Overcoming undesirable hERG affinity by incorporating fluorine atoms: A case of MAO-B inhibitors derived from 1 H-pyrrolo-[3,2-c]quinolines.

The incorporation of the fluorine motif is a strategy widely applied in drug design for modulating the activity, physicochemical parameters, and metabolic stability of chemical compounds. In this study, we attempted to reduce the affinity for ether-à-go-go-related gene (hERG) channel by introducing fluorine atoms in a group of 1H-pyrrolo[3,2-c]quinolines that are capable of inhibiting monoamine oxidase type B (MAO-B). A series of structural modifications guided by in vitro evaluation of MAO-B inhibition and antitargeting for hERG channels were performed, which led to the identification of 1-(3-chlorobenzyl)-4-(4,4-difluoropiperidin-1-yl)-1H-pyrrolo[3,2-c]quinoline (26). Compound 26 acted as a reversible MAO-B inhibitor exhibiting selectivity over 45 targets, enzymes, transporters, and ion channels, and showed potent glioprotective properties in cultured astrocytes. In addition, the compound demonstrated good metabolic stability in rat liver microsomes assay, a favorable safety profile, and brain permeability. It also displayed procognitive effects in the novel object recognition test in rats and antidepressant-like activity in forced swim test in mice. The findings of the study suggest that reversible MAO-B inhibitors can have potential therapeutic applications in Alzheimer's disease.

A dual-acting 5-HT6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties.

The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT6 receptor (5-HT6R) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking priviliged scaffolds of 5-HT6R with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HT6R at Gs signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay, artificial membrane permeability, no hepatotoxicity, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HT6R/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies.

Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives.

In this study, a series of compounds derived from 4-methoxy-1H-isoindole-1,3(2H)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1H-isoindole-1,3(2H)-dione derivatives with various amine moieties was synthesized and examined for their phosphodiesterase 10A (PDE10A)-inhibiting properties and their 5-HT1A and 5-HT7 receptor affinities. Based on in vitro studies, the most potent compound, 18 (2-[4-(1H-benzimidazol-2-yl)butyl]-4-methoxy-1H-isoindole-1,3(2H)-dione), was selected and its safety in vitro was evaluated. In order to explain the binding mode of compound 18 in the active site of the PDE10A enzyme and describe the molecular interactions responsible for its inhibition, computer-aided docking studies were performed. The potential antipsychotic properties of compound 18 in a behavioral model of schizophrenia were also investigated.

High bisphenol A concentrations augment the invasiveness of tumor cells through Snail-1/Cx43/ERRγ-dependent epithelial-mesenchymal transition.

Bisphenol A (BPA) is commonly present in plastics used for food storage and preservation. The release of BPA from these products results in a permanent human exposition to BPA; however, the quality and quantity of BPA adverse effects remain a matter of controversy. The common presence of BPA in the human environment and the controversies concerning the relations of human exposition to BPA and cancer incidence justify the research on the interactions between BPA and pro-metastatic signaling in cancer cells. Here, we describe a novel BPA-reactive signaling axis that induces the epithelial-mesenchymal transition (EMT) in lung adenocarcinoma A549 cells. BPA exerted negligible effects on their properties in a wide range of concentrations (10 nM - 100 nM), whereas it considerably induced A549 invasiveness at high concentrations (10 µM). The BPA-induced EMT was illustrated by morphologic changes, E/N-cadherin switch and vimentin/Snail-1/connexin(Cx)43 up-regulation in A549 populations. It was followed by enhancement of A549 drug-resistance. Corresponding effects of BPA were observed in prostate cancer cell populations. Concomitantly, we observed increased levels and perinuclear accumulation of estrogen-related receptor gamma (ERRγ) in BPA-treated cells, its interactions with Cx43/Snail-1, and the corresponding effects of phenol red on A549 cells. Collectively, these data identify a novel, pro-metastatic Snail-1/Cx43/ERRγ signaling pathway. Its reactivity to BPA underlies the induction of cancer cells' invasiveness in the presence of high BPA concentrations in vitro. Thus, the chronic exposition of cancer cells to extrinsic and intrinsic BPA should be considered as a potential obstacle in a cancer therapy.

Analgesic and antiallodynic activity of novel anticonvulsant agents derived from 3-benzhydryl-pyrrolidine-2,5-dione in mouse models of nociceptive and neuropathic pain.

