RESUMO
OBJECTIVES: The selected kyotorphin derivatives were tested to improve their antimicrobial and antibiofilm activity. The antimicrobial screening of the KTP derivatives were ascertained in the representative strains of bacteria, including Streptococcus pneumoniae, Streptococcus pyogenes, Escherichia coli and Pseudomonas aeruginosa. METHODS: Kyotorphin derivatives, KTP-NH2, KTP-NH2-DL, IbKTP, IbKTP-NH2, MetKTP-DL, MetKTP-LD, were designed and synthesized to improve lipophilicity and resistance to enzymatic degradation. Peptides were synthesized by standard solution or solid-phase peptide synthesis and purified using RP-HPLC, which resulted in >95 % purity, and were fully characterized by mass spectrometry and 1H NMR. The minimum inhibitory concentrations (MIC) determined for bacterial strains were between 20 and 419 µM. The direct effect of IbKTP-NH2 on bacterial cells was imaged using scanning electron microscopy. The absence of toxicity, high survival after infection and an increase in the hemocytes count was evaluated by injections of derivatives in Galleria mellonella larvae. Proteomics analyses of G. mellonella hemolymph were performed to investigate the underlying mechanism of antibacterial activity of IbKTP-NH2 at MIC. RESULTS: IbKTP-NH2 induces morphological changes in bacterial cell, many differentially expressed proteins involved in DNA replication, synthesis of cell wall, and virulence were up-regulated after the treatment of G. mellonella with IbKTP-NH2. CONCLUSION: We suggest that this derivative, in addition to its physical activity on the bacterial membranes, can elicit a cellular and humoral immune response, therefore, it could be considered for biomedical applications.
Assuntos
Anti-Infecciosos , Endorfinas , Mariposas , Animais , Proteômica , Mariposas/microbiologia , Antibacterianos/farmacologia , Larva , PeptídeosRESUMO
Recently, a designed class of efficient analgesic drugs derived from an endogenous neuropeptide, kyotorphin (KTP, Tyr-Arg) combining C-terminal amidation (KTP-NH2) and N-terminal conjugation to ibuprofen (Ib), IbKTP-NH2, was developed. The Ib moiety is an enhancer of KTP-NH2 analgesic action. In the present study, we have tested the hypothesis that KTP-NH2 is an enhancer of the Ib anti-inflammatory action. Moreover, the impact of the IbKTP-NH2 conjugation on microcirculation was also evaluated by a unified approach based on intravital microscopy in the murine cremasteric muscle. Our data show that KTP-NH2 and conjugates do not cause damage on microcirculatory environment and efficiently decrease the number of leukocyte rolling induced by lipopolysaccharide (LPS). Isothermal titration calorimetry showed that the drugs bind to LPS directly thus contributing to LPS aggregation and subsequent elimination. In a parallel study, molecular dynamics simulations and NMR data showed that the IbKTP-NH2 tandem adopts a preferential "stretched" conformation in lipid bilayers and micelles, with the simulations indicating that the Ib moiety is anchored in the hydrophobic core, which explains the improved partition of IbKTP-NH2 to membranes and the permeability of lipid bilayers to this conjugate relative to KTP-NH2. The ability to bind glycolipids concomitant to the anchoring in the lipid membranes through the Ib residue explains the analgesic potency of IbKTP-NH2 given the enriched glycocalyx of the blood-brain barrier cells. Accumulation of IbKTP-NH2 in the membrane favors both direct permeation and local interaction with putative receptors as the location of the KTP-NH2 residue of IbKTP-NH2 and free KTP-NH2 in lipid membranes is the same.
