RESUMEN
Covering: 2012 to 2021Cyclopropane attracts wide interests in the fields of synthetic and pharmaceutical chemistry, and chemical biology because of its unique structural and chemical properties. This structural motif is widespread in natural products, and is usually essential for biological activities. Nature has evolved diverse strategies to access this structural motif, and increasing knowledge of the enzymes forming cyclopropane (i.e., cyclopropanases) has been revealed over the last two decades. Here, the scientific literature from the last two decades relating to cyclopropane biosynthesis is summarized, and the enzymatic cyclopropanations, according to reaction mechanism, which can be grouped into two major pathways according to whether the reaction involves an exogenous C1 unit from S-adenosylmethionine (SAM) or not, is discussed. The reactions can further be classified based on the key intermediates required prior to cyclopropane formation, which can be carbocations, carbanions, or carbon radicals. Besides the general biosynthetic pathways of the cyclopropane-containing natural products, particular emphasis is placed on the mechanism and engineering of the enzymes required for forming this unique structure motif.
Asunto(s)
Productos Biológicos , Productos Biológicos/química , Vías Biosintéticas , Ciclopropanos , S-Adenosilmetionina/metabolismoRESUMEN
Sulfur-based homolytic substitution (SH reaction) plays an important role in synthetic chemistry, yet whether such a reaction could occur on the positively charged sulfonium compounds remains unknown. In the study of the anaerobic coproporphyrinogen III oxidase HemN, a radical S-adenosyl-l-methionine (SAM) enzyme involved in heme biosynthesis, we observed the production of di-(5'-deoxyadenosyl)methylsulfonium, which supports a deoxyadenosyl (dAdo) radical-mediated SH reaction on the sulfonium center of SAM. The sulfonium-based SH reactions were then investigated in detail by density functional theory calculations and model reactions, which showed that this type of reactions is thermodynamically favorable and kinetically competent. These findings represent the first report of sulfonium-based SH reactions, which could be useful in synthetic chemistry. Our study also demonstrates the remarkable catalytic promiscuity of the radical SAM superfamily enzymes.
Asunto(s)
Enzimas/química , Enzimas/metabolismo , S-Adenosilmetionina/metabolismo , Compuestos de Sulfonio/química , Biocatálisis , Radicales Libres/química , Cinética , TermodinámicaRESUMEN
Sulfoxides and sulfones are commonly found in nature as a result of thioether oxidation, whereas only a very few enzymes have been found to metabolize these compounds. Utilizing the strong reduction potential of the [4Fe-4S] cluster of radical S-adenosyl-l-methionine (SAM) enzymes, we herein report the first enzyme-catalyzed reductive cleavage of sulfoxide and sulfone. We show two radical SAM enzymes, tryptophan lyase NosL and the class C radical SAM methyltransferase NosN, are able to act on a sulfoxide SAHO and a sulfone SAHO2, both of which are structurally similar to SAM. NosL cleaves all of the three bonds (i.e., S-C(5'), S-C(γ), and S-O) connecting the sulfur center of SAHO, with a preference for S-C(5') bond cleavage. Similar S-C cleavage activity was also found for SHAO2, but no S-O cleavage was observed. In contrast to NosL, NosN almost exclusively cleaves the S-C(5') bonds of SAHO and SAHO2 with much higher efficiencies. Our study provides valuable insights into the [4Fe-4S] cluster-mediated reduction reactions and highlights the remarkable catalytic promiscuity of radical SAM enzymes.