The objective of this study was to evaluate analgesic and antiallodynic activity of four new 3-benzhydryl-pyrrolidine-2,5-dione derivatives, which demonstrated previously anticonvulsant activity in the seizure tests in mice. Analgesic activity was examined in acute (the hot plate test), tonic (the formalin test), as well as neuropathic (the oxaliplatin-induced peripheral neuropathy) pain models in mice. Moreover, potential sedative properties and hepatotoxicity were evaluated. To establish the plausible mechanism of action, in vitro assays were carried out. All tested compounds RS 34, RS 37, RS 48, and RS 49, similarly to pregabalin, were active in the second phase of formalin test, a model of tonic pain. The most promising effect was observed for compounds RS 34, RS 48, and RS 49, which in a statistically significant way attenuated the nocifensive response at all tested doses 1, 10, and 30 mg/kg. Furthermore, all compounds at a dose of 30 mg/kg revealed antiallodynic activity in neuropathic pain related to chemotherapy-induced peripheral neuropathy in mice. In experimental tests on three compounds RS 34, RS 37 and RS 48 at active doses no sedative properties were registered. In the in vitro assay the selected molecule RS 34 did not induce cytotoxic effect on hepatoma cells. The binding and functional studies did not provide firm evidence on possible mechanism of action of these derivatives. In conclusion, the tested pyrrolidine-2,5-dione derivatives with antiseizure activity exerted also analgesic and antiallodynic effects in mouse models of pain.

Novel phosphodiesterases inhibitors from the group of purine-2,6-dione derivatives as potent modulators of airway smooth muscle cell remodelling.

Airway remodelling (AR) is an important pathological feature of chronic asthma and chronic obstructive pulmonary disease. The etiology of AR is complex and involves both lung structural and immune cells. One of the main contributors to airway remodelling is the airway smooth muscle (ASM), which is thickened by asthma, becomes more contractile and produces more extracellular matrix. As a second messenger, adenosine 3',5'-cyclic monophosphate (cAMP) has been shown to contribute to ASM cell (ASMC) relaxation as well as to anti-remodelling effects in ASMC. Phosphodiesterase (PDE) inhibitors have drawn attention as an interesting new group of potential anti-inflammatory and anti-remodelling drugs. Recently, new hydrazide and amide purine-2,6-dione derivatives with anti-inflammatory properties have been synthesized by our team (compounds 1 and 2). We expanded our study of their PDE selectivity profile, ability to increase intracellular cAMP levels, metabolic stability and, above all, their capacity to modulate cell responses associated with ASMC remodelling. The results show that both compounds have subtype specificity for several PDE isoforms (including inhibition of PDE1, PDE3, PDE4 and PDE7). Interestingly, such combined PDE subtype inhibition exerts improved anti-remodelling efficacies against several ASMC-induced responses such as proliferation, contractility, extracellular matrix (ECM) protein expression and migration when compared to other non-selective and selective PDE inhibitors. Our findings open novel perspectives in the search for new chemical entities with dual anti-inflammatory and anti-remodelling profiles in the group of purine-2,6-dione derivatives as broad-spectrum PDE inhibitors.

Similar Safety Profile of the Enantiomeric N-Aminoalkyl Derivatives of Trans-2-Aminocyclohexan-1-ol Demonstrating Anticonvulsant Activity.

Epilepsy is one of the most common neurological disorder in the world. Many antiepileptic drugs cause multiple adverse effects. Moreover, multidrug resistance is a serious problem in epilepsy treatment. In the present study we evaluated the safety profile of three (1-3) new chiral N-aminoalkyl derivatives of trans-2-aminocyclohexan-1-ol demonstrating anticonvulsant activity. Our aim was also to determine differences between the enantiomeric compounds with respect to their safety profile. The results of the study indicated that compounds 1-3 are non-cytotoxic for astrocytes, although they exhibit cytotoxic activity against human glioblastoma cells. Moreover, 1-3 did not affect the viability of HepG2 cells and did not produce adducts with glutathione. Compounds 1-3 demonstrated no mutagenic activity either in the Salmonella typhimurium or in Vibrio harveyi tests. Additionally, the compounds displayed a strong or moderate antimutagenic effect. Finally, the P-glycoprotein (P-gp) ATPase assay demonstrated that both enantiomers are potent P-gp inhibitors. To sum up, our results indicate that the newly synthesized derivatives may be considered promising candidates for further research on anticonvulsant drug discovery and development. Our study indicated the similar safety profile of the enantiomeric N-aminoalkyl derivatives of trans-2-aminocyclohexan-1-ol, although in the previous studies both enantiomers differ in their biotransformation pathways and pharmacological activity.