Assuntos
Analgésicos/química , Anti-Inflamatórios/química , Endorfinas/metabolismo , Bicamadas Lipídicas/metabolismo , Analgésicos/metabolismo , Animais , Anti-Inflamatórios/metabolismo , Endorfinas/química , Feminino , Bicamadas Lipídicas/química , Lipopolissacarídeos/química , Lipopolissacarídeos/metabolismo , Masculino , Camundongos , Simulação de Dinâmica Molecular , Estrutura MolecularRESUMO
Amidated kyotorphin (L-Tyr-L-Arg-NH2; KTP-NH2) causes analgesia when systemically administered. The lipophilic ibuprofen-conjugated derivative of KTP-NH2 has improved analgesic efficacy. However, fast degradation by peptidases impacts negatively in the pharmacodynamics of these drugs. In this work, selected derivatives of KTP and KTP-NH2 were synthesized to combine lipophilicity and resistance to enzymatic degradation. Eight novel structural modifications were tested for the potential to transverse lipid membranes and to evaluate their efficacy in vivo. The rationale behind the design of the pool of the eight selected molecules consisted in the addition of individual group at the N-terminus, namely the tert-butyloxycarbonyl (Boc), γ-aminobutyric acid (GABA), acetyl, butanoyl, and propanoyl or in the substitution of the tyrosine residue by an indole moiety and in the replacement of the peptidic bond by a urea-like bond in some cases. All the drugs used in the study are intrinsically fluorescent, which enables the use of spectrofluorimetry to sample the drugs in the permeation assays. The results show that the BOC and indolyl derivatives of KTP-NH2 have maximal ability to permeate membranes with concomitant maximal analgesic power. Overall, the results demonstrate that membrane permeation is correlated with analgesic efficacy. However, this is not the only factor accounting for analgesia. KTP-NH2 for instance has low passive permeation but is known to have central action. In this case, hypothetical transcytosis over the blood-brain barrier seems to depend on dipeptide transporters.
Assuntos
Analgésicos/química , Analgésicos/metabolismo , Endorfinas/química , Endorfinas/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Humanos , Ácido gama-Aminobutírico/químicaRESUMO
The p-benzyloxybenzyloxy group is used to mask the oxo function of the 4(3H)-pyrimidinone ring in the synthesis of new unnatural amino acids. The synthetic approach is based on an aromatic nucleophilic substitution reaction between 4-[4-(benzyloxy)benzyloxy]-2-(benzylsulfonyl)pyrimidine and the nucleophilic side chain of several N(α)-Boc amino esters, as the key step, followed by a series of standard protecting group transformations. p-Benzyloxybenzyloxy is efficiently removed under mild acid conditions to recover the 4(3H)-pyrimidinone system.
Assuntos
Aminoácidos/síntese química , Derivados de Benzeno/química , Materiais Biomiméticos/síntese química , Pirimidinonas/química , Ésteres , EstereoisomerismoRESUMO
The adverse side-effects associated with opioid administration restrain their use as analgesic drugs and call for new solutions to treat pain. Two kyotorphin derivatives, kyotorphin-amide (KTP-NH2) and ibuprofen-KTP-NH2 (IbKTP-NH2) are promising alternatives to opioids: they trigger analgesia via an indirect opioid mechanism and are highly effective in several pain models following systemic delivery. In vivo side-effects of KTP-NH2 and IbKTP-NH2 are, however, unknown and were evaluated in the present study using male adult Wistar rats. For comparison purposes, morphine and tramadol, two clinically relevant opioids, were also studied. Results showed that KTP-derivatives do not cause constipation after systemic administration, in contrast to morphine. Also, no alterations were observed in blood pressure or in food and water intake, which were only affected by tramadol. A reduction in micturition was detected after KTP-NH2 or tramadol administrations. A moderate locomotion decline was detected after IbKTP-NH2-treatment. The side-effect profile of KTP-NH2 and IbKTP-NH2 support the existence of opioid-based mechanisms in their analgesic actions. The conjugation of a strong analgesic activity with the absence of the major side-effects associated to opioids highlights the potential of both KTP-NH2 and IbKTP-NH2 as advantageous alternatives over current opioids.
