity and plasma haemostasis, including clot formation, stabilization and fibrinolysis. Its findings confirm that metformin should constitute first line therapy of T2DM subjects; however, more comprehensive methodical studies are required to discover the full potential of this drug.

A novel trifluoromethyl 2-phosphonopyrrole analogue inhibits human cancer cell migration and growth by cell cycle arrest at G1 phase and apoptosis.

Pyrroles, an important class of heterocyclic compounds found in naturally occurring products, represent an interesting biologically active scaffold for drug design. Recently we have synthetized a series of five new fluorinated pyrrole derivatives for potential anticancer applications. All new compounds contain a trifluoromethyl and N-benzyl group, but they are different from each other by bearing a phenyl, ethoxycarbonyl or carboxylic moiety, with two of them possessing an additional phosphonyl function. The aim of this study was to evaluate anticancer activity of the new compounds in human lung and breast cancer cells. We found that compound 3, bearing a phosphonyl and phenyl group, was the most effective in attenuating growth of A549 and MCF-7 cells in a dose dependent manner with IC50 36.5 µM ± 1.80 and 27.9 µM ± 1.68, respectively. Compound 3 inhibited cancer cell proliferation by cell cycle arrest at G1 phase as detected by flow cytometry analysis. Furthermore, compound 3 induced apoptosis of A549 cells by activation of caspase-3. Cancer cell migration rate was significantly inhibited when A549 and MCF-7 cells were cultured in the presence of the compound. These results demonstrate that a novel trifluoromethyl-functionalized phosphonopyrrole with a phenyl group might be a promising pyrrole analogue with anticancer potential.

Synthesis, physicochemical and biological evaluation of tacrine derivative labeled with technetium-99m and gallium-68 as a prospective diagnostic tool for early diagnosis of Alzheimer's disease.

Design, physicochemical and biological studies of novel radioconjugates for the early diagnosis of Alzheimer's disease, based on the newly synthesized tacrine derivatives were performed. Novel tacrine analogues were labeled with technetium-99m and gallium-68. For all obtained radioconjugates ([99mTc]Tc-Hynic-(tricine)2NH(CH2)ntacrine and [68Ga]Ga-DOTA-NH(CH2)9tacrine, where n = 2-9 denotes the number of methylene groups CH2) the studies of physicochemical properties (lipophilicity, stability in the presence of an excess of standard amino acids cysteine or histidine, human serum and in cerebrospinal fluid) were performed. For two selected radioconjugates [99mTc]Tc-Hynic-(tricine)2NH(CH2)9Tac and [68Ga]Ga-DOTA-NH(CH2)9tacrine (characterized with the highest lipophilicity values) the biological tests (inhibition of cholinesterases action, molecular docking and biodistribution studies) have been performed. All novel radioconjugates showed high stability in biological solutions used. Both selected radioconjugates proved to be good inhibitors of cholinesterases and be able to cross the blood-brain barrier. Radioconjugates [99mTc]Tc-Hynic-(tricine)2NH(CH2)9tacrine and [68Ga]Ga-DOTA-NH(CH2)9tacrine fulfil the conditions for application in nuclear medicine. Radiopharmaceutical [68Ga]Ga-DOTA-NH(CH2)9tacrine, due to increased accuracy and improved sensitivity in PET imaging, may be better potential diagnostic tool for early diagnosis of Alzheimer's disease.

Generation 2 (G2) - Generation 4 (G4) PAMAM dendrimers disrupt key plasma coagulation parameters.