Metabolic stability and its role in the discovery of new chemical entities.

Determination of metabolic profiles of new chemical entities is a key step in the process of drug discovery, since it influences pharmacokinetic characteristics of therapeutic compounds. One of the main challenges of medicinal chemistry is not only to design compounds demonstrating beneficial activity, but also molecules exhibiting favourable pharmacokinetic parameters. Chemical compounds can be divided into those which are metabolized relatively fast and those which undergo slow biotransformation. Rapid biotransformation reduces exposure to the maternal compound and may lead to the generation of active, non-active or toxic metabolites. In contrast, high metabolic stability may promote interactions between drugs and lead to parent compound toxicity. In the present paper, issues of compound metabolic stability will be discussed, with special emphasis on its significance, in vitro metabolic stability testing, dilemmas regarding in vitro-in vivo extrapolation of the results and some aspects relating to different preclinical species used in in vitro metabolic stability assessment of compounds.

Saponins as chemosensitizing substances that improve effectiveness and selectivity of anticancer drug-Minireview of in vitro studies.

Triterpene saponins (saponosides) are found in higher plants and display a wide range of biological and pharmacological activities. The antitumor effects of saponins have been proved by their cytotoxic, cytostatic, proapoptotic, and anti-invasive effects in many cellular models. Saponins hold great potential for being developed into chemopreventive and chemotherapeutic drugs. A promising way of reducing the adverse effects of chemotherapy without attenuating its efficiency is provided by the combined application of chemotherapeutic agents and saponosides in subtoxic concentrations. Until recently, saponosides were primarily used as adjuvants that enhance the effect of vaccines. In cancer therapy, saponins are applied in combination with immunotoxins because they increase the selectivity of given immunotoxins against cancer cells and therefore inure normal cells to the cytotoxic effects of immunotoxins. Significantly, certain saponins have been identified that drastically enhance the efficacy of many chemotherapeutic agents, including cisplatin, paclitaxel, doxorubicin, docetaxel, mitoxantrone, and cyclophosphamide. Moreover, saponins used in combination therapy enhance the sensitivity of chemoresistant tumor cells to clinically used chemotherapeutic agents. This review sheds light on the molecular mechanisms underlying cancer co-treatment with saponins and chemotherapy, with a particular focus on modulation of the cell signaling pathways associated with the promotion and progression of cancer cell proliferation, apoptosis, and metastasis.

Microbial biotransformation of some novel hydantoin derivatives: Perspectives for bioremediation of potential sunscreen agents.

Having identified novel hydantoin derivatives (compounds 1-5) demonstrating promising photoprotective capacity against UV radiation, and understainding the problem of the biotic and abiotic degradation of UV filters, the aim of the study was to evaluate their metabolic fate with the environmental fungus Cunninghamella echinulata. In parallel, compound 1 in vitro microsomal metabolic pattern was evaluated. Finally, in silico toxicity of test compounds and their biotransformation products was estimated, and parent compounds photostability was assessed. The study demonstrated the capacity for C. echinulata to metabolize 1-5, which were biotransformed to a greater extent than the standard UV filter. O-dealkylation of the side chains attached to the phenyl or hydantoin rings, and hydroxylation of the phenyl ring occurred during microbial transformation. O-dealkylation product was a unique metabolite observed in microsomal biotransformation of 1, being its intrinsic clearance in the medium category range. In silico study demonstrated that compounds 1-5 have low toxicity risk. Among the resulting metabolites, four can increase the risk of reproductive effects as shown by OSIRIS prediction. Noteworthy, all indicated metabolites belong to minor metabolites, except for compound 3 major metabolite. Moreover, the results of the photostability study showed that 1-5 were considered to be photostable. To sum up, the obtained in vitro biotransformation, photostability, and in silico toxicity results encourage further studies on hydantoin derivatives as potential UV photoprotective agents. The presented biotransformation profile of compounds 1-5 by C. echinulata suggests that these compounds may follow a similar biodegradation fate when released into the environment.

Discovery of Novel UV-Filters with Favorable Safety Profiles in the 5-Arylideneimidazolidine-2,4-dione Derivatives Group.

