RESUMO
CREB (cyclic-AMP responsive element binding protein) binding protein (CBP) is a potential target for prostate cancer treatment. Herein, we report the structural optimization of a series of 1-(indolizin-3-yl)ethan-1-one compounds as new selective CBP bromodomain inhibitors, aiming to improve cellular potency and metabolic stability. This process led to compound 9g (Y08284), which possesses good liver microsomal stability and pharmacokinetic properties (F = 25.9%). Furthermore, the compound is able to inhibit CBP bromodomain as well as the proliferation, colony formation, and migration of prostate cancer cells. Additionally, the new inhibitor shows promising antitumor efficacy in a 22Rv1 xenograft model (TGI = 88%). This study provides new lead compounds for further development of drugs for the treatment of prostate cancer.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proteína de Ligação a CREB/antagonistas & inibidores , Indolizidinas/síntese química , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Células CACO-2 , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Indolizidinas/farmacocinética , Indolizidinas/farmacologia , Masculino , Camundongos , Camundongos SCID , Microssomos Hepáticos , Modelos Moleculares , Simulação de Acoplamento Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
13a-(S)-3-pivaloyloxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (CAT3) is a novel oral anti-glioma pro-drug with a potent anti-tumor effect against temozolomide-resistant glioma. 13a(S)-3-hydroxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (PF403) is the active in vivo lipase degradation metabolite of CAT3. Both CAT3 and PF403 can penetrate the blood-brain barrier to cause an anti-glioma effect. However, PF403, which is produced in the gastrointestinal tract and plasma, causes significant gastrointestinal side effects, limiting the clinical application of CAT3. The objective of this paper was to propose a metabolism modification for CAT3 using a self-microemulsifying drug delivery system (SMEDDS), in order to reduce the generation of PF403 in the gastrointestinal tract and plasma, as well as increase the bioavailability of CAT3 in vivo and the amount of anti-tumor substances in the brain. Thus, a CAT3-loaded self-microemulsifying drug delivery system (CAT3-SMEDDS) was prepared, and its physicochemical characterization was systematically carried out. Next, the pharmacokinetic parameters of CAT3 and its metabolite in the rats' plasma and brain were measured. Furthermore, the in vivo anti-glioma effects and safety of CAT3-SMEDDS were evaluated. Finally, Caco-2 cell uptake, MDCK monolayer cellular transfer, and the intestinal lymphatic transport mechanisms of SMEDDS were investigated in vitro and in vivo. Results show that CAT3-SMEDDS was able to form nanoemulsion droplets in artificial gastrointestinal fluid within 1 min, displaying an ideal particle size (15-30 nm), positive charge (5-9 mV), and controlled release behavior. CAT3-SMEDDS increased the membrane permeability of CAT3 by 3.9-fold and promoted intestinal lymphatic transport. Hence, the bioavailability of CAT3 was increased 79% and the level of its metabolite, PF403, was decreased to 49%. Moreover, the concentrations of CAT3 and PF403 were increased 2-6-fold and 1.3-7.2-fold, respectively, in the brain. Therefore, the anti-glioma effect in the orthotopic models was improved with CAT3-SMEDDS compared with CAT3 in 21 days. Additionally, CAT3-SMEDDS reduced the gastrointestinal side effects of CAT3, such as severe diarrhea, necrosis, and edema, and observed less inflammatory cell infiltration in the gastrointestinal tract, compared with the bare CAT3. Our work reveals that, through the metabolism modification effect, SMEDDS can improve the bioavailability of CAT3 and reduce the generation of PF403 in the gastrointestinal tract and plasma. Therefore, it has the potential to increase the anti-glioma effect and reduce the gastrointestinal side effects of CAT3 simultaneously.