The aim of the research was to evaluate the effects of G2 - G4 PAMAM dendrimers on basic plasma haemostasis parameters (Partially Activated Thrombin Time (APTT), Prothrombin Time (PT), Thrombin Time (TT)) as well as the activity of factor X, antithrombin III (AT), protein C and plasmin. Furthermore, tissue factor (TF) synthesis in endothelial cells and viability of smooth muscle cells in the presence of PAMAM dendrimers was investigated. APTT, PT and TT were performed according to the available commercial methods. The activity of factor X was conducted based on deficient plasma factor X. Protein C, AT and plasmin activity were measured spectrophotometrically using chromogenic substrates. Intracellular TF production in human umbilical vein endothelial cells (HUVECs) was measured using immunohistochemical method. Viability of Human Aortal Smooth Muscle cells (hAoSMCs) was established using WST-1 assay. PAMAM dendrimers decreased activity of factor X, and concomitantly prolonged PT and APTT. We also demonstrated shortened TT and increased fibrinogen concentrations in plasma treated with G4 PAMAM dendrimers, suggesting formation of fibrinogen aggregates. G2 - G4 PAMAM dendrimers decreased the activity of both naturally occurring anticoagulants AT and protein C. G2 and G3 PAMAM dendrimers did not affect the proteolytic reaction with plasmin. PAMAM dendrimers were found not to trigger TF production in undisturbed endothelial cells. PAMAM dendrimers, depending on the concentration and generation decreased viability of AoSMCs. The results presented within the current study suggest complex but mostly undesirable effect of G2 - G4 PAMAM dendrimers on plasma haemostasis and underscore the need for further in-depth research.

The Associations between Central Nervous System Diseases and Haemostatic Disorders.

The aim of this review was to examine the relationship between the occurrence of central nervous system (CNS) diseases, the medicines used in their treatment and the blood coagulation process. The paper mainly focuses on the effects of antidepressant and antipsychotic drugs. Special attention has been paid to the influence of drugs on platelets, the vascular endothelium, plasma coagulation and fibrinolysis, regarding coagulation.

Biocompatibility Studies of Gadolinium Complexes with Iminodiacetic Acid Derivatives.

Apart from using as radiopharmaceuticals, iminodiacetic acid derivatives, after complexation with gadolinium, have been also tested as MRI CAs (magnetic resonance imaging contrast agents) since they show high affinity to hepatocytes and therefore provide high-resolution MRI of the liver. The purpose of this study was to evaluate the biocompatibility of four gadolinium complexes with iminodiacetic acid (IDA) derivatives differing in substituent in aromatic ring by estimating their influence on plasma hemostasis, integrity of erythrocyte membrane, and toxicity towards human umbilical vein endothelial cells (HUVECs). The influence of gadolinium-based CAs on plasma hemostasis was evaluated by measuring PT (prothrombin time), APTT (activated partial tromboplastin time), and TT (thrombin time). The effects of tested compounds on RBCs (Red Blood Cells) were assessed using hemolysis assay and microscopy studies. The influence of gadolinium complexes on the barrier properties of HUVECs was assessed by means of real-time method based on the measurements of the impedance changes of the cells. Gadolinium complexes did not affect significantly PT and TT. APTT measurements revealed significant prolongation in the presence of all tested gadolinium complexes at the concentration higher than 0.5 µmol/mL. Hemolysis assay showed that compounds with alkyl substituents in benzene ring without halogen atom (1-3) do not exert unfavorable effect on the integrity of erythrocyte membrane over the entire concentration range. All gadolinium complexes at 1.0 µmol/mL contribute to the decrease in HUVEC viability and integrity. To conclude, the study describes biocompatibility studies of gadolinium-based CAs, provides additional insight into their potential toxicity associated with systemic administration, and underscores the necessity for further research.

Sulfenamide and sulfonamide derivatives of metformin can exert anticoagulant and profibrinolytic properties.

