RESUMO
Salinomycin (Sal) has attracted considerable attention in the field of tumor treatment, especially for its inhibitory effect on cancer stem cells (CSCs) and drug-resistant tumor cells. However, its solubility and targeting specificity pose significant challenges to its pharmaceutical development. Sal-A6, a novel peptide-drug conjugate (PDC), was formed by linking the peptide A6 targeting the CSC marker CD44 with Sal using a specific linker. This conjugation markedly enhances the physicochemical properties of Sal and compared to Sal, Sal-A6 demonstrated a significantly increased activity against ovarian cancer. Furthermore, Sal-A6, employing a disulfide bond as a linker, exhibited bystander killing effect. Moreover, it induces substantial cytotoxic effect on both cancer stem cells and drug-resistant cells in addition to enhance chemosensitivity of resistant ovarian cancer cells. In summary, the results indicated that Sal-A6, a novel PDC derived from Sal, has potential therapeutic applications in the treatment of ovarian cancer and drug-resistant patients. Additionally, this discovery offers insights for developing PDC-type drugs using Sal as a foundation.
Assuntos
Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Células-Tronco Neoplásicas , Neoplasias Ovarianas , Peptídeos , Piranos , Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Piranos/farmacologia , Piranos/química , Piranos/síntese química , Células-Tronco Neoplásicas/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Peptídeos/farmacologia , Peptídeos/química , Peptídeos/síntese química , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Efeito Espectador/efeitos dos fármacos , Estrutura Molecular , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Policetídeos de PoliéterRESUMO
BACKGROUND: Influenza virus is a kind of RNA virus. Nowadays, the high incidence of influenza and the morbidity and mortality of epidemic influenza are substantial. It has been reported that one hundred million people in the world are infected with influenza viruses, and two hundred and fifty thousand to five hundred thousand people die from the flu per year. In 2021, the number of infected persons in China was reported to be 654,700, and 0.07% of the infected persons died. The flu has caused a serious threat to human survival. Although several drugs, such as Zanamivir, Oseltamivir, Peramivir, and Laninamivir, have been used in clinics for the treatment of the influenza virus, there are some shortcomings of these drugs. The strain of influenza H5N1 (avian influenza) has been found to resist the effective drug Oseltamivir. Thus, there is an urgent demand to discover new influenza virus inhibitors to overcome the emergence of influenza antigens. AIMS: This study aimed to develop new influenza virus inhibitors based on the rupestonic acid parent core. OBJECTIVE: The rupestonic acid L-ephedrine ester (A) and rupestonic acid L-ephedrine complex (B) were synthesized in this work for the development of influenza virus inhibitors. METHODS: The target compounds were synthesized using rupestonic acid and L-ephedrine as starting materials. Their structures were characterized by 1H NMR and 13C NMR, and the purity was determined by HPLC. Then, their preliminary in vitro influenza activity was evaluated using Oseltamivir as a reference drug. RESULTS: The results showed that the synthesized rupestonic acid L-ephedrine derivatives A and B were more potent influenza virus inhibitors against the strains of A/PR/8/34 (H1N1) and A/FM/1/47 (H1N1) with the IC50 values of 51.0, 51.0 µM and 441.0, 441.0 µM, respectively, than that of rupestonic acid. By comparing the IC50 of compounds A and B, compound A can be regarded as a very promising lead compound for the development of influenza virus inhibitors. CONCLUSION: The rupestonic acid L-ephedrine ester (A) and rupestonic acid L-ephedrine complex (B) were synthesized and characterized using 1H NMR and 13C NMR. Moreover, their purity was determined by HPLC. Both compounds A and B exhibited more potent activities against the strains of A/PR/8/34 (H1N1) and A/FM/1/47 (H1N1) than rupestonic acid. Compound A can be regarded as a very promising lead compound for the development of influenza virus inhibitors. Based on these results, more rupestonic acid derivatives will be designed and synthesized in the future for the development of influenza virus inhibitors.
