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1.
J Org Chem ; 87(14): 8871-8883, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35759553

RESUMO

A Ni-catalyzed (4 + 2) cycloaddition of bicyclic 3-azetidinones and alkynes was developed to access indolizidine and quinolizidine alkaloids. A key element was the development of a diazomethylation procedure that allows the efficient synthesis of bicyclic azetidinones from pyroglutamic and 6-oxopiperidine-2-carboxylic acid. A ligand screening led to improved regioselectivity and enantiopurity during the Ni-catalyzed (4 + 2) cycloaddition. This straightforward methodology was leveraged to synthesize (+)-ipalbidine, (+)-septicine, (+)-seco-antofine, and (+)-7-methoxy-julandine.


Assuntos
Alcaloides , Indolizidinas , Quinolizidinas , Catálise , Reação de Cicloadição , Níquel
2.
Chembiochem ; 23(3): e202100517, 2022 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-34767291

RESUMO

Indolizidine alkaloids, which have versatile bioactivities, are produced by various organisms. Although the biosynthesis of some indolizidine alkaloids has been studied, the enzymatic machinery for their biosynthesis in Streptomyces remains elusive. Here, we report the identification and analysis of the biosynthetic gene cluster for iminimycin, an indolizidine alkaloid with a 6-5-3 tricyclic system containing an iminium cation from Streptomyces griseus. The gene cluster has 22 genes, including four genes encoding polyketide synthases (PKSs), which consist of eight modules in total. In vitro analysis of the first module revealed that its acyltransferase domain selects malonyl-CoA, although predicted to select methylmalonyl-CoA. Inactivation of seven tailoring enzyme-encoding genes and structural elucidation of four compounds accumulated in mutants provided important insights into iminimycin biosynthesis, although some of these compounds appeared to be shunt products. This study expands our knowledge of the biosynthetic machinery of indolizidine alkaloids and the enzymatic chemistry of PKS.


Assuntos
Alcaloides/biossíntese , Família Multigênica , Streptomyces griseus/química , Streptomyces griseus/genética , Alcaloides/química , Indolizidinas/química , Conformação Molecular , Streptomyces griseus/metabolismo
3.
J Med Chem ; 65(1): 785-810, 2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-34962793

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 Xenoenxerto
4.
Int J Mol Sci ; 22(15)2021 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-34360698

RESUMO

Smoking-cessation drugs bind many off-target nicotinic acetylcholine receptors (nAChRs) and cause severe side effects if they are based on nicotine. New drugs that bind only those receptors, such as α6ß2* nAChR, implicated in nicotine addiction would avoid the off-target binding. Indolizidine (-)-237D (IND (-)-237D), a bicyclic alkaloid, has been shown to block α6ß2* containing nAChRs and functionally inhibit the nicotine-evoked dopamine release. To improve the affinity of indolizidine (-)-237D for α6ß2*, we built a library of 2226 analogs. We screened virtually the library against a homology model of α6ß2 nAChR that we derived from the recent crystal structure of α4ß2 nAChR. We also screened the crystal structure of α4ß2 nAChR as a control on specificity. We ranked the compounds based on their predicted free energy of binding. We selected the top eight compounds bound in their best pose and subjected the complexes to 100 ns molecular dynamics simulations to assess the stability of the complexes. All eight analogs formed stable complexes for the duration of the simulations. The results from this work highlight nine distinct analogs of IND (-)-237D with high affinity towards α6ß2* nAChR. These leads can be synthesized and tested in in vitro and in vivo studies as lead candidates for drugs to treat nicotine addiction.


Assuntos
Descoberta de Drogas , Indolizidinas/química , Simulação de Dinâmica Molecular , Receptores Nicotínicos/química , Humanos , Antagonistas Nicotínicos/química , Ligação Proteica , Receptores Nicotínicos/metabolismo , Abandono do Hábito de Fumar
5.
J Org Chem ; 86(15): 10773-10781, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34236870

RESUMO

The Ir-catalyzed asymmetric hydrogenation of cyclic pyridinium salts is presented as a new strategy for the convenient and efficient synthesis of chiral indolizidines. The asymmetric hydrogenation of cyclic pyridinium salts derived from 2-(2-acylphenyl)pyridines proceeded smoothly in the presence of [Ir(cod)Cl]2 and (R)-DM-SegPhos to provide the desired chiral 7,8-benzoindolizidines 6 in high to excellent yields with moderate enantioselectivity (up to 86:14 er) and excellent diastereoselectivity (>20:1 dr). The enantiomeric purity of 6j was increased to 92:8 through recrystallization.