Asunto(s)
Liasas de Carbono-Carbono/metabolismo , Metiltransferasas/metabolismo , S-Adenosilmetionina/química , Safrol/análogos & derivados , Sulfonas/química , Triptófano/metabolismo , S-Adenosilmetionina/metabolismo , Safrol/química , Safrol/metabolismo , Sulfonas/metabolismoRESUMEN
The radical S-adenosylmethionine (SAM) superfamily is currently the largest known enzyme family. These enzymes reductively cleave SAM to produce a highly reactive 5'-deoxyadenosyl (dAdo) radical, which abstracts a hydrogen from the substrate and initiates diverse reactions. The canonic dAdo radical-mediated hydrogen abstraction can be changed to radical addition reactions by using olefin-containing substrate analogues, which result in adenosylation reactions. Here we report investigation of the adenosylation reactions catalyzed by four radical SAM l-Tyr lyases (RSTLs), including HydG, FbiC, and two ThiH enzymes from different organisms. We show RSTLs have diverse substrate specificity, and ThiH from E. coli exhibits the highest substrate tolerance toward the tested substrates. We also show ThiH from Clostridium berjerinckii does not act on 4-amino-l-phenylalanine, but catalyzes adenosylation of the corresponding olefin-containing analogue, suggesting adenosylation may occur more easily than the canonic radical SAM reactions. Our study highlights the remarkable catalytic promiscuity of radical SAM enzyme and the potential in using these enzymes for the synthesis of nucleotide-containing compounds.
Asunto(s)
Adenosina/biosíntesis , S-Adenosilmetionina/metabolismo , Tirosina Fenol-Liasa/metabolismo , Adenosina/química , Biocatálisis , Radicales Libres/química , Radicales Libres/metabolismo , Estructura Molecular , S-Adenosilmetionina/químicaRESUMEN
Sactionine-containing antibiotics (sactibiotics) are a growing class of peptide antibiotics belonging to the ribosomally synthesized and post-translationally modified peptide (RiPP) superfamily. We report the characterization of thuricinâ Z, a novel sactibiotic from Bacillus thuringiensis. Unusually, the biosynthesis of thuricinâ Z involves two radical S-adenosylmethionine (SAM) enzymes, ThzC and ThzD. Although ThzC and ThzD are highly divergent from each other, these two enzymes produced the same sactionine ring in the precursor peptide ThzA inâ vitro. Thuricinâ Z exhibits narrow-spectrum antibacterial activity against Bacillus cereus. A series of analyses, including confocal laser scanning microscopy, ultrathin-sectioning transmission electron microscopy, scanning electron microscopy, and large-unilamellar-vesicle-based fluorescence analysis, suggested that thuricinâ Z binds to the bacterial cell membrane and leads to membrane permeabilization.
Asunto(s)
Antibacterianos/uso terapéutico , Bacteriocinas/uso terapéutico , Membrana Celular/efectos de los fármacos , Antibacterianos/farmacología , Bacteriocinas/farmacología , HumanosRESUMEN
Bacterial resistance to existing drugs is becoming a serious public health issue, urging extensive search for new antibiotics. Teixobactin, a cyclic depsipeptide discovered in a screen of uncultured bacteria, shows potent activity against all the tested Gram-positive bacteria. Remarkably, no teixobactin-resistant bacterial strain has been obtained despite extensive efforts, highlighting the great potential of teixobactin as a lead compound in the fight against antimicrobial resistance (AMR). This review summarizes recent progresses in the understanding of many aspects of teixobactin, including chemical structure, biological activity, biosynthetic pathway, and mode of action. We also discuss the different synthetic strategies in producing teixobactin and its analogues, and the structure-activity relationship (SAR) studies.
Asunto(s)
Depsipéptidos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Antibacterianos/química , Infecciones Bacterianas , Depsipéptidos/química , Humanos , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A chemoenzymatic approach for the synthesis of teixobactin analogues has been established by using the tandem thioesterase (TE) of the nonribosomal peptide synthase (NRPS) Txo2. We show that, unlike the closely related counterparts involved in lysobactin biosynthesis (in which the N-terminal TE is solely responsible for the lactonization reaction), the two teixobactin TE domains are functionally exchangeable and likely act synergistically, representing an unprecedented off-loading mechanism in NRPS enzymology. The substrate specificity of this tandem TE was also investigated in this study.