Assuntos
Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Glioblastoma/tratamento farmacológico , Indolizidinas/farmacologia , Fenantrenos/farmacologia , Animais , Disponibilidade Biológica , Cães , Liberação Controlada de Fármacos , Emulsões , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Células Madin Darby de Rim Canino , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ratos , Ratos Sprague-DawleyRESUMO
Indolizidine alkaloids are chemical constituents isolated from various marine and terrestrial plants and animals, including but not limited to trees, fungi, ants, and frogs, with a myriad of important biological activities. In this review, we discuss the biological activity and pharmacological effects of indolizidine alkaloids and offer new avenues toward the discovery of new and better drugs based on these naturally occurring compounds.
Assuntos
Alcaloides , Indolizidinas , Alcaloides/farmacologia , Animais , Fungos , Indolizidinas/farmacologia , PlantasRESUMO
Eight new cyclizidine-type alkaloids (1-8) and one known alkaloid (9) were identified from the chemical investigations of a marine-derived actinomycete, Streptomyces sp. HNA39. Among these alkaloids, compounds 3, 7, and 8 contain a chlorine atom, and the known alkaloid, (+)-ent-cyclizidine (9), is now first reported as a natural product. Their structures were elucidated by extensive NMR-spectroscopic analysis and HRESIMS data. The absolute configurations of all of the compounds were established by ECD calculations. Cytotoxicity evaluations of all of the compounds showed that compound 2 exhibited significant activity against the PC3 and HCT116 human-cancer-cell lines with IC50 values of 0.52 ± 0.03 and 8.3 ± 0.1 µM, respectively. Interestingly, compounds 2, 5, 7, and 8 exhibited moderate inhibition against the ROCK2 protein kinase with IC50 values from 7.0 ± 0.8 to 42 ± 3 µM.
Assuntos
Alcaloides/química , Indolizidinas/química , Streptomyces/química , Alcaloides/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Cloro/química , Cloro/farmacologia , Citotoxinas/química , Citotoxinas/farmacologia , Células HCT116 , Humanos , Indolizidinas/farmacologia , Espectroscopia de Ressonância Magnética/métodos , Células PC-3 , Quinases Associadas a rho/antagonistas & inibidoresRESUMO
Medulloblastoma (MB) and glioblastoma (GBM) are the most prevalent malignant brain tumors. The identification of novel therapeutic strategies is urgent for MB and GBM patients. Herein, we discovered 13a-(S)-3-Hydroxyl-6,7-dimethoxyphenanthro[9,10-b]-indolizidine (PF403) strongly exhibited inhibitory activity against Hedgehog (Hh) pathway-hyperactivated MB and GBM cells with a 50% inhibitory concentration (IC50) of 0.01 nM. CAT3 was designed and synthesized as the prodrug of PF403 and displayed significant in vivo efficacy against MB and GBM. Mechanistic study revealed that CAT3 inhibited MB and GBM primarily by interrupting the Hh signaling pathway. At the molecular level, PF403 inhibited the cell surface accumulation of the Smoothened (Smo) receptor by directly binding or enhancing the interaction of Smo with the repressor Ptch1. Furthermore, PF403 significantly repressed Gli1 nuclear accumulation and transcription by promoting Sufu-Gli1 and PKA-Gli1 interactions. Collectively, our studies support the hypothesis that CAT3 is a promising therapeutic agent for the treatment of Hh-driven MB and GBM.
Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Cerebelares/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Proteínas Hedgehog/metabolismo , Indolizidinas/farmacologia , Meduloblastoma/tratamento farmacológico , Fenantrenos/farmacologia , Pró-Fármacos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/patologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Desenho de Fármacos , Feminino , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Indolizidinas/administração & dosagem , Indolizidinas/síntese química , Indolizidinas/farmacocinética , Concentração Inibidora 50 , Masculino , Meduloblastoma/genética , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Receptor Patched-1/genética , Receptor Patched-1/metabolismo , Fenantrenos/administração & dosagem , Fenantrenos/síntese química , Fenantrenos/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Receptor Smoothened/genética , Receptor Smoothened/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismoRESUMO
A new natural product, designated iminimycin A, was isolated from the cultured broth of a streptomycin-producing microbial strain, Streptomyces griseus OS-3601, via a physicochemical screening method using HP-20, silica gel and ODS column chromatographies and subsequent preparative HPLC. Iminimycin A is an indolizidine alkaloid, containing of an unusual iminium group and a cyclopropane ring with a triene side chain. The absolute configuration of iminimycin A was elucidated by NMR studies and electronic circular dichroism analysis. Iminimycin A shows anti-bacterial activity against Bacillus subtilis, Kocuria rhizophila and Xanthomonas campestris pv. orizae, and cytotoxic activity against HeLa S3 and Jurkat cells with IC50 values of 43 and 36 µM, respectively.
Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Streptomyces griseus/metabolismo , Alcaloides/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Bacillus subtilis/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Dicroísmo Circular , Células HeLa , Humanos , Indolizidinas/química , Indolizidinas/isolamento & purificação , Indolizidinas/farmacologia , Concentração Inibidora 50 , Células Jurkat , Espectroscopia de Ressonância Magnética , Micrococcaceae/efeitos dos fármacos , Xanthomonas campestris/efeitos dos fármacosRESUMO
A pair of racemic indolizidine enantiomers, (±)-homocrepidine A (1), and a piperidine derivative, homocrepidine B (2), were isolated from Dendrobium crepidatum along with the known alkaloid crepidine (3). The racemic mixture of 1 was separated into a pair of enantiomers, (+)-1 and (-)-1, by HPLC using a chiral chromatographic substrate, which represents the first successful example of resolving indolizidine racemic mixtures. The absolute configurations of (+)-1 and (-)-1 were assigned from single-crystal X-ray diffraction data. The evaluation of anti-inflammatory activity with LPS-induced RAW 264.7 macrophages revealed that (+)-1 strongly inhibited the production of nitric oxide (IC50, 3.6 µM) and significantly decreased the expression of inducible nitric oxide synthase, while (-)-1 and (±)-1 only had moderate inhibitory effects (IC50, 22.8 and 14.7 µM). Compound 2 showed moderate anti-inflammatory activity (IC50, 27.6 µM).
Assuntos
Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Anti-Inflamatórios não Esteroides/isolamento & purificação , Anti-Inflamatórios não Esteroides/farmacologia , Dendrobium/química , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Indolizidinas/isolamento & purificação , Indolizidinas/farmacologia , Alcaloides/química , Animais , Anti-Inflamatórios não Esteroides/química , Cristalografia por Raios X , Medicamentos de Ervas Chinesas/isolamento & purificação , Indolizidinas/química , Concentração Inibidora 50 , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Conformação Molecular , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Piperidinas , Caules de Planta/química , EstereoisomerismoRESUMO
α,α-Disubstituted piperidines and conformationally constrained polyhydroxylated indolizidines bearing a hydroxymethyl substituent in position 8a were synthesized from a readily available l-sorbose-derived ketonitrone. Diastereoselective vinylation under two sets of complementary conditions allowed access to both configurations of the newly formed quaternary stereocenter. Subsequent N-allylation and ring-closing metathesis afforded 8a-branched indolizidines in high yield. The newly prepared iminosugars demonstrated highly potent inhibition of α-glucosidases. Most interestingly, compound 9b exhibits very high selectivity toward this class of enzymes, with an unusual mode of binding.