Assuntos
Antivirais , Antivirais/farmacologia , Antivirais/síntese química , Antivirais/química , Humanos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Células Madin Darby de Rim Canino , Animais , Estrutura Molecular , Relação Dose-Resposta a Droga , Piranos/farmacologia , Piranos/síntese química , Piranos/química , Cães , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Dibenzotiepinas/farmacologia , Dibenzotiepinas/síntese química , Sesquiterpenos , AzulenosRESUMO
FR901464 is a natural product that exhibits antiproliferative activity at single-digit nanomolar concentrations in cancer cells. Its tetrahydropyran-spiroepoxide covalently binds the spliceosome. Through our medicinal chemistry campaign, we serendipitously discovered that a bromoetherification formed a tetrahydrofuran. The tetrahydrofuran analog was three orders of magnitude less potent than the corresponding tetrahydropyran analogs. This study shows the significance of the tetrahydropyran ring that presents the epoxide toward the spliceosome.
Assuntos
Compostos de Epóxi , Furanos , Piranos , Compostos de Espiro , Humanos , Linhagem Celular Tumoral , Compostos de Epóxi/síntese química , Compostos de Epóxi/farmacologia , Furanos/síntese química , Furanos/farmacologia , Piranos/síntese química , Piranos/farmacologia , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologiaRESUMO
The process of creating a series of 3-amino-1-aryl-8-methoxy-1H-benzo[f]chromene-2-carbonitriles (4a-q) involved reacting 6-methoxynaphthalen-2-ol (1), the appropriate aromatic aldehydes (2a-q), and malononitrile (3) in an absolute ethanol/piperidine solution under Ultrasonic irradiation. However, the attempt to create 3-amino-1-aryl-1H-benzo[f]chromene-2,8-dicarbonitrile (6a, d, e) was unsuccessful when 6-cyanonaphthalen-2-ol (5) was stirred at room temperature, reflux, Microwave irradiation, or Ultrasonic irradiation. In addition, the target molecules were screened against Staphylococcus aureus (MRSA), Staphylococcus aureus, Bacillus subtilis, Bacillus cereus, Escherichia coli and Klebsiella pneumonia, as well as a panel of three human cancer cells lines such as MCF-7, HCT-116, HepG-2 and two normal cell lines HFL-1 and WI-38. The obtained results confirmed that the pyran derivatives (4 m, i, k) which have a double chlorine at 3,4/2,3/2,5-positions, a single halogen atom 3-Cl/4-Br (4c, e) and a double bromine at 3,5-positions with a single methoxy group at 2-position (4n), of phenyl ring, and, to a lesser extent, other pyran derivatives with monoihalogenated (4a, b, d, f), dihalogenated (4 g, h, j, l) or trisubstituent phenyl ring (4o, p, q). Furthermore, compounds 4b-e, g, i, j, m, and n showed negligible activity against the two normal cell lines, HFL-1 and WI-38. Moreover, compound 4 g exhibited the strongest antimicrobial activity among the other pyran derivatives (4a-f, g-q) when compared to Ciprofloxacin. The MIC was assessed and screened for compound 4 g, revealing bactericidal effects. Lastly, SAR and molecular docking were studied.
Assuntos
Antineoplásicos , Testes de Sensibilidade Microbiana , Piranos , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Piranos/farmacologia , Piranos/química , Piranos/síntese química , Linhagem Celular Tumoral , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Simulação de Acoplamento Molecular , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/síntese química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/síntese química , Relação Estrutura-Atividade , Escherichia coli/efeitos dos fármacosRESUMO
Photoactive conjugated microporous polymers (CMPs) as heterogeneous photocatalysts provide a sustainable alternative to classical metal-based semiconductor photosensitizers. However, previously reported CMPs are typically synthesized through metal catalyzed coupling reactions, which bears product separation, but also increases the price of materials. Herein, a new type of sp2 carbon linked DCM-CMPs are successfully designed and synthesized by organic base catalyzed Knoevenagel reaction using 2,6-Dimethyl-4H-pyran-4-ylidene-malononitrile and aromatic polyaldehydes as monomers. The new polymers feature inherent porosity, excellent stability, and fully π-conjugated skeleton with broad visible-light absorption. They effectively induce the synthesis of benzimidazole compounds under light irradiation, and exhibit wide substrate adaptability with outstanding recyclability.