Assuntos
Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/uso terapêutico , Endorfinas/efeitos adversos , Endorfinas/uso terapêutico , Ibuprofeno/efeitos adversos , Analgésicos Opioides/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Constipação Intestinal/induzido quimicamente , Endorfinas/farmacologia , Ibuprofeno/farmacologia , Ibuprofeno/uso terapêutico , Locomoção/efeitos dos fármacos , Masculino , Morfina/efeitos adversos , Morfina/farmacologia , Morfina/uso terapêutico , Dor/tratamento farmacológico , Ratos , Ratos Wistar , Tramadol/efeitos adversos , Tramadol/farmacologiaRESUMO
Antimicrobial peptides (AMPs) are promising candidates as alternatives to conventional antibiotics for the treatment of resistant pathogens. In the last decades, new AMPs have been found from the cleavage of intact proteins with no antibacterial activity themselves. Bovine hemoglobin hydrolysis, for instance, results in AMPs and the minimal antimicrobial peptide sequence was defined as Tyr-Arg plus a positively charged amino acid residue. The Tyr-Arg dipeptide alone, known as kyotorphin (KTP), is an endogenous analgesic neuropeptide but has no antimicrobial activity itself. In previous studies new KTP derivatives combining C-terminal amidation and Ibuprofen (Ib) - KTP-NH(2), IbKTP, IbKTP-NH(2) - were designed in order to improve KTP brain targeting. Those modifications succeeded in enhancing peptide-cell membrane affinity towards fluid anionic lipids and higher analgesic activity after systemic injection resulted therefrom. Here, we investigated if this affinity for anionic lipid membranes also translates into antimicrobial activity because bacteria have anionic membranes. Atomic force microscopy revealed that KTP derivatives perturbed Staphylococcus aureus membrane structure by inducing membrane blebbing, disruption and lysis. In addition, these peptides bind to red blood cells but are non-hemolytic. From the KTP derivatives tested, amidated KTP proves to be the most active antibacterial agent. The combination of analgesia and antibacterial activities with absence of toxicity is highly appealing from the clinical point of view and broadens the therapeutic potential and application of kyotorphin peptides.
Assuntos
Analgésicos/farmacologia , Anti-Infecciosos/farmacologia , Endorfinas/farmacologia , Escherichia coli/efeitos dos fármacos , Ibuprofeno/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Analgésicos/química , Anti-Infecciosos/química , Células Cultivadas , Endorfinas/química , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/ultraestrutura , Eritrócitos/efeitos dos fármacos , Eritrócitos/ultraestrutura , Humanos , Ibuprofeno/química , Microscopia de Força AtômicaRESUMO
The pharmaceutical potential of natural analgesic peptides is mainly hampered by their inability to cross the blood-brain barrier, BBB. Increasing peptide-cell membrane affinity through drug design is a promising strategy to overcome this limitation. To address this challenge, we grafted ibuprofen (IBP), a nonsteroidal anti-inflammatory drug, to kyotorphin (l-Tyr-l-Arg, KTP), an analgesic neuropeptide unable to cross BBB. Two new KTP derivatives, IBP-KTP (IbKTP-OH) and IBP-KTP-amide (IbKTP-NH(2)), were synthesized and characterized for membrane interaction, analgesic activity and mechanism of action. Ibuprofen enhanced peptide-membrane interaction, endowing a specificity for anionic fluid bilayers. A direct correlation between anionic lipid affinity and analgesic effect was established, IbKTP-NH(2) being the most potent analgesic (from 25 µmol · kg(-1)). In vitro, IbKTP-NH(2) caused the biggest shift in the membrane surface charge of BBB endothelial cells, as quantified using zeta-potential dynamic light scattering. Our results suggest that IbKTP-NH(2) crosses the BBB and acts by activating both opioid dependent and independent pathways.