Assuntos
Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/farmacologia , Indolizidinas/síntese química , Indolizidinas/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , alfa-Glucosidases/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Indolizidinas/química , Conformação Molecular , Estrutura Molecular , Piperidinas/química , EstereoisomerismoRESUMO
On pursuing molecules that delay labour, so-called tocolytics, the prostaglandin F2α receptor (FP) was targeted, because of its role in the stimulation of uterine contractions leading to birth and preterm birth. Previously, both the indolizidinone PDC-113.824 (5) and the aza-glycinyl-proline analog 6 were shown to delay labour in mice by modulating the FP function, likely by an allosteric mechanism, which features biased signalling. The crystal structure and computational analyses of the indolizidin-2-one amino acid and aza-glycinyl-proline components of 5 and 6 in model peptides have shown them to adopt a geometry that mimics ideal type I and II'ß-turns. To elucidate the precise turn geometry for receptor recognition, analogs 1-4 have now been synthesized: macrocycle and pyrroloazepinone mimics 1 and 2 to mimic type I, and glycinyl-proline and d-alaninyl-proline analogs 3 and 4 to favour type II'ß-turn geometry. Notably, transannular cyclization of peptide macrocycle 13 has provided diastereoselectively pyrroloazepinone 15 by a novel route that provides effective access to mimics 1 and 2 by way of a common intermediate. Among the four analogs, none exhibited efficacy nor potency on par with 5 and 6; however, d-alaninyl-proline analog 4 proved superior to the other analogs in reducing PGF2α-induced myometrial contractions and inhibiting FP modulation of cell ruffling, a response dependent on the Gα12/RhoA/ROCK signaling pathway. Furthermore Gly-Pro analog 3 potentiated the effect of PGF2α on Gαq mediated ERK1/2 activation. Evidence that 4 adopted turn geometry was obtained by conformational analysis using NMR spectroscopy to characterize respectively the influence of solvent and temperature on the chemical shifts of the amide NH protons. Although mimicry of the type II' geometry by 3, 4, 5 and 6 may favour activity, distortion from ideal geometry by the indolizidinone and aza-glycinyl residues of the latter appears to enhance their biological effects.
Assuntos
Compostos Aza/farmacologia , Indolizidinas/farmacologia , Oligopeptídeos/farmacologia , Receptores de Prostaglandina/antagonistas & inibidores , Animais , Compostos Aza/química , Indolizidinas/química , Camundongos , Conformação Molecular , Oligopeptídeos/química , Relação Estrutura-AtividadeRESUMO
Neuroblastoma is the most common cancer in infants and the fourth most common cancer in children. Our previous study showed that PF403 had a potent antitumor ability. In the present study, we evaluated the anti-neuroblastoma property of PF403 and investigated the underlying mechanisms. MTT assay, colony formation assay and flow cytometry assay were used to assess cytotoxicity of PF403 on SH-SY5Y cells. Transwell assay was chosen to estimate the anti-invasion ability of PF403 on neuroblastoma cells. The protein expression was detected by western blot analysis. The SH-SY5Y brain xenograft model was used to assess in vivo antitumor activity of PF403. PF403-mediated SH-SY5Y cell death was found to be dose- and time-dependent, and PF403 was able to limit invasion and metastasis of neuroblastoma cells. MRI and pathology analysis proved that the pro-drug of PF403, CAT3, inhibited SH-SY5Y cells in vivo. PF403 decreased expression of phosphorylated FAK, MMP-2 and MMP-9 proteins, and downregulated the activity of PI3K/AKT and Raf/ERK pathways, followed by regulation of the proteins expression of Bcl-2 family, activated caspase-3, -9 and PARP and initiation of apoptosis of neuroblastoma cells. PF403 exerted cytotoxicity against SH-SY5Y neuroblastoma cell both in vitro and in vivo, and inhibited its invasion ability, suggesting PF403 has potential as a new anticancer drug for the treatment of neuroblastoma.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Indolizidinas/administração & dosagem , Indolizinas/administração & dosagem , Neuroblastoma/tratamento farmacológico , Fenantrenos/administração & dosagem , Pró-Fármacos/administração & dosagem , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indolizidinas/farmacologia , Indolizinas/farmacologia , Camundongos , Invasividade Neoplásica , Fenantrenos/farmacologia , Pró-Fármacos/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A practical one-pot synthesis of bi- and triantennated australine analogues from a pivotal sp(2)-iminosugar-type reducing castanospermine precursor is reported. The transformation involves a gem-diamine intermediate that undergoes the indolizidine â pyrrolizidine Amadori-type rearrangement and proceeds under strict control of the generalized anomeric effect to afford a single diastereomer. The final compounds behave as selective competitive inhibitors of ß-glucosidase and are promising candidates as pharmacological chaperones for Gaucher disease.