Asunto(s)
Depsipéptidos/síntesis química , Esterasas/metabolismo , Secuencia de Aminoácidos , Cromatografía Líquida de Alta Presión/métodos , Depsipéptidos/química , Espectrometría de Masas/métodos , Conformación Proteica , Homología de Secuencia de Aminoácido , Especificidad por SustratoRESUMEN
The radical S-adenosylmethionine (SAM) superfamily enzymes cleave SAM reductively to generate a highly reactive 5'-deoxyadenosyl (dAdo) radical, which initiates remarkably diverse reactions. Unlike most radical SAM enzymes, the classâ C radical SAM methyltransferase NosN binds two SAMs in the active site, using one SAM to produce a dAdo radical and the second as a methyl donor. Here, we report a mechanistic investigation of NosN in which an allyl analogue of SAM (allyl-SAM) was used. We show that NosN cleaves allyl-SAM efficiently and the resulting dAdo radical can be captured by the olefin moieties of allyl-SAM or 5'-allylthioadenosine (ATA), the latter being a derivative of allyl-SAM. Remarkably, we found that NosN produced two distinct sets of products in the presence and absence of the methyl acceptor substrate, thus suggesting substrate-triggered production of ATA from allyl-SAM. We also show that NosN produces S-adenosylhomocysteine from 5'-thioadenosine and homoserine lactone. These results support the idea that 5'-methylthioadenosine is the direct methyl donor in NosN reactions, and demonstrate great potential to modulate radical SAM enzymes for novel catalytic activities.
RESUMEN
Targeting tumor DNA damage and p53 pathway is a clinically established strategy in the development of cancer chemotherapeutics. Majority of anti-cancer drugs are delivered through parenteral route for reasons like severe toxicity, lack of stability, and poor enteral absorption. Current DNA targeting drugs in clinical like anthracycline suffers from major drawbacks like cardiotoxicity. Here, we report identification of a new orally active small molecule curcumin-triazole conjugate (CT-1) with significant anti-breast cancer activity in vitro and in vivo. CT-1 selectively and significantly inhibits viability of breast cancer cell lines; retards cells cycle progression at S phase and induce mitochondrial-mediated cell apoptosis. CT-1 selectively binds to minor groove of DNA and induces DNA damage leading to increase in p53 along with decrease in its ubiquitination. Inhibition of p53 with pharmacological inhibitor as well as siRNA revealed the necessity of p53 in CT-1-mediated anti-cancer effects in breast cancer cells. Studies using several other intact p53 and deficient p53 cancer cell lines further confirmed necessity of p53 in CT-1-mediated anti-cancer response. Pharmacological inhibition of pan-caspase showed CT-1 induces caspase-dependent cell death in breast cancer cells. Most interestingly, oral administration of CT-1 induces significant inhibition of tumor growth in LA-7 syngeneic orthotropic rat mammary tumor model. CT-1 treated mammary tumor shows enhancement in DNA damage, p53 upregulation, and apoptosis. Collectively, CT-1 exhibits potent anti-cancer effect both in vitro and in vivo and could serve as a safe orally active lead for anti-cancer drug development. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Mama/efectos de los fármacos , Curcumina/análogos & derivados , Curcumina/uso terapéutico , Animales , Antineoplásicos/farmacología , Mama/metabolismo , Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Curcumina/farmacología , ADN/genética , ADN/metabolismo , Daño del ADN/efectos de los fármacos , Femenino , Humanos , Simulación del Acoplamiento Molecular , Ratas , Triazoles/química , Triazoles/farmacología , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Estrogen Receptor-ß (ER-ß), a tumor-suppressor in prostate cancer, is epigenetically repressed by hypermethylation of its promoter. DNA-methyltransferases (DNMTs), which catalyze the transfer of methyl-groups to CpG islands of gene promoters, are overactive in cancers and can be inhibited by DNMT-inhibitors to re-express the tumor suppressors. The FDA-approved nucleoside DNMT-inhibitors like 5-Azacytidine and 5-Aza-deoxycytidine carry notable concerns due to their off-target toxicity, therefore non-nucleoside DNMT inhibitors are desirable for prolonged epigenetic therapy. Disulfiram (DSF), an antabuse drug, inhibits DNMT and prevents proliferation of cells in prostate and other cancers, plausibly through the re-expression of tumor suppressors like ER-ß. To increase the DNMT-inhibitory activity of DSF, its chemical scaffold was optimized and compound-339 was discovered as a doubly potent DSF-derivative with similar off-target toxicity. It potently and selectively inhibited cell proliferation of prostate cancer (PC3/DU145) cells in comparison to normal (non-cancer) cells by promoting cell-cycle arrest and apoptosis, accompanied with inhibition of total DNMT activity, and re-expression of ER-ß (mRNA/protein). Bisulfite-sequencing of ER-ß promoter revealed that compound-339 demethylated CpG sites more efficaciously than DSF, restoring near-normal methylation status of ER-ß promoter. Compound-339 docked on to the MTase domain of DNMT1 with half the energy of DSF. In xenograft mice-model, the tumor volume regressed by 24% and 50% after treatment with DSF and compound-339, respectively, with increase in ER-ß expression. Apparently both compounds inhibit prostate cancer cell proliferation by re-expressing the epigenetically repressed tumor-suppressor ER-ß through inhibition of DNMT activity. Compound-339 presents a new lead for further study as an anti-prostate cancer agent. © 2015 Wiley Periodicals, Inc.