Assuntos
Indolizidinas , Sais , Catálise , Hidrogenação , Estereoisomerismo
6.
J Am Chem Soc ; 143(7): 2970-2983, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33570388

RESUMO

Structurally unprecedented antibacterial alkaloids containing multiple electron-rich pyrrole units have recently been isolated from Curvularia sp. and Bipolaris maydis fungi. This article documents the evolution of a synthetic program aimed at accessing the flagship metabolites curvulamine and curindolizine which are presumably a dimer and trimer of a C10N biosynthetic building block, respectively. Starting with curvulamine, we detail several strategies to merge two simple, bioinspired fragments, which while ultimately unsuccessful, led us toward a pyrroloazepinone building block-based strategy and an improved synthesis of this 10π-aromatic heterocycle. A two-step annulation process was then designed to forge a conserved tetracyclic bis-pyrrole architecture and advanced into a variety of late-stage intermediates; unfortunately, however, a failed decarboxylation thwarted the total synthesis of curvulamine. By tailoring our annulation precursors, success was ultimately found through the use of a cyanohydrin nucleophile which enabled a 10-step total synthesis of curvulamine. Attempts were then made to realize a biomimetic coupling of curvulamine with an additional C10N fragment to arrive at curindolizine, the most complex family member. Although unproductive, we developed a 14-step total synthesis of this alkaloid through an abiotic coupling approach. Throughout this work, effort was made to harness and exploit the innate reactivity of the pyrrole nucleus, an objective which has uncovered many interesting findings in the chemistry of this reactive heterocycle.


Assuntos
Alcaloides/síntese química , Alcaloides Indólicos/síntese química , Alcaloides/química , Azepinas/química , Bipolaris/química , Bipolaris/metabolismo , Cristalografia por Raios X , Curvularia/química , Curvularia/metabolismo , Ciclização , Alcaloides Indólicos/química , Indolizidinas/química , Conformação Molecular , Pirróis/química , Estereoisomerismo
7.
Molecules ; 26(2)2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33477555

RESUMO

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-Dawley
8.
Med Res Rev ; 41(2): 928-960, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33128409

RESUMO

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 , Plantas
9.
J Am Chem Soc ; 142(30): 13041-13050, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32627545

RESUMO

Herein we report the synthesis of substituted indolizidines and related N-fused bicycles from simple saturated cyclic amines through sequential C-H and C-C bond functionalizations. Inspired by the Norrish-Yang Type II reaction, C-H functionalization of azacycles is achieved by forming α-hydroxy-ß-lactams from precursor α-ketoamide derivatives under mild, visible light conditions. Selective cleavage of the distal C(sp2)-C(sp3) bond in α-hydroxy-ß-lactams using a Rh-complex leads to α-acyl intermediates which undergo sequential Rh-catalyzed decarbonylation, 1,4-addition to an electrophile, and aldol cyclization, to afford N-fused bicycles including indolizidines. Computational studies provide mechanistic insight into the observed positional selectivity of C-C cleavage, which depends strongly on the groups bound to Rh trans to the phosphine ligand.


Assuntos
Compostos Aza/química , Compostos Heterocíclicos/síntese química , Indolizidinas/síntese química , Ciclização , Compostos Heterocíclicos/química , Indolizidinas/química , Estrutura Molecular , Estereoisomerismo
10.
Sci Rep ; 10(1): 9564, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32533030

RESUMO

Two new indolizidine alkaloids crepidatumines A (1) and B (2) together with the stereoisomer of dendrocrepidine B (3) and known analog dendrocrepine (4) were isolated from D. crepidatum. Their structures were determined by HR-ESI-MS, NMR, and Electronic Circular Dichroism (ECD) experiments together with comparison of analogues. Compound (1) possess a (5/6/6/5) tetra-hetero-cyclic ring, whereas compound (2) contains a tricyclic system with an unusual bridged ring, which are the first report in Nature. The biological evaluation revealed that dendrocrepine (4) displayed a potent hypoglycemic effect in vitro.