Type 2 diabetes mellitus (T2DM) is characterised not only by hyperglycaemia and insulin resistance but also an impaired balance between the processes of coagulation and fibrinolysis. The aim of this study was to examine the effects of metformin, a widely-used oral anti-diabetic drug, phenformin and eight sulfenamide and sulfonamide derivatives of metformin on several haemostasis parameters. Thrombin Time (TT) tests were performed according to the available commercial method. The activity of factor X was conducted based on deficient plasma factor X. The activity of two main enzymes involved in haemostasis, thrombin and plasmin, was measured spectrophotometrically with chromogenic substrates. Protein C and antithrombin III (AT) activity assays using chromogenic substrates were conducted to determine the effect of the derivatives of metformin on these both naturally occurring anticoagulants. Two of the compounds, sulfenamide with hexyl tail and para-nitro-benzenesulfonamide significantly shortened TT. ortho-nitro sulfonamide at a concentration of 0.3-1.5 µmol/mL contributed to a significant decrease in the activity of factor X. However, sulfenamides with cyclohexyl, butyl and branched ethyl-hexyl tails at 1.5 of µmol/mL increased its activity, and simultaneously shortened PT. Additionally, ortho-nitro-benzenesulfonamide at concentrations of 1.5 µmol/mL was found to significantly decrease reaction velocity (↓ dA/dt) in the thrombin activity assay. On contrary, it was noticed that branched sulfenamide at the concentration of 1.5 µmol/mL significantly increased the enzymatic activity of plasmin. Metformin, phenformin and octyl and butyl sulfenamides were associated with a significant increase in the activity of AT. Hexyl sulfenamide and para-nitro- as well as para-trifluoro-ortho-nitro-benzenesulfonamide contributed to the decrease in the activity of protein C, while the other tested compounds did not affect its activity. In conclusion, 2-nitro-benzenesulfonamide derivative of metformin presents highly beneficial anticoagulant properties. This compound is therefore promising candidate for further in vitro and in vivo studies.

Novel tetrahydroacridine derivatives with iodobenzoic acid moiety as multifunctional acetylcholinesterase inhibitors.

New synthesized series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with iodobenzoic acid moiety were studied for their inhibitory activity toward cholinesterase and against ß-amyloid aggregation. All novel molecules 3a-3i interacted with both cholinesterases-acetylcholinesterase and butyrylcholinesterase-delivered nanomolar IC50 values. The structure-activity relationship showed that N-butyl moiety derivatives are stronger inhibitors toward AChE and BuChE than N-ethyl and N-propyl moieties compounds. The most potent compound toward acetylcholinesterase was inhibitor 3f (IC50  = 31.2 nm), and it was more active than reference drug, tacrine (IC50  = 100.2 nm). Compound 3f showed strong inhibition of butyrylcholinesterase (IC50  = 8.0 nm), also higher than tacrine (IC50  = 16.3 nm). In the kinetic studies, compound 3f revealed mixed type of acetylcholinesterase inhibition. The computer modeling was carried out. The most active compound 3f was confirmed as peripheral anionic site inhibitor of acetylcholinesterase. Moreover, molecule 3f inhibited ß-amyloid aggregation (at the concentration 10 µm-24.96% of inhibition, 25 µm-72%, 50 µm-78.44%, and 100 µm-84.92%). Therefore, among all examined, compound 3f is the most promising molecule for further, more detailed research of novel multifunctional agents in the therapy of Alzheimer's disease.

New Perspectives of Alzheimer Disease Diagnosis - the Most Popular and Future Methods.

As lifespan tendency is increasing, age-related diseases are becoming a burden to the society and health care system. Mostly incurable, constitute a subject of researchers' work. In this review, the insight into the problem of Alzheimer Disease (AD) diagnostics will be given. The unquestionable diagnosis is possible only during a post-mortem examination. AD is known as one of the forms of dementia and its differentiation from mild cognitive impairments has to be improved. Despite a great diagnostic progress during last decades, medicine still needs more accurate tools for an early detection of this incurable disease. It is hoped that this strategy will enable an administration of more aggressive therapy preventing AD development. Nowadays, pharmacotherapy is based mainly on symptomatic treatment which is not able to reverse pathological changes caused by the disease. Hence, more accurate identifying testing and monitoring methods are crucial to reveal new therapeutic targets. The most popular techniques present for detecting local brain functional changes use nuclear medicine imaging devices: Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT). Constant process of improving is not possible without new radiotracers. Magnetic Resonance Imaging (MRI) is a tool for an assessment of structural changes in brain tissue. However, providing satisfying results, these methods are not completely specific and accurate. As very promising hallmarks of AD enhancing high accuracy of testing, biomarkers - tau tangles and ß-amyloid plaques have been found. At the present time they are being used only as an additional examination, one day they may become a gold standard of AD diagnostics.