Assuntos
Nitrilas , Processos Fotoquímicos , Polímeros , Catálise , Nitrilas/química , Porosidade , Polímeros/química , Polímeros/síntese química , Estrutura Molecular , Luz , Piranos/química , Piranos/síntese química , Propriedades de Superfície , Benzimidazóis/química , Tamanho da PartículaRESUMO
Dehydroacetic acid (DHA) was utilized as a fundamental precursor in the synthesis of novel pyrano [4,3-b] pyran and pyrano [2,3-b] pyridine systems. Whereas, a new series of fused polyheteronuclear systems was achieved through the reaction of DHA with active methylene compounds such as malononitrile and pyrazolone. Whereas, the treatment of DHA 1 with cyclic ketones involving cyclohexanone and cyclododecanone afforded annulated tricyclic systemâ 6 and spiro hybrid moleculeâ 7. Also, the reaction of DHA 1 with cyanoacetamide derivativesâ 8 and 11 yielded their corresponding novel pyrano [2,3-b] pyridine-6-carbonitrile frameworksâ 9 and 12, respectively. Also, inâ silico predictive theoretical molecular docking studies for bioactive synthesized scaffolds against both HER2 and 6BBP displayed an optimistic result for compounds 2 b, 5, 9, and 12 highlighting their expediency as up-and-coming candidates for future preclinical trials. Additionally, all compounds were assessed as antibacterial agents against various types of four candidates of bacteria in the presence of ampicillin as a reference. Notably, compounds 6, 7, and 12 showed promising antibacterial potential against Bacillus subtilis with activity indexes (69.6, 91.3, and 82.6 %), respectively.
Assuntos
Antibacterianos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Piridonas , Humanos , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Teoria da Densidade Funcional , Estrutura Molecular , Piranos/química , Piranos/farmacologia , Piranos/síntese química , Piridonas/química , Piridonas/farmacologia , Piridonas/síntese química , Relação Estrutura-Atividade , Acetatos/química , Acetatos/farmacologiaRESUMO
Seventeen C20-O-alkyl/benzyl oxime derivatives were synthesized by a concise and effective method. Most of these derivatives showed tens to several hundred nanomolar IC50 values against HT-29 colorectal, HGC-27 gastric and MDA-MB-231 breast cancer cells, whose antiproliferative activity is 15-240 fold better than that of salinomycin. The C20-oxime etherified derivatives can coordinate potassium ions, and further adjust the cytosolic Ca2+ concentrations in HT-29 cells. The significant improvement of the potency should be attributed to the better ion binding and transport ability of the modified derivatives. In addition, the C20-O-alkyl/benzyl oxime derivatives showed much better selectivity indexes (SI) than salinomycin, indicating that they present lower neurotoxic risk.
Assuntos
Antineoplásicos/farmacologia , Oximas/farmacologia , Piranos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Conformação Molecular , Oximas/síntese química , Oximas/química , Piranos/síntese química , Piranos/químicaRESUMO
Metabotropic glutamate receptor 2 (mGluR2) is a therapeutic target for several neuropsychiatric disorders. An mGluR2 function in etiology could be unveiled by positron emission tomography (PET). In this regard, 5-(2-fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide ([11C]13, [11C]mG2N001), a potent negative allosteric modulator (NAM), was developed to support this endeavor. [11C]13 was synthesized via the O-[11C]methylation of phenol 24 with a high molar activity of 212 ± 76 GBq/µmol (n = 5) and excellent radiochemical purity (>99%). PET imaging of [11C]13 in rats demonstrated its superior brain heterogeneity and reduced accumulation with pretreatment of mGluR2 NAMs, VU6001966 (9) and MNI-137 (26), the extent of which revealed a time-dependent drug effect of the blocking agents. In a nonhuman primate, [11C]13 selectively accumulated in mGluR2-rich regions and resulted in high-contrast brain images. Therefore, [11C]13 is a potential candidate for translational PET imaging of the mGluR2 function.