Assuntos
Diaminas/química , Inibidores Enzimáticos/síntese química , Doença de Gaucher/tratamento farmacológico , Indolizidinas/farmacologia , Indolizinas/química , Chaperonas Moleculares/química , Chaperonas Moleculares/farmacologia , Alcaloides de Pirrolizidina/síntese química , beta-Glucosidase/antagonistas & inibidores , beta-Glucosidase/química , Fenômenos Bioquímicos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Indolizidinas/química , Chaperonas Moleculares/síntese química , Estrutura Molecular , Alcaloides de Pirrolizidina/químicaRESUMO
Development of multi-target drugs is becoming increasingly attractive in the repertoire of protein kinase inhibitors discovery. In this study, we carried out molecular docking, molecular dynamics simulations, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations, principal component analysis (PCA), and dynamical cross-correlation matrices (DCCM) to dissect the molecular mechanism for the valmerin-19 acting as a dual inhibitor for glycogen synthase kinase 3ß (GSK3ß) and cyclin-dependent kinase 5 (CDK5). Detailed MM-PBSA calculations revealed that the binding free energies of the valmerin-19 to GSK3ß/CDK5 were calculated to be -12.60 ± 2.28 kcal mol(-1) and -11.85 ± 2.54 kcal mol(-1), respectively, indicating that valmerin-19 has the potential to act as a dual inhibitor of GSK3ß/CDK5. The analyses of PCA and DCCM results unraveled that binding of the valmerin-19 reduced the conformational dynamics of GSK3ß/CDK5 and the valmerin-19 bound to GSK3ß/CDK5 might occur mostly through a conformational selection mechanism. This study may be helpful for the future design of novel and potent dual GSK3ß/CDK5 inhibitors.
Assuntos
Desenho Assistido por Computador , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Desenho de Fármacos , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Indolizidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Ureia/análogos & derivados , Sítios de Ligação , Análise por Conglomerados , Quinase 5 Dependente de Ciclina/química , Quinase 5 Dependente de Ciclina/metabolismo , Estabilidade de Medicamentos , Transferência de Energia , Estabilidade Enzimática , Quinase 3 da Glicogênio Sintase/química , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Indolizidinas/química , Indolizidinas/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Terapia de Alvo Molecular , Análise de Componente Principal , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Relação Estrutura-Atividade , Propriedades de Superfície , Ureia/química , Ureia/metabolismo , Ureia/farmacologiaRESUMO
To investigate the influence of the variation of the original skeletons of natural phenanthroindo/quinolizidine alkaloids on antiviral activities, two types of structurally totally novel analogues 7a, 7b, 16a, and 16b were designed, synthesized, and evaluated against tobacco mosaic virus (TMV) for the first time. Bioassay results indicated that all four of the newly designed analogues showed good to excellent antiviral activities, among which analogue 16a dispalyed comparable activity with that of ningnanmycin, perhaps one of the most successful commercial antiviral agents, thus emerging as a potential inhibitor of plant virus and serving as a new lead for further optimization. Further structure-activity relationships are also discussed, demonstrating for the first time that the same changes of the original skeletons of phenanthroindolizidine and phenanthroquinolizidine exihibted totally different antiviral activities results, providing some original and useful information about the preferential conformation for maintaining high activities.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Indolizidinas/síntese química , Indolizidinas/farmacologia , Indolizinas/química , Fenantrenos/síntese química , Fenantrenos/farmacologia , Fenantrolinas/química , Quinolizinas/química , Desenho de Fármacos , Doenças das Plantas/virologia , Relação Estrutura-Atividade , Vírus do Mosaico do Tabaco/efeitos dos fármacosRESUMO
Compound 5 was selected from our in-house library as a suitable starting point for the rational design of new GSK-3ß inhibitors. MC/FEP calculations of 5 led to the identification of a structural class of new GSK-3ß inhibitors. Compound 18 inhibited GSK-3ß with an IC50 of 0.24 µM and inhibited tau phosphorylation in a cell-based assay. It proved to be a selective inhibitor of GSK-3 against a panel of 17 kinases and showed >10-fold selectivity against CDK2. Calculated physicochemical properties and Volsurf predictions suggested that compound 18 has the potential to diffuse passively across the blood-brain barrier.
