ABSTRACT
Novel analogues of C-2-substituted thienopyrimidine-based bisphosphonates (C2-ThP-BPs) are described that are potent inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS). Members of this class of compounds induce target-selective apoptosis of multiple myeloma (MM) cells and exhibit antimyeloma activity in vivo. A key structural element of these inhibitors is a linker moiety that connects their (((2-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methylene)bisphosphonic acid core to various side chains. The structural diversity of this linker moiety, as well as the side chains attached to it, was investigated and found to significantly impact the toxicity of these compounds in MM cells. The most potent inhibitor identified was evaluated in mouse and rat for liver toxicity and systemic exposure, respectively, providing further optimism for the potential value of such compounds as human therapeutics.
Subject(s)
Antineoplastic Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Geranylgeranyl-Diphosphate Geranylgeranyltransferase/antagonists & inhibitors , Multiple Myeloma/drug therapy , Pyrimidines/therapeutic use , Thiophenes/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Antineoplastic Agents/toxicity , Bone Marrow Cells/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/toxicity , Female , Fungal Proteins/antagonists & inhibitors , Fungal Proteins/metabolism , Geranylgeranyl-Diphosphate Geranylgeranyltransferase/metabolism , Humans , Liver/drug effects , Male , Mice, Inbred C57BL , Molecular Structure , Protein Binding , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Pyrimidines/toxicity , Rats , Saccharomyces cerevisiae/enzymology , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/metabolism , Thiophenes/toxicityABSTRACT
The scaffold of TIQ-A, a previously known inhibitor of human poly-ADP-ribosyltransferase PARP1, was utilized to develop inhibitors against human mono-ADP-ribosyltransferases through structure-guided design and activity profiling. By supplementing the TIQ-A scaffold with small structural changes, based on a PARP10 inhibitor OUL35, selectivity changed from poly-ADP-ribosyltransferases towards mono-ADP-ribosyltransferases. Binding modes of analogs were experimentally verified by determining complex crystal structures with mono-ADP-ribosyltransferase PARP15 and with poly-ADP-ribosyltransferase TNKS2. The best analogs of the study achieved 10-20-fold selectivity towards mono-ADP-ribosyltransferases PARP10 and PARP15 while maintaining micromolar potencies. The work demonstrates a route to differentiate compound selectivity between mono- and poly-ribosyltransferases of the human ARTD family.
Subject(s)
ADP Ribose Transferases/antagonists & inhibitors , Isoquinolines/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Proto-Oncogene Proteins/antagonists & inhibitors , Thiophenes/pharmacology , ADP Ribose Transferases/metabolism , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Models, Molecular , Molecular Structure , Poly(ADP-ribose) Polymerase Inhibitors/chemical synthesis , Poly(ADP-ribose) Polymerase Inhibitors/chemistry , Poly(ADP-ribose) Polymerases/metabolism , Proto-Oncogene Proteins/metabolism , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistryABSTRACT
Breast cancer consists of heterogenic subpopulations, which determine the prognosis and response to chemotherapy. Among these subpopulations, a very limited number of cancer cells are particularly problematic. These cells, known as breast cancer stem cells (BCSCs), are thought responsible for metastasis and recurrence. They are thus major contributor to the unfavorable outcomes seen for many breast cancer patients. BCSCs are more prevalent in the hypoxic niche. This is an oxygen-deprived environment that is considered crucial to their proliferation, stemness, and self-renewal but also one that makes BCSCs highly refractory to traditional chemotherapeutic regimens. Here we report a small molecule construct, AzCDF, that allows the therapeutic targeting of BCSCs and which is effective in normally refractory hypoxic tumor environments. A related system, AzNap, has been developed that permits CSC imaging. Several design elements are incorporated into AzCDF, including the CAIX inhibitor acetazolamide (Az) to promote localization in MDA-MB-231 CSCs, a dimethylnitrothiophene subunit as a hypoxia trigger, and a 3,4-difluorobenzylidene curcumin (CDF) as a readily released therapeutic payload. This allows AzCDF to serve as a hypoxia-liable molecular platform that targets BCSCs selectively which decreases CSC migration, retards tumor growth, and lowers tumorigenesis rates as evidenced by a combination of in vitro and in vivo studies. To the best of our knowledge, this is the first time a CSC-targeting small molecule has been shown to prevent tumorigenesis in an animal model.