Assuntos
Alcaloides/química , Dendrobium/química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Indolizidinas/química , Animais , Proliferação de Células , Glucose/metabolismo , Células Hep G2 , Humanos , Camundongos , Células RAW 264.7
11.
J Pharm Biomed Anal ; 181: 113106, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31962248

RESUMO

A rapid and reproducible method with high selectivity was developed for simultaneous determination of a promising anti-brain tumor agent CAT3 and its two metabolites PF403 and GLU-PF403 in mouse plasma and brain. An economic deproteinization with septuple acetonitrile (v/v) was applied to pretreat the samples in this study. All analytes were well retained and separated on a CAPCELL CORE PC (2.7 µm, 2.1 mm I.D. × 150 mm, SHISEIDO Technologies) column with an eluting solvent of acetonitrile /water containing 0.1 % formic acid (v/v) at the flow rate of 0.2 mL per minute. The detection was carried out on a Q Exactive high resolution mass spectrometer equipped with a HESI ion source in parallel reaction monitoring (PRM) mode. The corresponding transitions for quantitation were 434.23→ 70.07 for CAT3, 350.17→70.07 for PF403, 526.21→70.07 for GLU-PF403, 364.19→70.07 for IS-1 and 625.18→317.07 for IS-2, respectively. A well-linear fit curve was achieved among the range of 0.1∼50 ng/mL for CAT3, 0.2∼100 ng/mL for PF403 and 2.5∼600 ng/mL for GLU-PF403 both in mouse plasma and brain homogenate. The intra-/inter-day accuracies of three analytes were within ±14.5 % and precisions were below to 13.44 %. The mean values of recovery of three compounds in mouse plasma and brain homogenate were among 98.06 ∼ 118.63 % and 81.04∼108.69 %. The analytes in NaF-treated ice cold blood of mouse was stable within tested 30 min. Plasma and brain homogenate samples had no obvious changes during all storage, sample treatment and analytic process of mouse plasma sample. The reproducible and reliable method was well employed to the research of CAT3 pharmacokinetic characteristics in mouse plasma and brain after a single intragastric administration at dose of 10 mg/kg.


Assuntos
Antineoplásicos/sangue , Neoplasias Encefálicas/tratamento farmacológico , Indolizidinas/sangue , Fenantrenos/sangue , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Indolizidinas/administração & dosagem , Indolizidinas/farmacocinética , Limite de Detecção , Camundongos , Fenantrenos/administração & dosagem , Fenantrenos/farmacocinética , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Distribuição Tecidual
12.
Proc Natl Acad Sci U S A ; 117(2): 1174-1180, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31882449

RESUMO

Indolizidine alkaloids such as anticancer drugs vinblastine and vincristine are exceptionally attractive due to their widespread occurrence, prominent bioactivity, complex structure, and sophisticated involvement in the chemical defense for the producing organisms. However, the versatility of the indolizidine alkaloid biosynthesis remains incompletely addressed since the knowledge about such biosynthetic machineries is only limited to several representatives. Herein, we describe the biosynthetic gene cluster (BGC) for the biosynthesis of curvulamine, a skeletally unprecedented antibacterial indolizidine alkaloid from Curvularia sp. IFB-Z10. The molecular architecture of curvulamine results from the functional collaboration of a highly reducing polyketide synthase (CuaA), a pyridoxal-5'-phosphate (PLP)-dependent aminotransferase (CuaB), an NADPH-dependent dehydrogenase (CuaC), and a FAD-dependent monooxygenase (CuaD), with its transportation and abundance regulated by a major facilitator superfamily permease (CuaE) and a Zn(II)Cys6 transcription factor (CuaF), respectively. In contrast to expectations, CuaB is bifunctional and capable of catalyzing the Claisen condensation to form a new C-C bond and the α-hydroxylation of the alanine moiety in exposure to dioxygen. Inspired and guided by the distinct function of CuaB, our genome mining effort discovers bipolamines A-I (bipolamine G is more antibacterial than curvulamine), which represent a collection of previously undescribed polyketide alkaloids from a silent BGC in Bipolaris maydis ATCC48331. The work provides insight into nature's arsenal for the indolizidine-coined skeletal formation and adds evidence in support of the functional versatility of PLP-dependent enzymes in fungi.