Effective protection from the harmful effects of UV radiation may be achieved by using sunscreens containing organic or inorganic UV filters. The number of currently available UV filters is limited and some of the allowed molecules possess limitations such as systemic absorption, endocrine disruption properties, contact and photocontact allergy induction, and low photostability. In the search for new organic UV filters we designed and synthesized a series consisting of 5-benzylidene and 5-(3-phenylprop-2-en-1-ylidene)imidazolidine-2,4-dione (hydantoin) derivatives. The photoprotective activity of the tested compounds was confirmed in methanol solutions and macrogol formulations. The most promising compounds possessed similar UV protection parameter values as selected commercially available UV filters. The compound diethyl 2,2'-((Z)-4-((E)-3-(4-methoxyphenyl)allylidene)-2,5-dioxoimidazolidine-1,3-diyl)diacetate (4g) was characterized as an especially efficient UVA photoprotective agent with a UVA PF of 6.83 ± 0.05 and favorable photostability. Diethyl 2,2'-((Z)-4-(4-methoxybenzylidene)-2,5-dioxo- imidazolidine-1,3-diyl)diacetate (3b) was the most promising UVB-filter, with a SPFin vitro of 3.07 ± 0.04 and very good solubility and photostability. The main photodegradation products were geometric isomers of the parent compounds. These compounds were also shown to be non-cytotoxic at concentrations up to 50 µM when tested on three types of human skin cells and possess no estrogenic activity, according to the results of a MCF-7 breast cancer model.

Dual 5-HT6 and D3 Receptor Antagonists in a Group of 1H-Pyrrolo[3,2-c]quinolines with Neuroprotective and Procognitive Activity.

In light of the multifactorial origin of neurodegenerative disorders and some body of evidence indicating that pharmacological blockade of serotonin 5-HT6 and dopamine D3 receptors might be beneficial for cognitive decline, we envisioned (S)-1-[(3-chlorophenyl)sulfonyl]-4-(pyrrolidine-3-yl-amino)-1H-pyrrolo[3,2-c]quinoline (CPPQ), a neutral antagonist of 5-HT6R, as a chemical template for designing dual antagonists of 5-HT6/D3 receptors. As shown by in vitro experiments, supported by quantum chemical calculations and molecular dynamic simulations, introducing alkyl substituents at the pyrrolidine nitrogen of CPPQ, fulfilled structural requirements for simultaneous modulation of 5-HT6 and D3 receptors. The study identified compound 19 ((S)-1-((3-chlorophenyl)sulfonyl)-N-(1-isobutylpyrrolidin-3-yl)-1H-pyrrolo[3,2-c]quinolin-4-amine), which was classified as a dual 5-HT6/D3R antagonist (Ki(5-HT6) = 27 nM, Ki(D3) = 7 nM). Compound 19 behaved as a neutral antagonist at Gs signaling and had no influence on receptor-operated, cyclin-dependent kinase 5 (Cdk5)-dependent neurite growth. In contrast to the well characterized 5-HT6R antagonist intepirdine, compound 19 displayed neuroprotective properties against astrocyte damage induced by doxorubicin, as shown using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) staining to assess cell metabolic activity and lactate dehydrogenase (LDH) release as an index of cell membrane disruption. This feature is of particular importance considering the involvement of loss of homeostatic function of glial cells in the progress of neurodegeneration. Biological results obtained for 19 in in vitro tests, translated into procognitive properties in phencyclidine (PCP)-induced memory decline in the novel object recognition (NOR) task in rats.

Synergistic anticancer activity of doxorubicin and piperlongumine on DU-145 prostate cancer cells - The involvement of carbonyl reductase 1 inhibition.

One of the causes of therapeutic failure of chemotherapy is cancer cell resistance. In the case of anthracyclines, many resistance mechanisms have been described. One of them assumes the role of carbonyl reductase 1 (CBR1), a cytosolic enzyme that is responsible for the biotransformation process of anthracyclines to less active, undesirable metabolites. Therefore, CBR1 inhibitors are considered for use as a chemosensitizing agents. In the present study, piperlongumine (PL), a Piper longum L. alkaloid that has previously been described as a CBR1 inhibitor, was investigated for its chemosensitizing properties in co-treatment with doxorubicin (DOX). The biotransformation process of DOX in the presence of PL was tracked using human cytosol fraction and LC-MS, then a molecular modeling study was conducted to predict the interaction of PL with the active site of the CBR1. The biological interaction between DOX and PL was investigated using DU-145 prostate cancer cells. Cytotoxic and antiproliferative properties of DOX and PL were examined, and the type and potency of interaction was quantified by Combination Index. The mechanism of the cell death induced by the agents was investigated by flow cytometry and the anti-invasive properties of the drugs were determined by monitoring the movement of individual cells. PL showed dose-dependent inhibition of DOX metabolism in cytosol, which resulted in less doxorubicinol (DOXol) metabolite being formed. The possible mechanism of CBR1 inhibition was explained through molecular modeling studies by prediction of PL's binding mode in the active site of the enzyme's crystal structure-based model. DOX and PL showed a synergistic antiproliferative and proapoptotic effect on cancer cells. Significant anti-invasive properties of the combination of DOX and PL were found, but when the drugs were used separately they did not alter the cancer cells' motility. Cell motility inhibition was accompanied by significant changes in cytoskeleton architecture. DOX and PL used in co-treatment showed significant synergistic anticancer properties. Inhibition of DOX metabolism by PL was found to be a mechanism that was likely to be responsible for the observed interaction.