Subject(s)
Antineoplastic Agents/therapeutic use , Carbonic Anhydrase Inhibitors/therapeutic use , Carcinogenesis/drug effects , Cell Hypoxia/drug effects , Neoplasms/drug therapy , Neoplastic Stem Cells/drug effects , Acetazolamide/analogs & derivatives , Acetazolamide/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Carbonic Anhydrase IX/metabolism , Carbonic Anhydrase Inhibitors/chemical synthesis , Cell Line, Tumor , Cell Movement/drug effects , Curcumin/analogs & derivatives , Curcumin/chemical synthesis , Curcumin/therapeutic use , Diarylheptanoids/chemical synthesis , Diarylheptanoids/therapeutic use , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/therapeutic use , Humans , Mice, Inbred BALB C , Mice, Nude , Neoplasms/diagnostic imaging , Spheroids, Cellular/drug effects , Thiophenes/chemical synthesis , Thiophenes/therapeutic use , Tumor Microenvironment/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Natural compounds isolated from different medicinal plants remain one of the major resources of anticancer drugs due to their enormous chemical diversity. Studies suggested therapeutic potential for various tanshinones, key bioactive lipophilic compounds from the root extracts of Salvia miltiorrhiza Bunge, against multiple cancers including breast carcinoma. We designed, synthesized and evaluated anti-cancer properties of a series of condensed and doubly condensed furophenanthraquinones of tanshinone derivatives on two breast cancer lines - MCF7 and MDA-MB-231. We identified two thiophene analogues - compounds 48 and 52 with greater anti-proliferative efficiency (~4 fold) as compared to the natural tanshinones. Mechanistically, we showed that both compounds induced autophagy mediated cell death and partial but significant restoration of cell death in the presence of autophagy inhibitor further supported this notion. Both compounds transcriptionally activated several autophagy genes responsible for autophagosome formation along with two death regulators - GADD34 and CHOP for inducing cell death. Altogether, our studies provide strong evidence to support compounds 48 and 52 as promising leads for further development as anticancer agents through modulating autophagy mechanism.
Subject(s)
Antineoplastic Agents/pharmacology , Autophagy/drug effects , Breast Neoplasms/drug therapy , Thiophenes/pharmacology , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Thiophenes/chemical synthesis , Unfolded Protein Response/drug effectsABSTRACT
In our effort towards the identification of novel BuChE-IDO1 dual-targeted inhibitor for the treatment of Alzheimer's disease (AD), sertaconazole was identified through a combination of structure-based virtual screening followed by MM-GBSA rescoring. Preliminary chemical optimization was performed to develop more potent and selective sertaconazole analogues. In consideration of the selectivity and the inhibitory activity against target proteins, compounds 5c and 5d were selected for the next study. Further modification of compound 5c led to the generation of compound 10g with notably improved selectivity towards BuChE versus AChE. The present study provided us with a good starting point to further design potent and selective BuChE-IDO1 inhibitors, which may benefit the treatment of late stage AD.
Subject(s)
Alzheimer Disease/drug therapy , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Imidazoles/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Isoindoles/pharmacology , Thiophenes/pharmacology , Alzheimer Disease/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Isoindoles/chemical synthesis , Isoindoles/chemistry , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistryABSTRACT
As the continuous rise in the incidence of antibiotic resistance, it is urgent to develop novel chemical scaffolds with antibacterial activities to control the spread of resistance to conventional antibiotics. In this study, a series of phenylthiazole and phenylthiophene pyrimidindiamine derivatives were designed and synthesized by modifying the hit compound (N2-isobutyl-N4-((4-methyl-2-phenylthiazol-5-yl)methyl) pyrimidine-2,4-diamine) and their antibacterial activities were evaluated both in vitro and in vivo. Among the tested compounds, compound 14g (N4-((5-(3-bromophenyl)thiophen-2-yl)methyl)-N2-isobutylpyrimidine-2,4-diamine) displayed the best antibacterial activities, which was not only capable of inhibiting E. coli and S. aureus growth at concentrations as low as 2 and 3 µg/mL in vitro, but also efficacious in a mice model of bacteremia in vivo. Unlike conventional antibiotics, compound 14g was elucidated to mainly destroy the bacterial cell membrane, with the dissipation of membrane potential and leakage of contents, ultimately leading to cell death. The destruction of cell structure is challenging to induce bacterial resistance, which suggested that compound 14g may be a kind of promising alternatives to antibiotics against bacteria.