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This review describes our efforts toward achieving catalytic asymmetric total synthesis of leucinostatin A, a compound that interferes with the tumor-stroma interaction. The synthesis utilizes four catalytic asymmetric reactions, including direct-type reactions exemplified by high atom-economy, and three C-C bond forming reactions. Thorough analysis of the NMR data, HPLC profiles, and biologic activity led us to unambiguously revise the absolute configuration regarding the 6-position of the AHMOD residue side chain from S (reported) to R. Other examples of previously reported important studies on the stereoselective synthesis of HyLeu and AHMOD are also described.
Assuntos
Peptídeos Catiônicos Antimicrobianos/síntese química , Antineoplásicos/síntese química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Antineoplásicos/farmacologia , Catálise , Linhagem Celular Tumoral , Humanos , EstereoisomerismoRESUMO
Modulation of prostate stromal cells (PrSCs) within tumor tissues is gaining attention for the treatment of solid tumors. Using our original in vitro coculture system, we previously reported that leucinostatin (LCS)-A, a peptide mycotoxin, inhibited prostate cancer DU-145 cell growth through reduction of insulin-like growth factor 1 (IGF-I) expression in PrSCs. To further obtain additional bioactive compounds from LCS-A, we designed and synthesized a series of LCS-A derivatives as compounds that target PrSCs. Among the synthesized LCS-A derivatives, LCS-7 reduced IGF-I expression in PrSCs with lower toxicity to PrSCs and mice than LCS-A. As LCS-A has been suggested to interact with mitochondrial adenosine triphosphate (ATP) synthase, a docking study was performed to elucidate the mechanism of reduced IGF-I expression in the PrSCs. As expected, LCS-A and LCS-7 directly interacted with mitochondrial ATP synthase, and like LCS-A and LCS-7, other mitochondrial ATP synthase inhibitors also reduced the expression of IGF-I by PrSCs. Furthermore, LCS-A and LCS-7 significantly decreased the growth of mouse xenograft tumors. Based on these data, we propose that the mitochondrial ATP synthases-IGF-I axis of PrSCs plays a critical role on cancer cell growth and inhibition could be a potential anticancer target for prostate cancer.
Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , ATPases Mitocondriais Próton-Translocadoras/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Células Estromais/efeitos dos fármacos , Animais , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Linhagem Celular Tumoral , Técnicas de Cocultura , Feminino , Humanos , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Simulação de Acoplamento Molecular , Próstata/citologia , Próstata/efeitos dos fármacos , Próstata/patologia , Neoplasias da Próstata/patologia , Células Estromais/metabolismo , Células Estromais/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A fluorine-doped tin oxide-coated glass electrode modified with a bilayer film of underlying α-Co(OH)2 and overlying Mg-intercalated and Co-doped δ-type (layered) MnO2 (Mg|Co-MnO2) preferentially yielded oxygen with a Faradaic efficiency as high as 79% in the presence of chloride ions at high concentration (0.5 M). This noble metal-free electrode was fabricated by cathodic electrolysis of aqueous Co(NO3)2 followed by anodic electrolysis of a mixture of Mn2+, Co2+, and cetyltrimethylammonium (CTA+) ions in water. The CTA+ ions accommodated in the interlayer spaces of Co-doped δ-MnO2 were replaced with Mg2+ by ion exchange. The upper Mg|Co-MnO2 could effectively block the permeation of Cl- ions and allow only H2O and O2, while the under α-Co(OH)2 acted as an oxidation catalyst for the H2O penetrated through the upper coating. Thus, the oxygen evolution reaction (OER) was preferred to the chlorine evolution reaction (CER). In artificial seawater (pH 8.3), the blocking effect against Cl- decreased because of ion exchange of the intercalated Mg2+ ions with Na+ in solution, but the OER efficiency still remained at 57%, much higher than that (28%) without the upper Mg|Co-MnO2. This demonstrates that the interlayer spaces between MnO2 layers acted as pathways for H2O molecules to reach the active sites of the underlying Co(OH)2. Density functional theory (DFT) calculations revealed that the most stable structure of hydrated Mg2+ ion, in which a part of coordinated H2O molecules is hydrolyzed, has less affinity toward Cl- ion than that of hydrated Na+ ion.