Asunto(s)
Disulfiram/análogos & derivados , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/síntesis química , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Epigénesis Genética/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Simulación del Acoplamiento Molecular , Regiones Promotoras Genéticas/efectos de los fármacos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Proteínas Represoras/química , Proteínas Represoras/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The drug, theophylline is frequently used as an additive to medications for people suffering from chronic obstructive pulmonary diseases (COPD). We studied the effect of theophylline in bone cells, skeleton and parameters related to systemic calcium homeostasis. Theophylline induced osteoblast apoptosis by increasing reactive oxygen species production that was caused by increased cAMP production. Bone marrow levels of theophylline were higher than its serum levels, indicating skeletal accumulation of this drug. When adult Sprague-Dawley rats were treated with theophylline, bone regeneration at fracture site was diminished compared with control. Theophylline treatment resulted in a time-dependent (at 4- and 8 weeks) bone loss. At 8 weeks, a significant loss of bone mass and deterioration of microarchitecture occurred and the severity was comparable to methylprednisone. Theophylline caused formation of hypomineralized osteoid and increased osteoclast number and surface. Serum bone resorption and formation marker were respectively higher and lower in the theophylline group compared with control. Bone strength was reduced by theophylline treatment. After 8 weeks, serum 25-D3 and liver 25-hydroxylases were decreased in theophylline group than control. Further, theophylline treatment reduced serum 1, 25-(OH)2 vitamin D3 (1,25-D3), and increased parathyroid hormone and fibroblast growth factor-23. Theophylline treated rats had normal serum calcium and phosphate but displayed calciuria and phosphaturia. Co-administration of 25-D3 with theophylline completely abrogated theophylline-induced osteopenia and alterations in calcium homeostasis. In addition, 1,25-D3 protected osteoblasts from theophylline-induced apoptosis and the attendant oxidative stress. We conclude that theophylline has detrimental effects in bone and prophylactic vitamin D supplementation to subjects taking theophylline could be osteoprotective.
Asunto(s)
Enfermedades Óseas Metabólicas/inducido químicamente , Osteoblastos/metabolismo , Teofilina/farmacología , Vitamina D/farmacología , Animales , Apoptosis/efectos de los fármacos , Biomarcadores , Médula Ósea/metabolismo , Regeneración Ósea/efectos de los fármacos , Calcifediol/metabolismo , Técnicas de Cultivo de Célula , AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Fracturas Óseas/fisiopatología , Masculino , Metilprednisolona/farmacología , Hormona Paratiroidea/metabolismo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Teofilina/farmacocinética , Factores de TiempoRESUMEN
The anti-cancer property of curcumin, an active component of turmeric, is limited due to its poor solubility, stability and bioavailability. To enhance its efficacy, we designed a novel series of twenty-four monocarbonyl curcumin analogue-1,2,3-triazole conjugates and evaluated their anti-cancer activity towards endocrine related cancers. The new compounds (17-40) were synthesized through CuAAC click reaction and SAR analysis carried out. Out of these all, compound 17 showed most significant anti-cancer activity against prostate cancer cells with IC50 values of 8.8µM and 9.5µM in PC-3 and DU-145 cells, respectively. Another compound 26 showed significant anti-cancer activity against breast cancer cells with IC50 of 6µM, 10µM and 6.4µM in MCF-7, MDA-MB-231 and 4T1 cells, respectively while maintaining low toxicity towards non-cancer originated cell line, HEK-293. Compounds 17 and 26 arrested cell cycle and induced mitochondria-mediated apoptosis in cancer cells. Further, both of these compounds significantly down-regulated cell proliferation marker (PCNA), inhibited activation of cell survival protein (Akt phosphorylation), upregulated pro-apoptotic protein (Bax) and down-regulated anti-apoptotic protein (Bcl-2) in their respective cell lines. In addition, in vitro stability, solubility and plasma binding studies of the compounds 17 and 26 showed them to be metabolically stable. Thus, this study identified two new curcumin monocarbonyl-1,2,3-triazole conjugate compounds with more potent activity than curcumin against breast and prostate cancers.