Assuntos
Desenho de Fármacos , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Indolizidinas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Succinimidas/farmacologia , Linhagem Celular , Relação Dose-Resposta a Droga , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Indolizidinas/síntese química , Indolizidinas/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Succinimidas/síntese química , Succinimidas/químicaRESUMO
Synthesis of dihydroxymethyl dihydroxypyrrolidines from C-2 formyl D-glycals has been described via a common dicarbonyl intermediate. The hence obtained pyrrolidines have been further utilized for the synthesis of some steviamine analogues. The newly synthesized molecules have been evaluated for glycosidase inhibition against 6 commercially available enzymes and found to be active in the micromolar range, where one of the steviamine analogues showed good and selective inhibition of ß-mannosidase (Helix pomatia).
Assuntos
Carboidratos/química , Inibidores Enzimáticos/farmacologia , Imino Açúcares/farmacologia , Indolizidinas/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , beta-Galactosidase/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Caracois Helix/enzimologia , Imino Açúcares/síntese química , Imino Açúcares/química , Indolizidinas/síntese química , Indolizidinas/química , Estrutura Molecular , Pirrolidinas/química , Relação Estrutura-Atividade , beta-Galactosidase/metabolismoRESUMO
A general and efficient method for the synthesis of polyhydroxylated pyrrolizidines and indolizidines has been developed based on the NHC-catalyzed cross-coupling of sugar-derived cyclic nitrones with enals, which afforded the key intermediates, γ-hydroxyl amino esters, in good to excellent yields. Thus, a variety of polyhydroxylated pyrrolizidines and indolizidines have been synthesized and assayed against various glycosidases, which showed that aryl or alkyl substituents at C-7 of pyrrolizidines or at C-8 of indolizidines reduced the potency of the glycosidase inhibition of these bicyclic iminosugars.
Assuntos
Carboidratos/química , Compostos Heterocíclicos/química , Indolizidinas/síntese química , Cetonas/química , Metano/análogos & derivados , Óxidos de Nitrogênio/química , Alcaloides de Pirrolizidina/síntese química , Catálise , Técnicas de Química Sintética , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Indolizidinas/química , Indolizidinas/farmacologia , Metano/química , Alcaloides de Pirrolizidina/química , Alcaloides de Pirrolizidina/farmacologiaRESUMO
A concise synthesis of (-)-steviamine is reported along with the synthesis of its analogues 10-nor-steviamine, 10-nor-ent-steviamine and 5-epi-ent-steviamine. These compounds were tested against twelve glycosidases (at 143 µg mL(-1) concentrations) and were found to have in general poor inhibitory activity against most enzymes. The 10-nor analogues however, showed 50-54% inhibition of α-L-rhamnosidase from Penicillium decumbens while one of these, 10-nor-steviamine, showed 51% inhibition of N-acetyl-ß-D-glucosaminidase (from Jack bean) at the same concentration (760 µM).