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BACKGROUND: Helicobacter pylori (H. pylori) infection causes various gastrointestinal diseases including gastric cancer. Hence, eradication of this infection could prevent these diseases. The most popular first-line treatment protocol to eradicate H. pylori is termed "triple therapy" and consists of a proton pump inhibitor (PPI), clarithromycin, and amoxicillin or metronidazole. However, the antibiotics used to treat H. pylori infection are hindered by the antibiotics-resistant bacteria and by their antimicrobial activity against intestinal bacteria, leading to side effects. Therefore, an alternative treatment with fewer adverse side effects is urgently required to improve the overall eradication rate of H. pylori. OBJECTIVE: The aim of this study was to assess the effectiveness and mechanism of action of an antitumor agent, intervenolin, and its derivatives as an agent for the treatment of H. pylori infection. RESULTS: We demonstrate that intervenolin, and its derivatives showed selective anti-H. pylori activity, including antibiotic-resistant strains, without any effect on intestinal bacteria. We showed that dihydroorotate dehydrogenase, a key enzyme for de novo pyrimidine biosynthesis, is a target and treatment with intervenolin or its derivatives decreased the protein and mRNA levels of H. pylori urease, which protects H. pylori against acidic conditions in the stomach. Using a mouse model of H. pylori infection, oral monotherapy with the intervenolin derivative AS-1934 had a stronger anti-H. pylori effect than the triple therapy commonly used worldwide to eradicate H. pylori. CONCLUSION: AS-1934 has potential advantages over current treatment options for H. pylori infection.
Assuntos
Infecções por Helicobacter/tratamento farmacológico , Quinolonas/uso terapêutico , Antibacterianos/uso terapêutico , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/patogenicidade , Humanos , Resultado do TratamentoRESUMO
Total synthesis of leucinostatinâ A, a modulator of tumor-stroma interactions, using asymmetric catalyses, a nitroaldol reaction, thioamide-aldol reaction, Strecker-type reaction, and alcoholysis of 3-methylglutaric anhydride, is described. We demonstrated the applicability of the established catalytic asymmetric processes to the synthesis of molecules with a complex structure. Careful analysis of the NMR data, HPLC profiles, and biological activity revealed that the correct structure of leucinostatinâ A is the epimeric form of the reported structure; the secondary alcohol within the AHMOD residue has an R configuration.
Assuntos
Peptídeos/síntese química , Aldeídos/química , Peptídeos Catiônicos Antimicrobianos , Catálise , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Humanos , Espectroscopia de Ressonância Magnética , Peptídeos/química , Peptídeos/toxicidade , Estereoisomerismo , Tioamidas/químicaRESUMO
Syntheses of androprostamine A (1), and resormycin (3), anti-prostate cancer peptidyl natural products produced by microorganisms, were completed. The characteristic enamide structures of these compounds were installed using the Horner-Wadsworth-Emmons reaction from the corresponding phosphonates in reasonable Z-selectivity.