Asunto(s)
Antineoplásicos/síntesis química , Curcumina/química , Triazoles/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Química Clic , Regulación hacia Abajo/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Células HEK293 , Semivida , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Antígeno Nuclear de Célula en Proliferación/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Prophylactic prevention is considered as the most promising strategy to tackle STI/HIV. Twenty-five dithiocarbamate-thiourea hybrids (14-38) were synthesized as woman controlled topical vaginal microbicides to counter Trichomonas vaginalis and sperm along with RT inhibition potential. The four promising compounds (18, 26, 28 and 33) were tested for safety through cytotoxic assay against human cervical cell line (HeLa) and compatibility with vaginal flora, Lactobacillus. Docking study of most promising vaginal microbicide (33) revealed that it docked in a position and orientation similar to known reverse transcriptase inhibitor Nevirapine. The preliminary in vivo pharmacokinetics of compound 33 was performed in NZ-rabbits to evaluate systemic toxicity in comparison to Nonoxynol-9.
Asunto(s)
Antiinfecciosos/farmacología , Tiocarbamatos/farmacología , Tiourea/farmacología , Vagina , Antiinfecciosos/química , Femenino , VIH/efectos de los fármacos , Células HeLa , Humanos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Tiocarbamatos/química , Tiourea/química , Trichomonas vaginalis/efectos de los fármacosRESUMEN
A series of seventeen morpholin/piperidin-1-yl-carbamodithioate (3-19) were synthesized as topical vaginal microbicidal spermicides. The synthesized compounds were evaluated for their anti-Trichomonas activity against MTZ susceptible and resistant strains along with their spermicidal and antifungal potential. All the synthesized compounds were assessed for their safety through cytotoxic assay against human cervical cell line (HeLa) and compatibility with vaginal flora, Lactobacillus. The study identified eleven dually active compounds with apparent safety. The plausible mode of action of these compounds was through sulfhydryl binding, confirmed via reduction in available free thiols on human sperm. The most promising compound 9 significantly inhibited (P<0.001) thiol-sensitive sperm hexokinase. The stability of compound 9 in simulated vaginal fluid (SVF) was performed via HPLC-PDA method, which supported its utility for vaginal administration.
Asunto(s)
Antifúngicos/síntesis química , Diseño de Fármacos , Piperidinas/síntesis química , Espermicidas/síntesis química , Compuestos de Sulfhidrilo/química , Tiocarbamatos/síntesis química , Antifúngicos/farmacología , Antifúngicos/toxicidad , Supervivencia Celular/efectos de los fármacos , Femenino , Células HeLa , Hexoquinasa/antagonistas & inhibidores , Hexoquinasa/metabolismo , Humanos , Lactobacillus/efectos de los fármacos , Masculino , Pruebas de Sensibilidad Microbiana , Morfolinas/química , Piperidinas/química , Piperidinas/farmacología , Piperidinas/toxicidad , Espermicidas/farmacología , Espermicidas/toxicidad , Espermatozoides/efectos de los fármacos , Espermatozoides/enzimología , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/farmacología , Compuestos de Sulfhidrilo/toxicidad , Tiocarbamatos/farmacología , Tiocarbamatos/toxicidad , Trichomonas vaginalis/efectos de los fármacosRESUMEN
The linaridin antibiotic cypemycin is a ribosomal synthesized and post-translationally modified peptide (RiPP) that possesses potent activity against mouse leukemia cells. This peptide natural product contains an S-[(Z)-2-aminovinyl]-d-cysteine (AviCys) moiety in the C-terminus. Formation of AviCys moiety requires an oxidative decarboxylation of the C-terminal Cys of the precursor peptide CypA, and this process is catalyzed by a flavin-containing protein CypD. In this work, we tested CypD substrate specificity with a series of synthetic oligopeptides. We show that most of the N-terminal sequence of CypA is not required for CypD activity, and the C-terminal three residues serve as the minimal structural element for enzyme recognition. We also show that CypD tolerates various substrates with modified C-termini, allowing for the generation of four novel cypemycin variants with modified AviCys moiety by site direct mutagenesis of the precursor peptide CypA. Our study demonstrates the relaxed substrate specificity of CypD and lays a foundation for future bioengineering of AviCys-containing natural products.