Assuntos
Alcaloides/biossíntese , Ascomicetos/enzimologia , Ascomicetos/metabolismo , Indolizidinas/metabolismo , Policetídeo Sintases/metabolismo , Fosfato de Piridoxal/metabolismo , Alcaloides/genética , Alcaloides/isolamento & purificação , Antibacterianos/metabolismo , Ascomicetos/genética , Aspergillus oryzae/genética , Aspergillus oryzae/metabolismo , Catálise , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Genes Fúngicos/genética , Hidroxilação , Alcaloides Indólicos , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Família Multigênica , Filogenia , Policetídeo Sintases/classificação , Policetídeo Sintases/genética , Policetídeos , Fosfato de Piridoxal/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Transaminases/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
Molecules ; 24(17)2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31450800

RESUMO

Two new indolizidine alkaloids, crepidatumines C (1) and D (2), together with crepidine (3), isocrepidamine (4), and crepidamine (5) were isolated from the Dendrobium crepidatum Lindl. ex Paxt. X-ray diffraction experiments established the absolute configurations of known compounds 3 and 4. The planar structures and relative configurations of new compounds 1 and 2 were elucidated by extensive spectra analysis including HR-ESI-MS, NMR (1H, 13C, 1H-1H COSY, HSQC, HMBC, and NOESY spectra), and the absolute configurations of 1 and 2 were suggested on the basis of possible biosynthetic pathways. The biological results confirmed that isocrepidamine (4) displayed a potent hypoglycemic effect in vitro without cytotoxicity.


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Dendrobium/química , Indolizidinas/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Difração de Raios X
14.
J Med Chem ; 62(9): 4500-4525, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-30932486

RESUMO

Peptide mimicry employing a combination of aza-amino acyl proline and indolizidinone residues has been used to develop allosteric modulators of the prostaglandin F2α receptor. The systematic study of the N-terminal phenylacetyl moiety and the conformation and side chain functions of the central turn dipeptide residue has demonstrated the sensitive relationships between modulator activity and topology. Examination of aza-Gly-Pro and aza-Phe-Pro analogs 2a and 2b in a murine preterm labor model featuring treatment with lipopolysaccharide demonstrated their capacity to extend significantly (>20 h) the average time of delivery offering new prototypes for delaying premature birth.


Assuntos
Compostos Aza/uso terapêutico , Indolizidinas/química , Peptídeos/uso terapêutico , Nascimento Prematuro/prevenção & controle , Prolina/análogos & derivados , Receptores de Prostaglandina/metabolismo , Tocolíticos/uso terapêutico , Regulação Alostérica , Animais , Compostos Aza/síntese química , Compostos Aza/química , Escherichia coli/química , Feminino , Lipopolissacarídeos , Camundongos , Mimetismo Molecular , Peptídeos/síntese química , Peptídeos/química , Gravidez , Nascimento Prematuro/induzido quimicamente , Estereoisomerismo , Relação Estrutura-Atividade , Tocolíticos/síntese química , Tocolíticos/química , Contração Uterina/efeitos dos fármacos , Útero/efeitos dos fármacos
15.
Molecules ; 23(7)2018 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-29996473

RESUMO

In this study, 2,3-dihydro-1H-indolizinium alkaloid-prosopilosidine (PPD), that was isolated from Prosopis glandulosa, was evaluated against C. neoformans in a murine model of cryptococcosis. In vitro and in vivo toxicity of indolizidines were also evaluated. Mice were infected via the tail vein with live C. neoformans. Twenty-four hours post-infection, the mice were treated with PPD once a day (i.p.) or twice a day (bid) orally, or with amphotericin B (Amp B) intraperitoneally (IP), or with fluconazole (Flu) orally for 5 days. The brains of all of the animals were aseptically removed and the numbers of live C. neoformans were recovered. In vitro toxicity of indolizidine alkaloids was determined in HepG2 cells. PPD showed to be potent in vivo activity against C. neoformans at a dose of 0.0625 mg/kg by eliminating ~76% of the organisms compared to ~83% with Amp B (1.5 mg/kg). In addition, PPD was found to be equally efficacious, but less toxic, at either 0.125 or 0.0625 mg/kg compared to Amp B (1.5 mg/kg) when it was administered bid (twice a day) by an i.p. route. When tested by an oral route, PPD (10 mg/kg) showed potent activity in this murine model of cryptococcosis with ~82% of organisms eliminated from the brain tissue, whereas Flu (15 mg/kg) reduced ~90% of the infection. In vitro results suggest that quaternary indolizidines were less toxic as compared to those of tertiary bases. PPD (20 mg/kg) did not cause any alteration in the plasma chemistry profiles. These results indicated that PPD was active in eliminating cryptococcal infection by oral and i.p. routes at lower doses compared to Amp B. or Flu.