Biocompatible sulfenamide and sulfonamide derivatives of metformin can exert beneficial effects on plasma haemostasis.

As the pharmacokinetic properties of metformin are unfavourable, several analogues and prodrugs have been synthesised to improve its bioavailability. The aim of this study was to assess the plasma stability of sulfenamide and sulfonamide derivatives of metformin and establish their effects on plasma haemostasis and integrity of red blood cells (RBCs). The overall haemostasis potential was evaluated spectrophotometrically by clot formation and lysis test (CL-test). PT (Prothrombin Time) and APTT (Activated Partial Tromboplastin Time) were used to evaluate the effects if the compounds on the extrinsic and intrinsic coagulation pathway. Haemolysis assay, microscopy and flow cytometry studies were conducted to determine the effect of the compounds on RBCs. Two sulfonamide and one sulfenamide derivatives of metformin were associated with a statistically significant decrease in the overall potential of clot formation and fibrinolysis (↓ CLAUC), suggesting that these compounds may exert beneficial effects regarding plasma haemostasis, which is frequently impaired in diabetic patients. p- and o-Nitrobenzene sulfonamides contributed to the beneficial change in kinetic parameters of clot formation and fibrinolysis. o-Nitrobenzene sulfonamide significantly increased thrombin generation time (↑ TGt) and was also found to prolong both APTT and PT. All compounds did not exert any effects on the integrity of RBCs over the concentration range 0.006-0.6 µmol/mL which constitutes the expected therapeutic concentration. In conclusion, sulfonamide derivatives of metformin present potentially beneficial properties in terms of plasma haemostasis which is frequently impaired in T2DM patients. Therefore, metformin sulfonamides may become a prototype for further design and synthesis of novel metformin analogues and prodrugs with improved pharmacokinetic properties.

Synthesis and Biocompatibility Studies of New Iminodiacetic Acid Derivatives.

BACKGROUND: Iminodiacetic acid (IDA) derivatives can be used as ligands to form complexes with technetium, with potential application as hepatobiliary diagnostic agents. The aim of this study was to synthesize five novel IDA derivatives and to compare their effects on plasma haemostasis with clinically approved ligands for technetium complexation. METHODS: The influence of synthesized IDA derivatives on plasma haemostasis was evaluated spectrophotometrically by clot formation and lysis test (CL-test), coagulation assay, Prothrombin Time and Activated Partial Tromboplastin Time. The effects of the tested compounds on erythrocytes were assessed using haemolysis assays, microscopy and flow cytometry studies. RESULTS: Despite their significant influence on the kinetic parameters of the process of clot formation and fibrinolysis, the tested ligands, at potential diagnostic concentrations, did not alter the overall potential of clot formation and lysis (CLAUC). At potential diagnostic concentrations (0.4 µmol/mL) all the tested compounds showed no adverse effects on the membranes of RBCs (Red Blood Cells). CONCLUSION: IDA derivatives with methoxy substituents in aromatic ring, exert multidirectional effects on plasma haemostasis and should be considered safe as their significant impacts were mostly observed at 4 µmol/mL, which is about 10-fold higher than the theoretical plasma concentrations of these compounds.

Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity.