Assuntos
Meios de Contraste/química , Ácidos Picolínicos/química , Piranos/química , Compostos Radiofarmacêuticos/química , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de Carbono , Meios de Contraste/síntese química , Meios de Contraste/metabolismo , Feminino , Ligantes , Macaca fascicularis , Masculino , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/metabolismo , Tomografia por Emissão de Pósitrons , Piranos/síntese química , Piranos/metabolismo , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismo , Ratos Sprague-DawleyRESUMO
A new synthetic strategy for the total synthesis of norhalichondrin B featuring a highly convergent approach and our recently disclosed reverse approach for the synthesis of cyclic ether structural motifs is disclosed. Resulting in the shortest route to norhalichondrin B disclosed thus far, the reported total synthesis was achieved through the synthesis of two almost equally complex fragments whose coupling and short elaboration sequence featured an essential epimerization of the C16 stereocenter occurring concurrently with a simple acid-induced deprotection, a tactic based on a prior study along the synthetic route. This unprecedented strategy within the halichondrin family of natural products could find practical application to the synthesis of other more or less complex natural or designed halichondrin analogues.
Assuntos
Furanos/síntese química , Piranos/síntese química , Ciclização , EstereoisomerismoRESUMO
Src kinase activity controls diverse cellular functions, including cell growth, migration, adhesion, and survival. It is de-regulated in several cancers, including breast cancer, where it is highly expressed and phosphorylated. Thus, targeting Src by a small molecule is a feasible strategy for managing different breast cancer types. Several Src kinase inhibitors are available, including the FDA-approved drug (dasatinib). However, they are primarily ATP-competitive inhibitors that have been reported to lack specificity towards Src. We have a long-time interest in discovering protein kinase inhibitors that are non-competitive for ATP. In this project, three groups of 2'-aminospiro[pyrano[3,2-c]quinoline]-3'-carbonitrile derivatives were designed and synthesized, hypothesizing that small molecules with a spiro scaffold appended to a pyrano[3,2-c]quinoline analog could act as non-ATP competitive Src kinase inhibitors. 3b, 3c, and 3d inhibited Src kinase activity with IC50s of 4.9, 5.9, and 0.9 µM, respectively. At the same time, they did not impact the MDM2/p53 interaction in HEK293 cells, which has been reported to be affected by some spirocyclic compounds. 25 µM of 3b, 3c, or 3d did not inhibit the kinase activity of ERK2, JNK1, or p38-alpha in an in-vitro kinase assay. Steady-state kinetic studies for the effect of 3d on the ability of recombinant Src to phosphorylate its substrate (Srctide) revealed a non-ATP competitive inhibition mechanism. 1.6 µM of 3d was enough to diminish Src, Fak, and paxillin phosphorylation in the breast cancer cell lines MDA-MB-231 and MCF7. In the NCI screening, 3d induced broad tumor cytotoxicity for the NCI-60 cell lines, including all the breast cancer cell lines. The potency of 3b, 3c, and 3d to inhibit migration, proliferation, and colony formation of MDA-MB-231 and proliferation of MCF7 cells correlates with their potency to suppress Src kinase activity in the same cell line. Noticeably, the cell growth suppression and apoptosis induction in the tested cell lines can be attributed to the ability of the new derivatives to suppress the ERK and Akt survival pathways downstream of Src.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Desenvolvimento de Medicamentos , Inibidores de Proteínas Quinases/farmacologia , Piranos/farmacologia , Quinolinas/farmacologia , Quinases da Família src/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piranos/síntese química , Piranos/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Quinases da Família src/metabolismoRESUMO
The initial objective of our work was to synthesize a series of 2-amino-4H-pyran-3-carbonitriles to be tested for their antifungal activities against economically relevant phytopathogenic fungi. Fourteen compounds were prepared in up to 94% yield and shown percentages of Botrytis cinerea inhibition above 70%. Despite the promising biological results, we observed that stock solutions prepared for biological tests showed color changing when kept for a few days on the laboratory bench, under room conditions, illuminated by common LED daylight tubes (4500-6000 k). This prompted us to investigate the possible photo-induced degradation of our compounds. FT-IR ATR experiments evidenced variations in the expected bands for functional of -amino-4H-pyran-3-carbonitriles stored under LED daylight. Following, HPLC-UV analysis showed reductions in the intensity of chromatographic peaks of 2-amino-4H-pyran-3-carbonitriles, and but not for solutions kept in the dark. A solution of (E)-2-amino-8-(4-nitrobenzylidene)-4-(4-nitrophenyl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile underwent 84.4% of conversion after 72 h of exposure to continuous LED daylight in a BOD chamber, and the reaction product was isolated in 36% yield and characterized as (E)-7-cyano-5-(4-nitrobenzylidene)-8-(4-nitrophenyl)bicyclo[4.2.0]oct-1(6)-ene-7-carboxamide (7*). Despite freshly prepared solutions of 2-amino-4H-pyran-3-carbonitriles produced antifungal activities, these solutions lost biological activity when left on the bench for a week. Besides, compound 7* formed from photo-induced degradation of 7 also showed no antifungal activity. With this, we hope to bring two contributions: (1) production of cyclobutenes through photochemical reactions of 2-amino-4H-pyran-3-carbonitriles can be carried out through exposure to simple white LED daylight; (2) biological applications of such 2-amino-4H-pyran-3-carbonitriles may be impaired by their poor photostability.