Assuntos
Criptococose/tratamento farmacológico , Criptococose/microbiologia , Cryptococcus neoformans/fisiologia , Indolizidinas/uso terapêutico , Prosopis/química , Administração Oral , Alcaloides/administração & dosagem , Alcaloides/química , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Animais , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Peso Corporal/efeitos dos fármacos , Criptococose/sangue , Cryptococcus neoformans/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Células Hep G2 , Humanos , Indolizidinas/administração & dosagem , Indolizidinas/sangue , Indolizidinas/química , Camundongos , Resultado do Tratamento
16.
J Nat Prod ; 81(2): 394-399, 2018 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-29389122

RESUMO

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 & inibidores
17.
Org Lett ; 20(4): 991-994, 2018 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-29364678

RESUMO

Fluvirosaones A (1) and B (2), together with virosecurinine (3), were isolated from Flueggea virosa. Their structures were determined by physical, spectroscopic, and X-ray analysis and confirmed through comparison of the calculated and experimental 13C NMR and electronic circular dichroism (ECD) data. Compounds 1 and 2 represent the first examples of a pentacyclic Securinega alkaloid containing a pentacyclic system and an α,ß-unsaturated ketone. Plausible biogenetic pathways of compounds 1 and 2 are proposed.


Assuntos
Euphorbiaceae , Alcaloides , Indolizidinas , Estrutura Molecular , Sementes
18.
Org Biomol Chem ; 15(14): 2953-2961, 2017 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-28291271

RESUMO

A homo-chiral synthesis of (7R,8aS)-octahydro-5,5-dimethylindolizin-7-amine 8 and (7S, 8aS)-octahydro-5,5-dimethylindolizin-7-ol 9, amine building blocks which have found applications within the pharmaceutical industry, is presented. The approach uses a Novozym 435-mediated kinetic resolution of racemic octahydroindolizine (indolizidine) alcohol 13 as a key step (up to 100 g scale).


Assuntos
Álcoois/química , Indolizidinas/química , Indolizidinas/síntese química , Lipase/metabolismo , Biocatálise , Técnicas de Química Sintética , Enzimas Imobilizadas , Proteínas Fúngicas , Cinética , Modelos Moleculares , Conformação Molecular , Estereoisomerismo
19.
Mini Rev Med Chem ; 17(12): 1002-1012, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27151143

RESUMO

BACKGROUND: Plants produce a vast variety of specialized metabolites which can be a rich source for lead compounds for the development of new drugs. Alkaloids are one the largest groups of plant specialized metabolites important for natural product based pharmaceuticals. Of these, lysine (Lys)-derived alkaloids exhibit a wide range of pharmacological properties which are beneficial for humans. For instance they have anticancer, anti-Alzheimer's disease, anti-inflammatory, hypocholesterolemic and antiarrhtymic effects. Lys-derived alkaloids are widely distributed throughout the plant kingdom: they can be found in various species from clubmosses to flowering plants. Lys is one of the most essential amino acids for humans and livestock and is synthesized in the plastids of land plants. Lys-derived alkaloids can be divided into four major groups including quinolizidine, lycopodium, piperidine, and indolizidine alkaloids. Despite the importance of these compounds, the biosynthetic pathways of Lys-derived alkaloids are not well understood. With the exception of indolizidine alkaloids, Lys decarboxylase (LDC) is the enzyme involved in the first committed step of the biosynthesis by catalyzing the transformation of L-Lys into cadaverine. Cadaverine is then oxidized by copper amine oxidase (CuAO) and spontaneously cyclized to Δ1-piperideine Schiff base which is a universal intermediate for the production of various Lys-derived alkaloids. CONCLUSION: In this review, we briefly summarize the recent understanding about the structures, occurrences, analytical procedures, biosyntheses, and potential health effects and medical applications of Lys-derived alkaloids with emphasis on quinolizidine alkaloids (QAs).


Assuntos
Alcaloides/biossíntese , Lisina/química , Quinolizidinas/química , Alcaloides/química , Indolizidinas/química , Lycopodium/química , Lycopodium/metabolismo , Piperidinas/química , Plantas/química , Plantas/metabolismo
20.
Chemistry ; 23(3): 533-536, 2017 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-27805289

RESUMO

A facile and convergent approach has been developed for the stereoselective construction of biologically important polyhydroxylated 2-acyl indolizidine framework using aza-Cope rearrangement-Mannich cyclization as a key step. The generality of this methodology is demonstrated with various lactol-tosylates derived from carbohydrates. The presented method provides an easy access to indolizidine- and tetrahydroindolizine-based iminosugar derivatives in good yields.


Assuntos
Indolizidinas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Aza/química , Carboidratos/química , Cristalografia por Raios X , Ciclização , Indolizidinas/síntese química , Conformação Molecular , Estereoisomerismo
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