Assuntos
Cinamatos/síntese química , Oligopeptídeos/síntese química , Propionatos/síntese química , Cinamatos/química , Estrutura Molecular , Oligopeptídeos/química , Propionatos/química , EstereoisomerismoRESUMO
The total synthesis of NBRI16716B (2), a naturally occurring modulator of tumor-stroma interactions, was successfully achieved. Using this synthetic route, a dehydroxy analogue (21) and a derivative lacking the 5-hydroxy-3-methylpentenoyl side chain (22) became accessible. A preliminary structure-activity relationship study to unveil the structural requirements for selective inhibition of tumor cells cocultured with stromal cells revealed that both of the hydroxamate structures of 2 are indispensable, whereas the 5-hydroxy-3-methylpentenoyl side chain is not essential.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Dicetopiperazinas/química , Dicetopiperazinas/farmacologia , Antineoplásicos/síntese química , Produtos Biológicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dicetopiperazinas/síntese química , Humanos , Neoplasias/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
The proteasome degrades numerous regulatory proteins that are critical for tumor growth. Thus, proteasome inhibitors are promising antitumor agents. New proteasome inhibitors, such as tyropeptins and tyropeptin-boronic acid derivatives, have a potent inhibitory activity. Here we report the antitumor effects of two new tyropeptin-boronic acid derivatives, AS-06 and AS-29. AS-06 and AS-29 significantly suppress the degradation of the proteasome-sensitive fluorescent proteins in HEK293PS cells, and induce the accumulation of ubiquitinated proteins in human multiple myeloma cells. We show that these derivatives also suppress the degradation of the NF-κB inhibitor IκB-α and the nuclear translocation of NF-κB p65 in multiple myeloma cells, resulting in the inhibition of NF-κB activation. Furthermore, we demonstrate that AS-06 and AS-29 induce apoptosis through the caspase-8 and caspase-9 cascades. In a xenograft mouse model, i.v. administration of tyropeptin-boronic acid derivatives inhibits proteasome in tumors and clearly suppresses tumor growth in mice bearing human multiple myeloma. Our results indicate that tyropeptin-boronic acid derivatives could be lead therapeutic agents against human multiple myeloma.
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Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Dipeptídeos/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/farmacologia , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Camundongos , Mieloma Múltiplo/patologia , Neoplasias Experimentais , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The abuse of antibacterial drugs imposes a selection pressure on bacteria that has driven the evolution of multidrug resistance in many pathogens. Our efforts to discover novel classes of antibiotics to combat these pathogens resulted in the discovery of amycolamicin (AMM). The absolute structure of AMM was determined by NMR spectroscopy, X-ray analysis, chemical degradation, and modification of its functional groups. AMM consists of trans-decalin, tetramic acid, two unusual sugars (amycolose and amykitanose), and dichloropyrrole carboxylic acid. The pyranose ring named as amykitanose undergoes anomerization in methanol. AMM is a potent and broad-spectrum antibiotic against Gram-positive pathogenic bacteria by inhibiting DNA gyrase and bacterial topoisomerase IV. The target of AMM has been proved to be the DNA gyrase B subunit and its binding mode to DNA gyrase is different from those of novobiocin and coumermycin, the known DNA gyrase inhibitors.
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Antibacterianos/química , Antibacterianos/farmacologia , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/química , Glucosídeos/química , Glucosídeos/farmacologia , Pirróis/química , Pirróis/farmacologia , Inibidores da Topoisomerase II , Bactérias/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade MicrobianaRESUMO
Superhot geothermal environments in granitic crusts of approximately 400-500 °C are a frontier of geothermal energy. In the development of such environments, there is a concern of a reduction of permeability of fractured granite due to the formation of fine particles of amorphous silica induced by the phase change from subcritical water to supercritical water or superheated steam. However, the formation of silica particles and a resultant reduction in permeability have not been demonstrated to date. Therefore, experiments were conducted on the formation of amorphous silica particles with various combinations of temperature (430-500 °C) and pressure (20-30 MPa), in which the phase change of Si-containing water from liquid to either supercritical fluid or vapor was induced. Amorphous silica nanoparticles occurred under all conditions with smaller particles for higher temperature. The permeability of fractured granite was also observed to decrease significantly within several hours during injection of the particles into rock at 450 °C and 30 MPa under a confining stress of 40 MPa, with slower permeability reduction at a smaller number of particles or in the presence of larger aperture fractures. The present study suggests that the nanoparticles are likely to form and destroy the permeability in superhot geothermal environments, against which countermeasures should be investigated.
RESUMO
The androgen receptor (AR) is an important therapeutic target for all clinical states of prostate cancer. We screened cultured broths of microorganisms for their ability to suppress androgen-dependent growth of human prostate cancer LNCaP and VCaP cells without cytotoxicity. We have already identified androprostamine A (APA) from a Streptomyces culture broth as a functional inhibitor of AR. APA repressed R1881 (the synthetic androgen methyltrienolone)-induced androgen-regulated gene expression and dramatically inhibited R1881-induced prostate-specific antigen levels. However, APA did not act as an AR antagonist and did not inhibit AR transcriptional activity. Moreover, AS2405, an APA derivative, significantly inhibited the growth of VCaP cells in SCID mice upon oral administration.