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Bacteremia/drug therapy , Cell Membrane/drug effects , Pyrimidines/therapeutic use , Thiazoles/therapeutic use , Thiophenes/therapeutic use , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Drug Design , Escherichia coli/drug effects , Hemolysis/drug effects , Male , Mice, Inbred C57BL , Microbial Sensitivity Tests , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Rabbits , Staphylococcus aureus/drug effects , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Thiophenes/chemical synthesis , Thiophenes/pharmacologyABSTRACT
NIR-II fluorescence imaging has great potential in diagnosis, but the quantum efficiency of contrast agents is an urgent problem to be solved. We synthesized two new multifunctional polymers, P-TT and P-DPP, with a tetrahedral C (sp3) and branched alkyl chains in the main chain, which were beneficial to obtain high quantum efficiency. P-TT and P-DPP showed absorption peaks of 686 nm and 763 nm, respectively, and fluorescence emission peaks of 1071 nm and 1066 nm, respectively. The photothermal effect of P-DPP can reach 52 °C, and the quantum yield reaches 1.5%, which was three times higher than that of nanotube fluorophores (quantum yield 0.4%). P-DPP is used for stable fluorescence imaging of blood vessels and photoacoustic imaging of nude mice, and successfully applied to phototherapy of nude mouse tumours.
Subject(s)
Antineoplastic Agents/therapeutic use , Nanoparticles/therapeutic use , Neoplasms/diagnostic imaging , Neoplasms/drug therapy , Polymers/therapeutic use , Thiophenes/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/radiation effects , Antineoplastic Agents/toxicity , Female , Fluorescent Dyes , HeLa Cells , Humans , Hyperthermia, Induced/methods , Infrared Rays , Liver/diagnostic imaging , Mice, Nude , Nanoparticles/radiation effects , Nanoparticles/toxicity , Photoacoustic Techniques/methods , Photochemotherapy/methods , Polymers/chemical synthesis , Polymers/radiation effects , Polymers/toxicity , Thiophenes/chemical synthesis , Thiophenes/radiation effects , Thiophenes/toxicity , Xenograft Model Antitumor AssaysABSTRACT
Leishmaniasis, a major health problem worldwide, has a limited arsenal of drugs for its control. The appearance of resistance to first- and second-line anti-leishmanial drugs confirms the need to develop new and less toxic drugs that overcome spontaneous resistance. In the present study, we report the design and synthesis of a novel library of 38 flavonol-like compounds and their evaluation in a panel of assays encompassing parasite killing, pharmacokinetics, genomics and ADME-Toxicity resulting in the progression of a compound in the drug discovery value chain. Compound 19, 2-(benzo[b]thiophen-3-yl)-3-hydroxy-6-methoxy-4H-chromen-4-one, exhibited a broad-spectrum activity against Leishmania spp. (EC50 1.9⯵M for Leishmania infantum, 3.4⯵M for L. donovani, 6.7⯵M for L. major), Trypanosoma cruzi (EC50 7.5⯵M) and T. brucei (EC50 0.8⯵M). Focusing on anti-Leishmania activity, compound 19 challenge in vitro did not select for resistance markers in L. donovani, while a Cos-Seq screening for dominant resistance genes identified a gene locus on chromosome 36 that became ineffective at concentrations beyond EC50. Thus, compound 19 is a promising scaffold to tackle drug resistance in Leishmania infection. In vivo pharmacokinetic studies indicated that compound 19 has a long half-life (intravenous (IV): 63.2â¯h; per os (PO): 46.9â¯h) with an acceptable ADME-Toxicity profile. When tested in Leishmania infected hamsters, no toxicity and limited efficacy were observed. Low solubility and degradation were investigated spectroscopically as possible causes for the sub-optimal pharmacokinetic properties. Compound 19 resulted a specific compound based on the screening against a protein set, following the intrinsic fluorescence changes.