RESUMEN
The cypemycin decarboxylase CypD is investigated by using a synthetic oligopeptide, which contains the to-be-cyclized dehydroalanine (Dha) residue. It was shown that CypD efficiently catalyzes the decarboxylation of this Dha-containing peptide, but the expected AviCys ring is not formed in the product, suggesting that CypD alone is not enough to form the AviCys ring. It was also shown that the Dha-containing peptide is a better substrate than two similar peptides with a Ser or a Cys residue, supporting that, in cypemycin biosynthesis, Dha formation is prior to decarboxylation of the C-terminal Cys.
RESUMEN
Sexually transmitted diseases like trichomoniasis along with opportunistic fungal infections like candidiasis are major global health burden in female reproductive health. In this context a novel non-nitroimidazole class of substituted carbamothioic amine-1-carbothioic thioanhydride series was designed, synthesized, evaluated for trichomonacidal and fungicidal activities, and was found to be more active than the standard drug Metronidazole (MTZ). Compounds were trichomonicidal in the MIC ranges of 4.77-294.1 µM and 32.46-735.20 µM against MTZ-susceptible and -resistant strains, respectively. Further, compounds inhibited the growth of at least two out of ten fungal strains tested at MIC of 7.50-240.38 µM. The most active compound (20) of this series was 3.8 and 9.5 fold more active than the MTZ against the two Trichomonas strains tested. Compound 20 also significantly inhibited the sulfhydryl groups present over Trichomonas vaginalis and was found to be more active than the MTZ in vivo. Further, a docking analysis carried out with cysteine proteases supported their thiol inhibiting ability and preliminary pharmacokinetic study has shown good distribution and systemic clearance.
Asunto(s)
Anhidrasas Carbónicas/farmacología , Diseño de Fármacos , Fungicidas Industriales/farmacología , Compuestos de Sulfhidrilo/farmacología , Trichomonas/efectos de los fármacos , Anhidrasas Carbónicas/síntesis química , Anhidrasas Carbónicas/química , Relación Dosis-Respuesta a Droga , Fungicidas Industriales/síntesis química , Fungicidas Industriales/química , Metronidazol/química , Metronidazol/farmacología , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Compuestos de Sulfhidrilo/síntesis química , Compuestos de Sulfhidrilo/química , Trichomonas/crecimiento & desarrolloRESUMEN
A series of seventeen piperazine derivatives have been synthesized and biologically evaluated for the management of andropause-associated prostatic disorders and depression. Five compounds 16, 19, 20, 21 and 22 significantly inhibited proliferation of androgen-sensitive LNCaP prostatic cell line with EC50 values of 12.4 µM, 15.6 µM, 11.8 µM, 10.4 µM, 12.2 µM respectively and decreased Ca2+ entry through adrenergic-receptor α1A blocking activity. Anti-androgenic behaviour of compound 19 and 22 was evident by decreased luciferase activity. The high EC50 value in AR-negative cells PC3 and DU145 suggested that the cytotoxicity of compounds was due to AR down regulation. Compound 19 reduced the prostate weight of rats by 53.8%. Further, forced-swimming and tail-suspension tests revealed antidepressant-like activity of compound 19, lacking effects on neuromuscular co-ordination. In silico ADMET predictions revealed that the compound 19 had good oral absorption, aqueous solubility, non-hepatotoxic and good affinity for plasma protein binding. Pharmacokinetic and tissue uptake of 19 at 10 mg/kg demonstrated an oral bioavailability of 35.4%. In silico docking studies predicted similar binding pattern of compound 19 on androgen receptor as hydroxyflutamide. Compound 19 appears to be a unique scaffold with promising activities against androgen associated prostatic disorders in males like prostate cancer and BPH and associated depression.