Assuntos
Antineoplásicos/uso terapêutico , Cinamatos/uso terapêutico , Oligopeptídeos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Antineoplásicos/química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cinamatos/química , Cinamatos/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Estrutura Molecular , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Streptomyces/metabolismoRESUMO
The disruption of the tumor microenvironment (TME) is a promising anti-cancer strategy, but its effective targeting for solid tumors remains unknown. Here, we investigated the anti-cancer activity of the mitochondrial complex I inhibitor intervenolin (ITV), which modulates the TME independent of energy depletion. By modulating lactate metabolism, ITV induced the concomitant acidification of the intra- and extracellular environment, which synergistically suppressed S6K1 activity in cancer cells through protein phosphatase-2A-mediated dephosphorylation via G-protein-coupled receptor(s). Other complex I inhibitors including metformin and rotenone were also found to exert the same effect through an energy depletion-independent manner as ITV. In mouse and patient-derived xenograft models, ITV was found to suppress tumor growth and its mode of action was further confirmed. The TME is usually acidic owing to glycolytic cancer cell metabolism, and this condition is more susceptible to complex I inhibitors. Thus, we have demonstrated a potential treatment strategy for solid tumors.
RESUMO
The structure-activity relationship of the boronic acid derivatives of tyropeptin, a proteasome inhibitor, was studied. Based on the structure of a previously reported boronate analog of tyropeptin (2), 41 derivatives, which have varying substructure at the N-terminal acyl moiety and P2 position, were synthesized. Among them, 3-phenoxyphenylacetamide 6 and 3-fluoro picolinamide 22 displayed the most potent inhibitory activity toward chymotryptic activity of proteasome and cytotoxicity, respectively. The replacement of the isopropyl group in the P2 side chain to H or Me had negligible effects on the biological activities examined in this study.
Assuntos
Compostos de Boro/química , Ácidos Borônicos/química , Dipeptídeos/química , Inibidores Enzimáticos/química , Oligopeptídeos/química , Inibidores de Proteassoma , Compostos de Boro/síntese química , Compostos de Boro/toxicidade , Ácidos Borônicos/síntese química , Ácidos Borônicos/toxicidade , Linhagem Celular Tumoral , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/toxicidade , Humanos , Oligopeptídeos/síntese química , Oligopeptídeos/toxicidade , Complexo de Endopeptidases do Proteassoma/metabolismo , Relação Estrutura-AtividadeRESUMO
Boronic acid derivatives of tyropeptin were synthesized with TP-110 as the lead compound. Due to the lability of the aminoboronic acid moiety, careful design of the deprotection and coupling sequence was required. Liquid-liquid partition chromatography was found to be a powerful tool for purification of compounds of this class. The obtained derivatives showed potent inhibitory activities against the human 20S proteasome in vitro.
Assuntos
Ácidos Borônicos/síntese química , Dipeptídeos/síntese química , Inibidores de Proteases/síntese química , Inibidores de Proteassoma , Ácidos Borônicos/farmacologia , Linhagem Celular Tumoral , Dipeptídeos/farmacologia , Humanos , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Inibidores de Proteases/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismoRESUMO
Fibroblast-like stromal cells modulate the growth of cancer cells, both positively and negatively. Growth modulation is achieved through the secretion of regulatory factors as well as by proteins within the extracellular matrix. Those cellular interactions present attractive targets for cancer chemotherapy. It was demonsrated a novel natural compound, intervenolin (ITV), inhibited the in vitro growth of human gastric cancer cells when co-cultured with stromal cells. Importantly, the inhibition was enhanced by the presence of stromal cells. The present study reported a mechanism of ITV action. Human gastric fibroblast-like stromal cells (Hs738) were treated with ITV. The resultant conditioned medium (ITV CM) inhibited the growth of human gastric cancer cells and suppressed the level of c-Myc protein. This result suggested that ITV negatively modulated cancer cell growth by upregulating the secretion of factors originating from stromal cells in the co-culture system. To better understand the mechanism, ITV CM was subjected to proteomic analysis. The data revealed that one of the candidate regulators was thrombospondin-1 (TSP-1). Recombinant human TSP-1 protein inhibited the growth of gastric cancer cells. Moreover, the growth-inhibitory activities of ITV CM as well as that of recombinant TSP-1 were blocked by neutralizing antibody targeting TSP-1. These results suggested that ITV inhibited the growth of gastric cancer cells through its modulation of stromal cell function.