Assuntos
Analgésicos/química , Anti-Inflamatórios não Esteroides/química , Barreira Hematoencefálica/metabolismo , Endorfinas/química , Ibuprofeno/análogos & derivados , Analgésicos/metabolismo , Analgésicos/uso terapêutico , Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/metabolismo , Analgésicos não Narcóticos/uso terapêutico , Analgésicos Opioides/antagonistas & inibidores , Analgésicos Opioides/química , Analgésicos Opioides/metabolismo , Analgésicos Opioides/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Bovinos , Membrana Celular/química , Membrana Celular/metabolismo , Células Cultivadas , Reagentes de Ligações Cruzadas/química , Desenho de Fármacos , Endorfinas/metabolismo , Endorfinas/uso terapêutico , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ibuprofeno/química , Ibuprofeno/metabolismo , Ibuprofeno/uso terapêutico , Bicamadas Lipídicas/química , Bicamadas Lipídicas/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos WistarRESUMO
Coupling reaction between electron-rich 2-morpholino-4(3H)-pyrimidinone and nucleophilic side chains of several natural α-amino acids promoted by phosphonium salt has been developed to prepare new optically active pyrimidin-4-yl amino acids. The best results were obtained using a two-step method through the easily available benzotriazolyl-1-oxy intermediate. A detailed optimization study of this reaction is discussed.
Assuntos
Aminoácidos/química , Morfolinos/química , Organofosfonatos/química , Pirimidinas/química , Pirimidinonas/química , Aminoácidos/síntese química , Pirimidinas/síntese química , Sais/químicaRESUMO
A highly straightforward strategy for the synthesis of the acremolide class of lipodepsipeptides has been developed. Synthetic highlights include a cross-metathesis to couple the C1-C7 and the C8-C12 fragments, an esterification to introduce the dipeptide unit, a macrolactamization to build the macrolide core, and two stereoselective allylations/crotylations to control all four stereogenic centers of the C1-C12 polypropionate segment.
Assuntos
Depsipeptídeos/síntese química , Lipopeptídeos/química , Lipopeptídeos/síntese química , Oligopeptídeos/química , Propionatos/química , Depsipeptídeos/química , Esterificação , Macrolídeos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , EstereoisomerismoRESUMO
Kyotorphin (KTP, l-tyrosyl-l-arginine) is an endogenous analgesic neuropeptide first isolated from bovine brain in 1979. Previous studies have shown that kyotorphins possess anti-inflammatory and antimicrobial activity. Six kyotorphins-KTP-NH2, KTP-NH2-DL, ibuprofen-conjugated KTP (IbKTP), IbKTP-NH2, N-methyl-D-Tyr-L-Arg, and N-methyl-L-Tyr-D-Arg-were designed and synthesized to improve lipophilicity and resistance to enzymatic degradation. This study assessed the antimicrobial and antibiofilm activity of these peptides. The antifungal activity of kyotorphins was determined in representative strains of Candida species, including Candida albicans ATCC 10231, Candida krusei ATCC 6258, and six clinical isolates-Candida dubliniensis 19-S, Candida glabrata 217-S, Candida lusitaniae 14-S, Candida novergensis 51-S, Candida parapsilosis 63, and Candida tropicalis 140-S-obtained from the oral cavity of HIV-positive patients. The peptides were synthesized by standard solution or solid-phase synthesis, purified by RP-HPLC (purity >95 %), and characterized by nuclear magnetic resonance. The results of the broth microdilution assay and scanning electron microscopy showed that IbKTP-NH2 presented significant antifungal activity against Candida strains and antibiofilm activity against the clinical isolates. The absence of toxic activity and survival after infection was assessed after injecting the peptide in larvae of Galleria mellonella as experimental infection model. Furthermore, IbKTP-NH2 had strong antimicrobial activity against multidrug-resistant bacteria and fungi and was not toxic to G. mellonella larvae up to a concentration of 500 mM. These results suggest that IbKTP-NH2, in addition to its known effect on cell membranes, can elicit a cellular immune response and, therefore, is promising for biomedical application.