The results of epidemiological and pathophysiological studies suggest that type 2 diabetes mellitus (T2DM) may predispose to Alzheimer's disease (AD). The two conditions present similar glucose levels, insulin resistance, and biochemical etiologies such as inflammation and oxidative stress. The diabetic state also contributes to increased acetylcholinesterase (AChE) activity, which is one of the factors leading to neurodegeneration in AD. The aim of this study was to assess in vitro the effects of metformin, phenformin, and metformin sulfenamide prodrugs on the activity of human AChE and butyrylcholinesterase (BuChE) and establish the type of inhibition. Metformin inhibited 50% of the AChE activity at micromolar concentrations (2.35 µmol/mL, mixed type of inhibition) and seemed to be selective towards AChE since it presented low anti-BuChE activity. The tested metformin prodrugs inhibited cholinesterases (ChE) at nanomolar range and thus were more active than metformin or phenformin. The cyclohexyl sulfenamide prodrug demonstrated the highest activity towards both AChE (IC50 = 890 nmol/mL, noncompetitive inhibition) and BuChE (IC50 = 28 nmol/mL, mixed type inhibition), while the octyl sulfenamide prodrug did not present anti-AChE activity, but exhibited mixed inhibition towards BuChE (IC50 = 184 nmol/mL). Therefore, these two bulkier prodrugs were concluded to be the most selective compounds for BuChE over AChE. In conclusion, it was demonstrated that biguanides present a novel class of inhibitors for AChE and BuChE and encourages further studies of these compounds for developing both selective and nonselective inhibitors of ChEs in the future.

Metformin - a Future Therapy for Neurodegenerative Diseases : Theme: Drug Discovery, Development and Delivery in Alzheimer's Disease Guest Editor: Davide Brambilla.

Type 2 diabetes mellitus (T2DM) is a complex, chronic and progressive metabolic disease, which is characterized by relative insulin deficiency, insulin resistance, and high glucose levels in blood. Esteemed published articles and epidemiological data exhibit an increased risk of developing Alzheimer's disease (AD) in diabetic pateints. Metformin is the most frequently used oral anti-diabetic drug, which apart from hypoglycaemic activity, improves serum lipid profiles, positively influences the process of haemostasis, and possesses anti-inflammatory properties. Recently, scientists have put their efforts in establishing metformin's role in the treatment of neurodegenerative diseases, such as AD, amnestic mild cognitive impairment and Parkinson's disease. Results of several clinical studies confirm that long term use of metformin in diabetic patients contributes to better cognitive function, compared to participants using other anti-diabetic drugs. The exact mechanism of metformin's advantageous activity in AD is not fully understood, but scientists claim that activation of AMPK-dependent pathways in human neural stem cells might be responsible for the neuroprotective activity of metformin. Metformin was also found to markedly decease Beta-secretase 1 (BACE1) protein expression and activity in cell culture models and in vivo, thereby reducing BACE1 cleavage products and the production of Aß (ß-amyloid). Furthermore, there is also some evidence that metformin decreases the activity of acetylcholinesterase (AChE), which is responsible for the degradation of acetylcholine (Ach), a neurotransmitter involved in the process of learning and memory. In regard to the beneficial effects of metformin, its anti-inflammatory and anti-oxidative properties cannot be omitted. Numerous in vitro and in vivo studies have confirmed that metformin ameliorates oxidative damage.

New prodrugs of metformin do not influence the overall haemostasis potential and integrity of the erythrocyte membrane.

Although metformin, an oral anti-diabetic drug, has been found to have multidirectional effects over the past decade, it is characterised by unfavourable pharmacokinetic properties. This study discusses the effects of metformin, phenformin and three prodrugs of metformin on the haemostasis and integrity of Red Blood Cells (RBCs). The influence of examined biguanide derivatives on haemostasis was evaluated spectrophotometrically by clot formation and lysis test (CL-test) at 405nm. The extrinsic and intrinsic coagulation pathway were examined by measuring the PT (Prothrombin Time) and aPTT (Activated Partial Tromboplastin Time). Haemolysis assay, microscopy and flow cytometry studies were used to assess the effect of the tested compounds on RBCs. Although none of the tested biguanide derivatives significantly influenced the overall potential of clot formation and fibrinolysis (CLAUC constants), statistically significant changes were seen in the values of the kinetic parameters of fibrinolysis. Furthermore, only prodrug 2, with an 8-carbon alkyl chain, unfavourably affected RBCs by interaction with the erythrocyte membrane leading to significant haemolysis. Our results provide a further insight into the effects of metformin and its prodrugs on haemostasis and RBCs and underscore the necessity for further research.