Correction to: Fibroblast-to-myofibroblast transition in bronchial asthma.

In the original publication, funding information was inadvertently omitted.

Characteristics of metabolic stability and the cell permeability of 2-pyrimidinyl-piperazinyl-alkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione with antidepressant- and anxiolytic-like activities.

A series of 2-pyrimidinyl-piperazinyl-alkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione has been synthesized in an attempt to discover a new class of psychotropic agents. Compounds were evaluated for their in vitro affinity for serotonin 5-HT1A , 5-HT7 , and phosphodiesterases PDE4 and PDE10. The most potent compound 2-pyrimidinyl-1-piperazinyl-butyl-imidazo[2,1-f]purine-2,4-dione (4b) behaved as strong and selective antagonist of 5-HT1A . Molecular modeling studies revealed differences in binding mode between compound 4b and buspirone, which might reflect variation of the ligands' affinity and potency in the 5-HT1A receptor. Compound 4b in silico models demonstrated drug-likeness properties and, contrary to buspirone, showed a metabolic stability in mouse liver microsomes system. Experimentally obtained value of apparent permeability coefficient Papp for 4b in parallel artificial permeability assay indicates the possibility of binding weakly to plasma proteins and high intestinal absorption fraction. Evaluation of the antidepressant- and anxiolytic-like activities of 4b revealed both activities at the same dose of 1.25 mg/kg and seemed to be specific. The antidepressant and/or anxiolytic properties of 4b may be related to its first-pass effect.

Photostability of Terbinafine Under UVA Irradiation: The Effect of UV Absorbers.

The photostability of drugs administered topically on unprotected skin is a complex phenomenon that could be connected with the loss of activity or, rather rarely, the occurrence of toxic degradation products. In this study, an in-depth investigation of the photostability of terbinafine, in both solutions and formulations, was conducted, taking into account the presence of UV absorbers such as TiO2 , ZnO, avobenzone, 3-(4-methylbenzylidene)camphor, octocrylene, benzophenone-1 and benzophenone-2. The clear photocatalytic degradation of terbinafine in ethanol solution was observed in the presence of TiO2 and/or ZnO. In other cases, terbinafine was stable, with the exception of, in the presence of octocrylene. The presumed degradation products of terbinafine were identified for the first time using LC/MS/MS, and transformation pathways were proposed. In the case of a cream formulation, the percentage of initial terbinafine content was almost unchanged in the presence of the UV absorbers benzophenone-1, benzophenone-2 and 3-(4-methylbenzylidene)camphor. In vitro cytotoxicity risk assessment of terbinafine based on photostability under UVA irradiation was evaluated using the human skin fibroblast BJ (ATCC® CRL-2522™), and this showed no statistically significant difference in cell viability for all samples analyzed.

Synthesis and anticonvulsant activity of phenoxyacetyl derivatives of amines, including aminoalkanols and amino acids.

A series of 17 new phenoxyacetamides has been prepared via multistep chemical synthesis as a continuation of the research carried out by our group on di- and tri-substituted phenoxyalkyl and phenoxyacetyl derivatives of amines. The obtained compounds vary in an amide component, for example aminoalkanol or (un)modified amino acid moieties were introduced. The structures of selected products were confirmed by means of crystallographic methods. All 17 compounds were the subject of preliminary screening for potential anticonvulsant activity (MES, 6 Hz and/or scMET tests) and neurotoxicity (rotarod) in mice after intraperitoneal administration, while several active compounds were subsequently examined in additional models (e.g. MES and rotarod - rats, p.o. or i.p., hippocampal kindling - rats, i.p.). Finally, safety studies (cytotoxicity and cell proliferation assays on astrocytes, metabolic stability assessment, mutagenicity evaluation) were performed for several active compounds, including the most promising one (R-(-)-2-(2,6-dimethylphenoxy)-N-(1-hydroxypropan-2-yl)acetamide, MES ED50 = 12.00 mg per kg b.w., rats, p.o.).