Subject(s)
Antiprotozoal Agents , Flavonols , Leishmania/drug effects , Leishmaniasis/drug therapy , Phosphorylcholine/analogs & derivatives , Thiophenes , Animals , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Cricetinae , Drug Evaluation, Preclinical , Drug Resistance/drug effects , Flavonols/chemical synthesis , Flavonols/chemistry , Flavonols/pharmacology , Genomics , Humans , Phosphorylcholine/chemistry , Phosphorylcholine/pharmacology , Thiophenes/chemical synthesis , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
Dorzolamide HCl (DRZ) ophthalmic drop is one of the most common glaucoma medications which rapidly eliminates after instillation leading to short residence time of the drug on cornea. The purpose of the present study is to develop a pH-triggered in situ gel system for ophthalmic delivery of DRZ for treatment of ocular hypertension. In this study, a 32 full factorial design was used for preparation of in situ gel formulations using different levels of Carbopol® and hydroxyl propyl methyl cellulose (HPMC). Rheological behavior, in vitro drug release, ex vivo corneal permeability, and IOP-lowering activity were investigated. DRZ solution (2% w/v) containing of 0.1% (w/v) Carbopol® and 0.1% (w/v) HPMC was selected as the optimal formulation considering its free flow under non-physiological conditions (initial pH and 25 ± 2°C) and transition to appropriate gel form under physiological circumstance (pH 7.4 and 34°C). This in situ gel presented the mucoadhesive property. Ex vivo corneal permeability of this combined solution was similar to those of DRZ solution. The developed formulation compared to the marketed drop (Biosopt®) and DRZ 2% solution had a better performance in intraocular pressure activity. The efficiency and long duration of IOP reduction could be due to the prolonged residence time of the in situ gel. The presence of Carbopol® as a pH triggered and mucoadhesive polymer causes to attach to the ocular mucosal surface for a long term.
Subject(s)
Acrylic Resins/pharmacokinetics , Antihypertensive Agents/pharmacokinetics , Drug Carriers/pharmacokinetics , Hypromellose Derivatives/pharmacokinetics , Sulfonamides/pharmacokinetics , Thiophenes/pharmacokinetics , Acrylic Resins/administration & dosage , Acrylic Resins/chemical synthesis , Administration, Ophthalmic , Animals , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/chemical synthesis , Cornea/drug effects , Cornea/metabolism , Drug Carriers/administration & dosage , Drug Carriers/chemical synthesis , Drug Evaluation, Preclinical/methods , Drug Liberation , Gels , Glaucoma/drug therapy , Glaucoma/metabolism , Hydrogen-Ion Concentration , Hypromellose Derivatives/administration & dosage , Hypromellose Derivatives/chemical synthesis , Intraocular Pressure/drug effects , Intraocular Pressure/physiology , Male , Ophthalmic Solutions/administration & dosage , Ophthalmic Solutions/chemical synthesis , Ophthalmic Solutions/pharmacokinetics , Rabbits , Sulfonamides/administration & dosage , Sulfonamides/chemical synthesis , Swine , Thiophenes/administration & dosage , Thiophenes/chemical synthesisABSTRACT
In this work, design, synthesis, and screening of thiophene carboxamides 4-13 and 16-23 as dual vascular endothelial growth factor receptors (VEGFRs) and mitotic inhibitors was reported. All compounds were screened against two gastrointestinal solid cancer cells, HepG-2 and HCT-116 cell lines. The most active cytotoxic derivatives 5 and 21 displayed 2.3- and 1.7-fold higher cytotoxicity than Sorafenib against HepG-2 cells. Cell cycle and apoptosis analyses for compounds 5 and 21 showed cells accumulation in the sub-G1 phase, and cell cycle arrest at G2/M phase. The apoptotic inducing activities of compounds 5 and 21were correlated to the elevation of p53, increase in Bax/Bcl-2 ratio, and increase in caspase-3/7.Compounds 5 and 21 showed potent inhibition againstVEGFR-2 (IC50 = 0.59 and 1.29 µM) and ß-tubulin polymerization (73% and 86% inhibition at their IC50 values).Molecular docking was performed with VEGFR-2 and tubulin binding sites to explain the displayed inhibitory activities.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/drug therapy , Drug Design , Drug Evaluation, Preclinical , Liver Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Thiophenes/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HCT116 Cells , Hep G2 Cells , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Molecular Docking Simulation , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Quantitative Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistry , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