Tetrahydroacridine derivatives with fluorobenzoic acid moiety as multifunctional agents for Alzheimer's disease treatment.

A novel series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with 2-fluorobenzoic acid or 3-fluorobenzoic acid moiety were designed, synthesized and evaluated as inhibitors of cholinesterases and aggregation of ß-amyloid. In the study target compounds were very potent inhibitors of AChE and BChE. The most promising agents had higher inhibitory potency than the reference drugs which was tacrine. Ultimately, the kinetic assay shows the most active target compound 3c against AChE. Almost all of them were more potent against BChE than AChE. Compound 3c in various concentrations was tested by aggregation experiment. Inhibition of ß-amyloid aggregation was 77.32% and 80.43% at 50µM and 100µM, respectively. Therefore, compound 3c is a promising agent for the treatment of AD.

Metabolite Profiling of Eastern Teaberry (Gaultheria procumbens L.) Lipophilic Leaf Extracts with Hyaluronidase and Lipoxygenase Inhibitory Activity.

The phytochemical profile and anti-inflammatory activity of Gaultheria procumbens dry lipophilic leaf extracts were evaluated. Forty compounds were identified by GC-MS, representing 86.36% and 81.97% of the petroleum ether (PE) and chloroform (CHE) extracts, respectively, with ursolic acid (28.82%), oleanolic acid (10.11%), methyl benzoate (10.03%), and methyl salicylate (6.88%) dominating in CHE, and methyl benzoate (21.59%), docosane (18.86%), and octacosane (11.72%) prevailing in PE. Three components of CHE were fully identified after flash chromatography isolation and spectroscopic studies as (6S,9R)-vomifoliol (4.35%), 8-demethyl-latifolin (1.13%), and 8-demethylsideroxylin (2.25%). Hyaluronidase and lipoxygenase inhibitory activity was tested for CHE (IC50 = 282.15 ± 10.38 µg/mL and 899.97 ± 31.17 µg/mL, respectively), PE (IC50 = 401.82 ± 16.12 µg/mL and 738.49 ± 15.92 µg/mL), and nine of the main constituents versus heparin (IC50 = 366.24 ± 14.72 µg/mL) and indomethacin (IC50 = 92.60 ± 3.71 µg/mL) as positive controls. With the best activity/concentration relationships, ursolic and oleanolic acids were recommended as analytical markers for the extracts and plant material. Seasonal variation of both markers following foliar development was investigated by UHPLC-PDA. The highest levels of ursolic (5.36-5.87 mg/g DW of the leaves) and oleanolic (1.14-1.26 mg/g DW) acids were observed between August and October, indicating the optimal season for harvesting.

Novel tetrahydroacridine and cyclopentaquinoline derivatives with fluorobenzoic acid moiety induce cell cycle arrest and apoptosis in lung cancer cells by activation of DNA damage signaling.