Fibroblast-to-myofibroblast transition in bronchial asthma.

Bronchial asthma is a chronic inflammatory disease in which bronchial wall remodelling plays a significant role. This phenomenon is related to enhanced proliferation of airway smooth muscle cells, elevated extracellular matrix protein secretion and an increased number of myofibroblasts. Phenotypic fibroblast-to-myofibroblast transition represents one of the primary mechanisms by which myofibroblasts arise in fibrotic lung tissue. Fibroblast-to-myofibroblast transition requires a combination of several types of factors, the most important of which are divided into humoural and mechanical factors, as well as certain extracellular matrix proteins. Despite intensive research on the nature of this process, its underlying mechanisms during bronchial airway wall remodelling in asthma are not yet fully clarified. This review focuses on what is known about the nature of fibroblast-to-myofibroblast transition in asthma. We aim to consider possible mechanisms and conditions that may play an important role in fibroblast-to-myofibroblast transition but have not yet been discussed in this context. Recent studies have shown that some inherent and previously undescribed features of fibroblasts can also play a significant role in fibroblast-to-myofibroblast transition. Differences observed between asthmatic and non-asthmatic bronchial fibroblasts (e.g., response to transforming growth factor ß, cell shape, elasticity, and protein expression profile) may have a crucial influence on this phenomenon. An accurate understanding and recognition of all factors affecting fibroblast-to-myofibroblast transition might provide an opportunity to discover efficient methods of counteracting this phenomenon.

Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile.

Benign prostatic hyperplasia (BPH) is the most common male clinical problem impacting the quality of life of older men. Clinical studies have indicated that the inhibition of α1A-/α1D adrenoceptors might offer effective therapy in lower urinary tract symptoms. Herein, a limited series of arylsulfonamide derivatives of (aryloxy)ethyl alicyclic amines was designed, synthesized, and biologically evaluated as potent α1-adrenoceptor antagonists with uroselective profile. Among them, compound 9 (3-chloro-2-fluoro-N-([1-(2-(2-(2,2,2-trifluoroethoxy)phenoxy]ethyl)piperidin-4-yl)methyl)benzenesulfonamide) behaved as an α1A-/α1D-adrenoceptor antagonist (Ki(α1) = 50 nM, EC50(α1A) = 0.8 nM, EC50(α1D) = 1.1 nM), displayed selectivity over α2-adrenoceptors (Ki(α2) = 858 nM), and a 5-fold functional preference over the α1B subtype. Compound 9 showed adequate metabolic stability in rat-liver microsome assay similar to the reference drug tamsulosin (Clint = 67 and 41 µL/min/mg, respectively). Compound 9 did not decrease systolic and diastolic blood pressure in normotensive anesthetized rats in the dose of 2 mg/kg, i.v. These data support development of uroselective agents in the group of arylsulfonamides of alicyclic amines with potential efficacy in the treatment of lower urinary tract symptoms associated to benign prostatic hyperplasia.

Piperlongumine (piplartine) as a lead compound for anticancer agents - Synthesis and properties of analogues: A mini-review.

Piperlongumine, also known as piplartine, is an amide alkaloid of Piper longum L. (long piper), a medical plant known from Ayurvedic medicine. Although was discovered well over fifty years ago, its pharmacological properties have been uncovered in the past decade. In particular, piperlongumine has been most extensively studied as a potential anticancer agent. Piperlongumine has exhibited cytotoxicity against a broad spectrum of human cancer cell lines, as well as demonstrated antitumor activity in rodents. Piperlongumine has also been found to be a proapoptotic, anti-invasive, antiangiogenic agent and synergize with modern chemotherapeutic agents. Because of its clinical potential, several studies were undertaken to obtain piperlongumine analogues, which have exhibited more potent activity or more appropriate drug-like parameters. In this review, the synthesis of piperlongumine analogues and piperlongumine-based hybrid compounds, as well as their anticancer properties and the molecular basis for their activity are explored. General structure-activity relationship conclusions are drawn and directions for the future research are indicated.