Assuntos
Antifúngicos/farmacologia , Botrytis/efeitos dos fármacos , Luz , Piranos/química , Antifúngicos/síntese química , Antifúngicos/química , Cromatografia Líquida de Alta Pressão , Conformação Molecular , Fotólise/efeitos da radiação , Piranos/síntese química , Piranos/farmacologia , Espectrofotometria UltravioletaRESUMO
A novel catalyst has been afforded by attaching of a Cu(proline)2 complex to magnetic nanoparticles through cheap, simple, and readily available chemicals. This catalyst was characterized by Fourier transform infrared, energy-dispersive X-ray, X-ray diffraction, vibrating-sample magnetometry, transmission electron microscopy, scanning electron microscopy, and inductively coupled plasma analyses. The catalytic activity of the Fe3O4@NH2@TCT@HProCu nanocatalyst was investigated in a green and effective synthesis of pyran derivatives in high yields by applying three-component reactions of malononitrile, dimedone, and aldehydes in ethanol. Conversion was high under optimal conditions. The obtained nanocatalyst could be easily separated from the mixture of the reaction and was recyclable nine times via a simple magnet without considerable reduction of its catalytic efficiency. Operational simplicity, high product yields, environmental friendliness, ecofriendliness, economical processing, and easy workup are the features of this methodology.
Assuntos
Complexos de Coordenação/química , Cobre/química , Hidroxiprolina/química , Nanopartículas de Magnetita/química , Piranos/síntese química , Catálise , Complexos de Coordenação/síntese química , Ciclização , Estrutura Molecular , Piranos/químicaRESUMO
Bruton's tyrosine kinase (BTK) is a key drug target for B-cell related malignancies. Irreversible covalent BTK inhibitors have been approved for the treatment of B-cell malignancies, yet BTK C481S mutation at the covalent binding site has caused drug-resistance of BTK covalent binding inhibitors. The proteolysis targeting chimera (PROTAC) technology increases the sensitivity to drug-resistant targets compared to classic inhibitors, which provides a new strategy for mutant BTK related B-cell malignancies. ARQ531, a reversible non-covalent BTK inhibitor that inhibits wild type (WT) and mutated BTK with high selectivity, could be an ideal warhead for PROTACs targeting the mutant BTK. Herein, we designed a novel series of PROTACs using the selective non-covalent BTK inhibitor ARQ531 as warhead, with the goal of improving the degradation of both wild-type and C481S mutant BTKs, and increasing the selectivity of BTK over other kinases. This effort will provide some basis for further preclinical study of BTK PROTACs as a novel strategy for treatment of B-cell lymphomas.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/farmacologia , Descoberta de Drogas , Linfoma de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Piranos/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteólise/efeitos dos fármacos , Piranos/síntese química , Piranos/química , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-AtividadeRESUMO
Enlightened by the available structural biology information, a novel series of dihydrothiopyrano[4,3-d]pyrimidine derivatives were rationally designed via scaffold hopping and molecular hybridization strategies. Notably, compound 20a yielded exceptionally potent antiviral activities (EC50 = 4.44-54.5 nM) against various HIV-1 strains and improved resistance profiles (RF = 0.5-5.6) compared to etravirine and rilpivirine. Meanwhile, 20a exhibited reduced cytotoxicity (CC50 = 284 µM) and higher SI values (SI = 5210-63992). Molecular dynamics simulations were performed to rationalize the distinct resistance profiles. Besides, 20a displayed better solubility (sol. = 12.8 µg/mL) and no significant inhibition of the main CYP enzymes. Furthermore, 20a was characterized for prominent metabolic stability and in vivo safety properties. Most importantly, the hERG inhibition profile of 20a (IC50 = 19.84 µM) was a remarkable improvement. Overall, 20a possesses huge potential to serve as a promising drug candidate due to its excellent potency, low toxicity, and favorable drug-like properties.