Leishmania major (L. major) is a protozoan parasite that causes cutaneous leishmaniasis. About 12 million people are currently infected with an annual incidence of 1.3 million cases. The purpose of this study was to synthesize a small library of novel thiophene derivatives, and evaluate its parasitic activity, and potential mechanism of action (MOA). We developed a structureâ»activity relationship (SAR) study of the thiophene molecule 5A. Overall, eight thiophene derivatives of 5A were synthesized and purified by silica gel column chromatography. Of these eight analogs, the molecule 5D showed the highest in vitro activity against Leishmania major promastigotes (EC50 0.09 ± 0.02 µM), with an inhibition of the proliferation of intracellular amastigotes higher than 75% at only 0.63 µM and an excellent selective index. Moreover, the effect of 5D on L. major promastigotes was associated with generation of reactive oxygen species (ROS), and in silico docking studies suggested that 5D may play a role in inhibiting trypanothione reductase. In summary, the combined SAR study and the in vitro evaluation of 5A derivatives allowed the identification of the novel molecule 5D, which exhibited potent in vitro anti-leishmanial activity resulting in ROS production leading to cell death with no significant cytotoxicity towards mammalian cells.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Leishmania major/drug effects , NADH, NADPH Oxidoreductases/antagonists & inhibitors , Small Molecule Libraries/chemical synthesis , Thiophenes/chemical synthesis , Animals , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Cell Line , Drug Evaluation, Preclinical , Leishmania major/metabolism , Leishmaniasis, Cutaneous/drug therapy , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Protozoan Proteins/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
Malaria eradication is a global health priority, but current therapies are not always suitable for providing a radical cure. Artemisinin has paved the way for the current malaria treatment, the so-called Artemisinin-based Combination Therapy (ACT). However, with the detection of resistance to ACT, innovative compounds active against multiple parasite species and at multiple life stages are needed. GlaxoSmithKline has recently disclosed the results of a phenotypic screening of an internal library, publishing a collection of 400 antimalarial chemotypes, termed the "Malaria Box". After analysis of the data set, we have carried out a medicinal chemistry campaign in order to define the structure-activity relationships for one of the released compounds, which embodies a benzothiophene-2-carboxamide core. Thirty-five compounds were prepared, and a description of the structural features responsible for the in vitro activity against different strains of P. falciparum, the toxicity, and the metabolic stability is herein reported.
Subject(s)
Antimalarials/pharmacology , Thiophenes/pharmacology , Amides/chemistry , Antimalarials/chemical synthesis , Antimalarials/chemistry , Drug Discovery , Drug Evaluation, Preclinical , Humans , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistryABSTRACT
Adult hippocampal neurogenesis can be modulated by various physiological and pathological conditions, including stress, affective disorders, and several neurological conditions. Given the proposed role of this form of structural plasticity in the functioning of the hippocampus (namely learning and memory and affective behaviors), it is believed that alterations in hippocampal neurogenesis might underlie some of the behavioral deficits associated with these psychiatric and neurological conditions. Thus, the search for compounds that can reverse these deficits with minimal side effects has become a recognized priority. In the present study we tested the pro-neurogenic effects of isoxazole 9 (Isx-9), a small synthetic molecule that has been recently identified through the screening of chemical libraries in stem cell-based assays. We found that administration of Isx-9 for 14days was able to potentiate cell proliferation and increase the number of immature neurons in the hippocampal DG of adult rats. In addition, Isx-9 treatment was able to completely reverse the marked reduction in these initial stages of the neurogenic process observed in vehicle-treated animals (which were submitted to repeated handling and exposure to daily intraperitoneal injections). Based on these results, we recommend that future neurogenesis studies that require repeated handling and manipulation of animals should include a naïve (non-manipulated) control to determine the baseline levels of hippocampal cell proliferation and neuronal differentiation. Overall, these findings demonstrate that Isx-9 is a promising synthetic compound for the mitigation of stress-induced deficits in adult hippocampal neurogenesis. Future studies are thus warranted to evaluate the pro-neurogenic properties of Isx-9 in animal models of affective and neurological disorders associated with impaired hippocampal structural plasticity.