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Imino Açúcares/síntese química , Imino Açúcares/farmacologia , Indolizidinas/síntese química , Indolizidinas/farmacologia , Técnicas de Química Sintética , Desenho de Fármacos , Inibidores Enzimáticos/química , Geobacillus stearothermophilus/enzimologia , Imino Açúcares/química , Indolizidinas/química , Modelos Moleculares , Conformação Molecular , Penicillium/enzimologiaRESUMO
On the basis of our previous structure-activity relationship (SAR) and antiviral mechanism studies, a series of phenanthroindolizidines and their analogues 3-20 were designed, targeting tobacco mosaic virus (TMV) RNA, synthesized, and systematically evaluated for their antiviral activity against TMV. The bioassay results showed that most of these compounds displayed good anti-TMV activity, and some of them exhibited higher antiviral activity than that of commercial Ningnanmycin (perhaps the most successful registered antiplant viral agent). Especially, (S)-deoxytylophorinine (5) with excellent anti-TMV activity (inactivation activity, 59.8%/500 µg mL(-1) and 40.3%/100 µg mL(-1); curative activity, 65.1%/500 µg mL(-1) and 43.7%/100 µg mL(-1); and protection activity, 70.2%/500 µg mL(-1) and 51.3%/100 µg mL(-1)) emerged as a potential inhibitor of the plant virus. Compound 20 exhibited a strong in vivo protection effect against TMV at 100 µg mL(-1), which indicated that phenanthroindolizidine analogues with a seven-membered D ring have a new and interesting structural scaffold and have great potential for further development as tobacco protection agents.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Indolizidinas/síntese química , Indolizidinas/farmacologia , Indolizinas/química , Fenantrolinas/química , Fenantrolinas/síntese química , Fenantrolinas/farmacologia , Vírus do Mosaico do Tabaco/efeitos dos fármacos , Desenho de Fármacos , Doenças das Plantas/virologia , RNA Viral/efeitos dos fármacos , Vírus do Mosaico do Tabaco/genéticaRESUMO
Based on our previous structure-activity relationship and antiviral mechanism studies, a series of 14-aminophenanthroindolizidines (1a-i, 2, and 3) were designed, targeting tobacco mosaic virus (TMV) RNA, and synthesized and systematically evaluated for their antiviral activity against TMV. The bioassay results showed that most of these compounds exhibited good to excellent in vivo anti-TMV activity, of which compounds 1d and 1h displayed significantly higher activity than commercial ningnanmycin, and thus emerged as potential inhibitors of plant virus. The introduction of amino groups at the 14-position of phenanthroindolizidines, which is proposed to interact with arginine residues around the TMV RNA, increased anti-TMV activity.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Indolizidinas/síntese química , Indolizidinas/farmacologia , Fenantrenos/síntese química , Fenantrenos/farmacologia , Vírus do Mosaico do Tabaco/efeitos dos fármacos , RNA Viral/química , Relação Estrutura-AtividadeRESUMO
The synthesis, conformational study and inhibitory properties of diverse indolizidine and quinolizidine iminocyclitols are described. The compounds were chemo-enzymatically synthesized by two-step aldol addition and reductive amination reactions. The aldol addition of dihydroxyacetone phosphate (DHAP) to N-Cbz-piperidine carbaldehyde derivatives catalyzed by L-rhamnulose 1-phosphate aldolase from Escherichia coli provides the key intermediates. The stereochemical outcome of both aldol addition and reductive amination depended upon the structure of the starting material and intermediates. The combination of both reactions furnished five indolizidine and six quinolizidine type iminocyclitols. A structural analysis by NMR and in silico density functional theory (DFT) calculations allowed us to determine the population of stereoisomers with the trans or cis ring fusion, as a consequence of the inversion of configuration of the bridgehead nitrogen. The trans fusion was by far the most stable, but for certain stereochemical configurations of the 3-hydroxymethyl and hydroxyl substituents both trans and cis fusion stereoisomers coexisted in different proportions. Some of the polyhydroxylated indolizidines and quinolizidines were shown to be moderate to good inhibitors against α-L-rhamnosidase from Penicillium decumbens. Indolizidines were found to be moderate inhibitors of the rat intestinal sucrase and of the exoglucosidase amyloglucosidase from Aspergillus niger. In spite of their activity against α-L-rhamnosidase, all the compounds were ineffective to inhibit the growth of the Mycobacterium tuberculosis, the causative agent of tuberculosis.