Assuntos
Fármacos Anti-HIV/farmacologia , Piranos/farmacologia , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/toxicidade , Linhagem Celular , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Piranos/síntese química , Piranos/metabolismo , Piranos/toxicidade , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/toxicidade , Ratos Sprague-Dawley , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/toxicidade , Relação Estrutura-AtividadeRESUMO
Campylobacter jejuni is the leading cause of human diarrheal diseases and has been designated as one of highly resistant pathogens by the World Health Organization. The C. jejuni capsular polysaccharides feature broad existence of uncommon 6dHepp residues and have proven to be potential antigens to develop innovative antibacterial glycoconjugation vaccines. To address the lack of synthetic methods for rare 6dHepp architectures of importance, we herein describe a novel and efficient approach for the preparation of uncommon d-/l-6dHepp fluorides that have power as glycosylating agents. The synthesis is achieved by a C1-to-C5 switch strategy relying on radical decarboxylative fluorination of uronic acids arising from readily available allyl d-C-glycosides. To further showcase the application of this protocol, a structurally unique hexasaccharide composed of â3)-ß-d-6didoHepp-(1â4)-ß-d-GlcpNAc-(1â units, corresponding to the capsular polysaccharide of C. jejuni strain CG8486 has been assembled for the first time. The assembly is characterized by highly efficient construction of the synthetically challenging ß-(1,2-cis)-d-ido-heptopyranoside by inversion of the C2 configuration of ß-(1,2-trans)-d-gulo-heptopyranoside, which is conveniently obtained by anchimerically assisted stereoselective glycosylation of the orthogonally protected 6dgulHepp fluoride. Ready accessibility of 6dHepp fluorides and the resulting glycans could serve as a rational starting point for the further development of synthetic vaccines fighting Campylobacter infection.
Assuntos
Campylobacter jejuni/química , Fluoretos/síntese química , Polissacarídeos Bacterianos/química , Piranos/síntese química , Configuração de Carboidratos , Fluoretos/química , Glicosilação , Piranos/químicaRESUMO
A gram-scale synthesis of iboxamycin, an antibiotic candidate bearing a fused bicyclic amino acid residue, is presented. A pivotal transformation in the route involves an intramolecular hydrosilylation-oxidation sequence to set the ring-fusion stereocenters of the bicyclic scaffold. Other notable features of the synthesis include a high-yielding, highly diastereoselective alkylation of a pseudoephenamine amide, a convergent sp3-sp2 Negishi coupling, and a one-pot transacetalization-reduction reaction to form the target compound's oxepane ring. Implementation of this synthetic strategy has provided ample quantities of iboxamycin to allow for its in vivo profiling in murine models of infection.
Assuntos
Antibacterianos/síntese química , Oxepinas/síntese química , Piranos/síntese química , Antibacterianos/química , Cristalografia por Raios X , Modelos Moleculares , Conformação Molecular , Oxepinas/química , Piranos/química , EstereoisomerismoRESUMO
Cancer cells reprogram their metabolism to survive and grow. Small-molecule inhibitors targeting cancer are useful for studying its metabolic pathways and functions and for developing anticancer drugs. Here, we discovered that glutipyran and its derivatives inhibit glycolytic activity and cell growth in human pancreatic cancer cells. According to proteomic profiling of glutipyran-treated cells using our ChemProteoBase, glutipyran was clustered within the group of endoplasmic reticulum (ER) stress inducers that included glycolysis inhibitors. Glutipyran inhibited glucose uptake and suppressed the growth of various cancer cells, including A431 cells that express glucose transporter class I (GLUT1) and DLD-1 GLUT1 knockout cells. When cotreated with the mitochondrial respiration inhibitor metformin, glutipyran exhibited a synergistic antiproliferative effect. Metabolome analysis revealed that glutipyran markedly decreased most metabolites of the glycolytic pathway and the pentose phosphate pathway. Glutipyran significantly suppressed tumor growth in a xenograft mouse model of pancreatic cancer. These results suggest that glutipyran acts as a broad-spectrum GLUT inhibitor and reduces cancer cell growth.