Subject(s)
Cell Proliferation/drug effects , Central Nervous System Agents/pharmacology , Dentate Gyrus/drug effects , Isoxazoles/pharmacology , Neurogenesis/drug effects , Neurons/drug effects , Thiophenes/pharmacology , 2-Hydroxypropyl-beta-cyclodextrin , Animals , Central Nervous System Agents/chemical synthesis , Corticosterone/blood , Dentate Gyrus/cytology , Dentate Gyrus/physiology , Drug Evaluation, Preclinical , Immunohistochemistry , Isoxazoles/chemical synthesis , Male , Molecular Structure , Neurons/cytology , Neurons/physiology , Rats, Sprague-Dawley , Stress, Psychological/drug therapy , Stress, Psychological/pathology , Stress, Psychological/physiopathology , Thiophenes/chemical synthesis , beta-Cyclodextrins/pharmacologyABSTRACT
Hydrogen sulfide (H2S) was traditionally considered as a toxic gas. However, recent studies have demonstrated H2S is an endogenously generated gaseous signaling molecule (gasotransmitter) with importance on par with that of two other well-known endogenous gasotransmitters, nitric oxide (NO) and carbon monoxide (CO). Although H2S's exact mechanisms of action are still under investigation, the production of endogenous H2S and the exogenous administration of H2S have been demonstrated to elicit a wide range of physiological responses including modulation of blood pressure and protection of ischemia reperfusion injury, exertion of anti-inflammatory effects, and reduction of metabolic rate. These results strongly suggest that modulation of H2S levels could have potential therapeutic values. In this regard, synthetic H2S-releasing agents (i.e., H2S donors) are not only important research tools, but also potential therapeutic agents. This chapter summarizes the knowledge of currently available H2S donors. Their preparation, H2S releasing mechanisms, and biological applications are discussed.
Subject(s)
Hydrogen Sulfide/chemistry , Chemistry, Pharmaceutical , Garlic/chemistry , Hydrogen Sulfide/metabolism , Morpholines/chemical synthesis , Organothiophosphorus Compounds/chemical synthesis , Sulfides/chemical synthesis , Thiones/chemical synthesis , Thiophenes/chemical synthesisABSTRACT
Fibroblast grow factor receptor 1 (FGFR1) is an important anti-cancer target that plays crucial role in oncogenesis and oncogenic angiogenesis. The structure-activity relationship (SAR) of N-phenylthieno[2,3-d]pyrimidin-4-amines was investigated. Binding of active compounds with FGFR1 kinase was analyzed by molecular modeling studies. Selected active thieno[2,3-d]pyrimidines were tested for selectivity and antiproliferative activity. The most active compounds, 3-({6-phenylthieno[2,3-d]pyrimidin-4-yl}amino)phenol and 3-({5-phenylthieno[2,3-d]pyrimidin-4-yl}amino)phenol have IC50 0.16 and 0.18 µM, respectively. The results presented here may help to identify new thienopyrimidines with optimized cell growth inhibitory activity which may be further used as anticancer agents.
Subject(s)
Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Humans , Molecular Docking Simulation , Molecular Structure , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Structure-Activity Relationship , Thiophenes/chemistryABSTRACT
Series of diethyl 2,5-diaminothiophene-3,4-dicarboxylate (DDTD) derivatives: azomethines of DDTD (2a-l) have been synthesized and screened for their anticancer, antimicrobial and anti-diabetic activities. The novel synthesized compounds were characterized by (1)H, (13)C NMR, MS and FT-IR analyses. All compounds were evaluated for their antiproliferative activity against three types of cancer cell line such as T47D and MCF-7 (human breast cancer), Hela (human cervical cancer) and Ishikawa (human endometrial cancer) lines. The results showed that most compounds exhibited significant antiproliferative activity against breast cancer cells. The majority of azomethines DDTD influenced strongly against breast cancer cells T47D and MCF-7, among them compounds 2b (2.3 µM), 2c (12.1 µM), 2e (13.2 µM), 2i (14.9 µM), 2j (16.0 µM), 2k (7.1 µM), 2l (8.6 µM) manifest potent anticancer activity against cancer cell T47D than Doxorubicin (DOX, 15.5 µM). Compound 2j has shown potent activity on all three types of cancer cells concurrently and IC50 values were considerably low in comparison with positive control DOX. In addition, all compounds were tested for antimicrobial activity against Staphylococcus aureus ATCC 6538 (Gram positive bacteria), Escherichia coli ATCC 11229 (Gram negative bacteria) and Candida albicans ATCC 10231 (Fungi) strains and 2j which contains in the ring nitrofurfural fragment, showed the highest effect on the three species of microbial pathogens simultaneously. Some compounds induced enzymatic inhibition in a concentration-dependent manner on PTP-1B inhibitor.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Antineoplastic Agents/pharmacology , Drug Discovery , Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Thiophenes/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Candida albicans/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Escherichia coli/drug effects , HeLa Cells , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , MCF-7 Cells , Microbial Sensitivity Tests , Molecular Structure , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Staphylococcus aureus/drug effects , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistryABSTRACT
The Dyrk family of protein kinases is implicated in the pathogenesis of several diseases, including cancer and neurodegeneration. Pharmacological inhibitors were mainly described for Dyrk1A so far, but in fewer cases for Dyrk1B, Dyrk2 or other isoforms. Herein, we report the development and optimization of 2,4-bisheterocyclic substituted thiophenes as a novel class of Dyrk inhibitors. The optimized hit compounds displayed favorable pharmacokinetic properties and high ligand efficiencies, and inhibited Dyrk1B in intact cells. In a larger selectivity screen, only Clk1 and Clk4 were identified as additional targets of compound 48, but no other kinases frequently reported as off-targets. Interestingly, Dyrk1A is implicated in the regulation of alternative splicing, a function shared with Clk1/Clk4; thus, some of the dual inhibitors might be useful as efficient splicing modulators. A further compound (29) inhibited Dyrk1A and 1B with an IC50 of 130 nM, showing a moderate selectivity over Dyrk2. Since penetration of the central nervous system (CNS) seems possible based on the physicochemical properties, this compound might serve as a lead for the development of potential therapeutic agents against glioblastoma. Furthermore, an inhibitor selective for Dyrk2 (24) was also identified, which might be are suitable as a pharmacological tool to dissect Dyrk2 isoform-mediated functions.
Subject(s)
Drug Design , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Thiophenes/chemistry , Thiophenes/pharmacology , Animals , Caspase 3/metabolism , Caspase 7/metabolism , Cell Line, Tumor , Cricetinae , Drug Evaluation, Preclinical/methods , Drug Screening Assays, Antitumor/methods , Gene Expression Regulation/drug effects , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Conformation , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/metabolism , Reactive Oxygen Species/metabolism , Recombinant Fusion Proteins , Small Molecule Libraries , Structure-Activity Relationship , Thiophenes/chemical synthesis , Dyrk KinasesABSTRACT
Tamoxifen has been shown to be active in vitro against Leishmania and effective in the treatment for leishmaniasis in murine models. Through the screening of a compound library of estrogen receptor modulator analogs, we identified the major characteristics required for antileishmanial activity. To overcome the difficulties presented by tamoxifen's propensity for E/Z isomerization, we used the 2-arylbenzothiophene compound BTP as a more stable alternative. Directed screening of a small compound library based on BTP led to active compounds against Leishmania. Subsequent structure-activity data for the synthetic 2-arylbenzothiophenes evaluated in this study indicate that optimal antileishmanial potency is dependent on the presence of two basic side chains. In addition, the primary structural features required for estrogen receptor binding, the phenols, are not required for inhibiting parasitic growth. Significantly, the most active antileishmanial benzothiophenes lack the pharmacophore for estrogen receptor activity and therefore address potential concerns about the undesirable effects of using selective estrogen receptor modulators in women and children with leishmaniasis. Three compounds selected from the screening have shown consistent activity against all species and stages of Leishmania in vitro although improvements in selectivity are needed. These compounds represent viable starting points for further optimization as antileishmanial agents.
Subject(s)
Antiprotozoal Agents/pharmacology , Leishmania/drug effects , Thiophenes/chemistry , Thiophenes/pharmacology , Animals , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Cell Survival/drug effects , Chlorocebus aethiops , Drug Evaluation, Preclinical , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemical synthesis , Vero CellsABSTRACT
An aza-15-crown-5-ether functionalized bisthienylethene (BTE-15C5) was synthesized, which can reversibly capture and release calcium ions by UV/Vis irradiation. After doping this photochromic bisthienylethene with a two-component lecithin-Ca(2+) organogel, the original deep-blue gel changed to light-blue fluid due to the cooperative binding with Ca(2+) by the open-form bisthienylethene dopant. Upon UV irradiation, the closed isomer was formed which released the Ca(2+) and the organogel was retrieved. Hence, a novel organic simple doped-type three-component photo-induced gel-to-sol transition system was constructed.
Subject(s)
Calcium/chemistry , Ethylenes/chemistry , Lecithins/chemistry , Micelles , Photochemical Processes , Thiophenes/chemical synthesis , Gels/chemistry , Ions , Molecular Structure , Thiophenes/chemistryABSTRACT
Long chain L-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2.