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Intervenolin analogs with a phenyl substituent at the 2- or 3-position were synthesized. The compounds (3-11) showed weak or no inhibitory activity toward the growth of MKN-74 gastric adenocarcinoma cells, even in the presence or absence of the corresponding Hs738 stromal cells, whereas 2-substituted analogs exhibited selective anti-Helicobacter pylori activity. Introduction of a pendant side chain on the nitrogen alleviated their acute toxicity in mice. The 2-phenyl-substituted analogs are reasonable structural templates for structure-activity relationship studies toward the development of anti-H. pylori agents that do not affect human cells.The Journal of Antibiotics advance online publication, 11 October 2017; doi:10.1038/ja.2017.123.
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Fibroblast-like stromal cells modulate cancer cells through secreted factors and adhesion, but those factors are not fully understood. Here, we have identified critical stromal factors that modulate cancer growth positively and negatively. Using a cell co-culture system, we found that gastric stromal cells secreted IL-6 as a growth and survival factor for gastric cancer cells. Moreover, gastric cancer cells secreted PGE2 and TNFα that stimulated IL-6 secretion by the stromal cells. Furthermore, we found that stromal cells secreted glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Extracellular GAPDH, or its N-terminal domain, inhibited gastric cancer cell growth, a finding confirmed in other cell systems. GAPDH bound to E-cadherin and downregulated the mTOR-p70S6 kinase pathway. These results demonstrate that stromal cells could regulate cancer cell growth through the balance of these secreted factors. We propose that negative regulation of cancer growth using GAPDH could be a new anti-cancer strategy.
Assuntos
Caderinas/metabolismo , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Interleucina-6/metabolismo , Neoplasias/metabolismo , Células Estromais/fisiologia , Animais , Processos de Crescimento Celular , Linhagem Celular Tumoral , Técnicas de Cocultura , Dinoprostona/metabolismo , Dinoprostona/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-6/fisiologia , Camundongos , Neoplasias/genética , Neoplasias/fisiopatologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Células Estromais/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
Catalytic asymmetric total synthesis of caprazol, a lipo-nucleoside antibiotic, has been accomplished employing two of the stereoselective C-C bond forming reactions as key transformations. The stereochemistries of the ß-hydroxy-α-aminoester moiety at the juncture of the uridine part and diazepanone part, and of the ß-hydroxy-α-amino acid moiety embedded in the diazepanone system, were constructed using a diastereoselective isocyanoacetate aldol reaction (dr = 88:12) and an enantioselective anti-nitroaldol reaction catalyzed by a Nd/Na-chiral amide ligand (dr = 12:1, 95% ee), respectively.
Assuntos
Antibacterianos/síntese química , Azepinas/síntese química , Uridina/análogos & derivados , Aldeídos/química , Aminoácidos/síntese química , Aminoácidos/química , Antibacterianos/química , Antibacterianos/farmacologia , Azepinas/química , Azepinas/farmacologia , Catálise , Estrutura Molecular , Nucleosídeos/química , Estereoisomerismo , Uridina/síntese química , Uridina/química , Uridina/farmacologiaRESUMO
Synthesis of intervenolin, a natural quinolone discovered by screening for selective growth inhibitors of cancer cells cocultured with stromal cells over monocultured cells, was achieved. The synthesis utilized a thiocyanate-isothiocyanate rearrangement and Suzuki-Miyaura coupling to furnish the characteristic substituents, the iminodithiocarbonate moiety, and the geranyl side chain, respectively. In vivo studies showed that intervenolin inhibited tumor tissue growth in model mice.