Assuntos
Antineoplásicos/uso terapêutico , Proteínas Facilitadoras de Transporte de Glucose/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Piranos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Metabolômica , Metformina/uso terapêutico , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteômica , Piranos/síntese química , Piranos/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Pyranopyrazole and its derivatives are classified to be a pharmacologically significant active scaffold for almost all modes of biological activities. In this work, An efficient, green, and facile three-component reaction for preparing pyrano[2,3-c]pyrazole derivatives via the condensation reaction of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one, ethyl acetoacetate, and malononitrile in the presence of ZnO Nanoparticle. The products are produced with high yields and in shorter reaction times. It also is mild, safe, green, and environmentally friendly. The geometric parameters such as dipole moment, bond length, dihedral angles, total energy, heat of formation, atomic charges and energies at a highly accurate for prepared compounds were computed by Denisty Functional Theory along with the B3LYP functional. The newly synthesized compounds were screened for their anti-inflammatory and antioxidant activity. Some of the tested compounds displayed promising activities. The newly prepared compounds were found to be potent towards the antioxidant activity. Results indicated that compounds 11 and 12 exhibited significant (p ≥ 0.05) in vitro total antioxidant activity as 44.93 ± 0.15 and 39.60 ± 0.10 U/ML, respectively higher than standard ascorbic acid (29.40 ± 0.62).
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Teoria da Densidade Funcional , Inibidores de Lipoxigenase/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antioxidantes/síntese química , Antioxidantes/química , Araquidonato 5-Lipoxigenase/metabolismo , Catálise , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Relação Dose-Resposta a Droga , Humanos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Prostaglandina-Endoperóxido Sintases/metabolismo , Piranos/síntese química , Piranos/química , Piranos/farmacologia , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
We studied the effect of nanostructured clathrate complex 9-phenyl-symm-octahydoselenoxanthene (selenopyran) with ß-cyclodextrin on the generation of Ðз radicals in the Fenton system and parameters of oxidative stress in rat liver cells incubated at 37°Ð¡ for 1 h. The complex inhibits the development of free-radical oxidative processes induced by ROS and the most toxic Ðз radicals, reduces the increased level of ROS induced by prooxidants, and exhibits antioxidant activity.
Assuntos
Antioxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , beta-Ciclodextrinas/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Células Cultivadas , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Substâncias Macromoleculares/farmacologia , Masculino , Modelos Biológicos , Nanoestruturas/química , Piranos/síntese química , Piranos/química , Piranos/farmacologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Compostos de Selênio/síntese química , Compostos de Selênio/química , Compostos de Selênio/farmacologia , Terpenos/química , Terpenos/farmacologia , beta-Ciclodextrinas/síntese química , beta-Ciclodextrinas/químicaRESUMO
Breast cancer remains one of the leading cancers among women. Cancer stem cells (CSCs) are tumor-initiating cells which drive progression, metastasis, and reoccurrence of the disease. CSCs are resistant to conventional chemo- and radio-therapies and their ability to survive such treatment enables tumor reestablishment. Metastasis is the main cause of mortality in women with breast cancer, thus advances in treatment will depend on therapeutic strategies targeting CSCs. Salinomycin (SAL) is a naturally occurring polyether ionophore antibiotic known for its anticancer activity towards several types of tumor cells. In the present work, a library of 17 C1-single and C1/C20-double modified SAL analogs was screened to identify compounds with improved activity against breast CSCs. Six single- and two double-modified analogs were more potent (IC50 range of 1.1 ± 0.1-1.4 ± 0.2 µM) toward the breast cancer cell line MDA-MB-231 compared to SAL (IC50 of 4.9 ± 1.6 µM). Double-modified compound 17 was found to be more efficacious than SAL against the majority of cancer cell lines in the NCI-60 Human Tumor Cell Line Panel. Compound 17 was more potent than SAL in inhibiting cell migration and cell renewal properties of MDA-MB-231 cells, as well as inducing selective loss of the CD44+/CD24/low stem-cell-like subpopulation in both monolayer (2D) and organoid (3D) culture. The present findings highlight the therapeutic potential of SAL analogs towards breast CSCs and identify select compounds that merit further study and clinical development.