Lung cancer is still the leading cause of cancer-related death worldwide, indicating a necessity to develop more effective therapy. Acridine derivatives are potential anticancer agents due to their ability to intercalate DNA as well as inhibit enzymes involved in replication and transcription. Recently, we have evaluated anticancer activity of 32 novel acridine-based compounds. We found that the most effective were tetrahydroacridine and cyclopentaquinoline derivatives with fluorobenzoic acid containing eight and nine carbon atoms in the aliphatic chain. The aim of this study was to determine the molecular mechanisms of compounds-induced cell cycle arrest and apoptosis in human lung adenocarcinoma cells. All compounds activated Ataxia telangiectasia mutated kinase and phosphorylated histone H2A.X at Ser139 indicating DNA damage. Treatment of cells with the compounds increased phosphorylation and accumulation of p53 that regulate cell cycle as well as apoptosis. All compounds induced G0/1 cell cycle arrest by phosphorylation of cyclin-dependent kinase 2 at Tyr15 resulting in attenuation of the kinase activity. In addition, cyclopentaquinoline derivatives induced expression of cyclin-dependent kinase 2 inhibitor, p21; however, tetrahydroacridine derivatives had no significant effect on p21. Moreover, all compounds decreased the mitochondrial membrane potential accompanied by increased expression of Bax and down-regulation of Bcl-2, suggesting activation of the mitochondrial pathway. All compounds also significantly attenuated the migration rates of lung cancer cells. Collectively, our findings suggest a central role of activation of DNA damage signaling in response to new acridine derivatives treatment to induce cell cycle arrest and apoptosis in cancer cells and provide support for their further development as potential drug candidates.

Synthesis, physicochemical and biological studies of technetium-99m labeled tacrine derivative as a diagnostic tool for evaluation of cholinesterase level.

In the present work the synthesis and physicochemical investigations of new tacrine analogues labeled with technetium-99m are reported. All obtained novel radioconjugates showed high stability in the presence of an excess of standard amino acids cysteine or histidine, as well as in human serum. Lipophilicity (LogD values) of these compounds is within the range from 0.92 to 1.56. For the selected radioconjugate 99mTc(NS3)(CN-NH(CH2)7Tac) (LogD=1.56) the biological activity studies in the course of inhibition of acetylcholinesterase action have been performed (IC50=45.0nM, estimated by means of Ellman's method). Biodistribution studies of this compound showed its uptake in brain on the level of 0.07%ID/g and its clearance through the hepatic and renal route in comparable degree. The ascertained presence of the radioconjugate in brain indicates its possibility to cross the blood-brain barrier. Molecular modeling of 99mTc(NS3)(CN-NH(CH2)7Tac) radioconjugate showed that the main structural fragment is tacrine moiety which is responsible for most interactions within catalytic and peripheral active sites and provides the anti-acetylcholinesterase activity. The 99mTc(NS3)(CN-NH(CH2)7Tac) radioconjugate may be considered to be a diagnostic tool for patients suffering from Alzheimer's disease as well as a marker to determine the physiological condition of liver and intestines.

Is Metformin a Perfect Drug? Updates in Pharmacokinetics and Pharmacodynamics.

Metformin, a synthetic biguanide, is currently one of the most frequently recommended medications for type 2 diabetes treatment around the world. This review presents the latest discoveries in the pharmacokinetics of metformin, especially the role of transporters (e.g. Organic Cation Transporters OCTs, Multidrug and Toxin Extrusion transporters MATE) in oral absorption, distribution, elimination and biochemical effects of metformin in humans. We also review the associations between genetic variations of metformin transporters, their pharmacokinetics and drug efficacy or drug responses. In the second part of this paper, we highlight the current knowledge on novel metformin actions including favourable effects on lipid profile (e.g. decreasing plasma triglycerides (TG) and low density lipoprotein (LDL) cholesterol levels) and the cardiovascular system (e.g. decline in systolic and diastolic blood pressure, and vasoprotective effects). Furthermore, we provide an up-to-date overview of multidirectional activities of metformin, including the effects on coagulation and fibrinolysis, polycystic ovary syndrome, as well as the anti-ageing and antiinflammatory properties. Over the past two decades, metformin's antineoplastic properties have been drawing increasing attention of scientists; herein, we outline the state-of-the-art discoveries concerning metformin use in the field of oncology. Finally, we review the newly synthesized derivatives and pro-drugs of metformin and other biguanides.