Asunto(s)
Antagonistas de Andrógenos/síntesis química , Andropausia , Depresión/tratamiento farmacológico , Piperazinas/farmacocinética , Enfermedades de la Próstata/tratamiento farmacológico , Antagonistas de Andrógenos/farmacología , Animales , Línea Celular , Regulación hacia Abajo/efectos de los fármacos , Humanos , Masculino , Simulación del Acoplamiento Molecular , Piperazina , Piperazinas/síntesis química , Piperazinas/química , Ratas , Receptores Androgénicos/efectos de los fármacosRESUMEN
Chemical attenuation of the reactive oxygen species (ROS)-sensitive anaerobes Trichomonas vaginalis, which is the most prevalent non-viral sexually transmitted infection, and two often coexisting vaginal infections, namely Candida albicans and Staphylococcus aureus, which are opportunistic reproductive tract infections, was attempted with novel ammonium salts of carbamodithioic acid through inhibition of free thiols. In vitro and in vivo efficacies of the designed compounds were evaluated as topical vaginal microbicides. Five compounds showed exceptional activity against drug-resistant and -susceptible strains with negligible toxicity to host (HeLa) cells in vitro in comparison with the standard vaginal microbicide nonoxynol-9 (N-9), without disturbing the normal vaginal flora (i.e. Lactobacillus). The compounds significantly inhibited the cytopathic effects of Trichomonas on HeLa cells in vitro with efficacies comparable with metronidazole (MTZ); however, their efficacy to rescue host cells from co-infection (protozoal and fungal) was greater than that of MTZ. The compounds inhibited ß-haemolysis of red blood cells caused by Trichomonas and were found to be active in vivo in the mouse subcutaneous abscess assay. Some compounds rapidly immobilized human sperm. A mechanism involving inhibition of free thiols and consequently the cysteine proteases of T. vaginalis by the new compounds has been proposed. Thus, a unique scaffold of antimicrobial agents has been discovered that warrants further investigation for development as contraceptive vaginal microbicides.
Asunto(s)
Antiinfecciosos Locales/química , Antiinfecciosos Locales/farmacología , Candida/efectos de los fármacos , Ditiocarba/análogos & derivados , Ditiocarba/farmacología , Staphylococcus aureus/efectos de los fármacos , Trichomonas vaginalis/efectos de los fármacos , Administración Intravaginal , Animales , Antiinfecciosos Locales/administración & dosificación , Antiinfecciosos Locales/efectos adversos , Supervivencia Celular/efectos de los fármacos , Ditiocarba/administración & dosificación , Ditiocarba/efectos adversos , Células Epiteliales/efectos de los fármacos , Femenino , Células HeLa , Humanos , Lactobacillus/efectos de los fármacos , Ratones , Pruebas de Sensibilidad MicrobianaRESUMEN
Trichomoniasis is the most prevalent, non-viral sexually transmitted diseases (STD) caused by amitochondriate protozoan Trichomonas vaginalis. Increased resistance of T. vaginalis to the marketed drug Metronidazole necessitates the development of newer chemical entities. A library of sixty 2-methyl-4/5-nitroimidazole derivatives was synthesized via nucleophilic ring opening reaction of epoxide and the efficacies against drug-susceptible and -resistant Trichomonas vaginalis were evaluated. All the molecules except two were found to be active against both susceptible and resistant strains with MICs ranging 8.55-336.70 µM and 28.80-1445.08 µM, respectively. Most of the compounds were remarkably more effective than the standard Metronidazole. This study analyzes the in vitro and in vivo activities of the new 5-nitroimidazoles, which were found to be safe against human cervical HeLa cells with good selectivity index. The exploration of SAR by the synthesis of four different prototypes and 3D-QSAR study has shown the importance of prototype 1 over other prototypes.