Assuntos
Antifúngicos , Biofilmes , Candida , Endorfinas , Animais , Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Resistência a Medicamentos/efeitos dos fármacos , Endorfinas/química , Endorfinas/farmacologia , Larva/microbiologia , Testes de Sensibilidade Microbiana , Mariposas/microbiologiaRESUMO
Kyotorphin (KTP, l-tyrosyl-l-arginine) is an endogenous dipeptide initially described to have analgesic properties. Recently, KTP was suggested to be an endogenous neuroprotective agent, namely for Alzheimer's disease (AD). In fact, KTP levels were shown to be decreased in the cerebrospinal fluid of patients with AD, and recent data showed that intracerebroventricular (i.c.v.) injection of KTP ameliorates memory impairments in a sporadic rat model of AD. However, this administration route is far from being a suitable therapeutic strategy. Here, we evaluated if the blood-brain permeant KTP-derivative, KTP-NH2, when systemically administered, would be effective in preventing memory deficits in a sporadic AD animal model and if so, which would be the synaptic correlates of that action. The sporadic AD model was induced in male Wistar rats through i.c.v. injection of amyloid ß peptide (Aß). Animals were treated for 20 days with KTP-NH2 (32.3 mg/kg, intraperitoneally (i.p.), starting at day 3 after Aß administration) before memory testing (Novel object recognition (NOR) and Y-maze (YM) tests). Animals were then sacrificed, and markers for gliosis were assessed by immunohistochemistry and Western blot analysis. Synaptic correlates were assessed by evaluating theta-burst induced long term potentiation (LTP) of field excitatory synaptic potentials (fEPSPs) recorded from hippocampal slices and cortical spine density analysis. In the absence of KTP-NH2 treatment, Aß-injected rats had clear memory deficits, as assessed through NOR or YM tests. Importantly, these memory deficits were absent in Aß-injected rats that had been treated with KTP-NH2, which scored in memory tests as control (sham i.c.v. injected) rats. No signs of gliosis could be detected at the end of the treatment in any group of animals. LTP magnitude was significantly impaired in hippocampal slices that had been incubated with Aß oligomers (200 nM) in the absence of KTP-NH2. Co-incubation with KTP-NH2 (50 nM) rescued LTP toward control values. Similarly, Aß caused a significant decrease in spine density in cortical neuronal cultures, and this was prevented by co-incubation with KTP-NH2 (50 nM). In conclusion, the present data demonstrate that i.p. KTP-NH2 treatment counteracts Aß-induced memory impairments in an AD sporadic model, possibly through the rescuing of synaptic plasticity mechanisms.
RESUMO
Neuropeptide kyotorphin (KTP) is a potent analgesic if administered directly into the brain. In contrast, KTP-amide (KTP-NH2) is analgesic, neuroprotective, and anti-inflammatory following systemic administration, albeit its mechanism of action is unknown. The aim of this study was to shed light on the mechanism of action of KTP-NH2 at the molecular level. KTP-NH2 does not inhibit the enkephalinases angiotensin-converting-enzyme and dipeptidyl-peptidase 3. Intravital microscopy showed that KTP-NH2 decreased the number of rolling leukocytes in a mouse model of inflammation induced by lipopolysaccharide (LPS). Pretreatment with metyrapone abrogated the action of KTP-NH2. Interestingly, stimulating rolling leukocytes using CXCL-1 is also counteracted by the KTP-NH2, but this effect is not abrogated by metyrapone. We conclude that KTP-NH2 has dual action: a glucocorticoid-mediated action, which is dominant in the full-fledged LPS-induced inflammation model, and a glucocorticoid-independent mechanism, which is predominant in models in which leukocyte rolling is stimulated but inflammation is not totally developed.
Assuntos
Dipeptídeos/metabolismo , Endorfinas/metabolismo , Glucocorticoides/metabolismo , Inflamação/metabolismo , Animais , Quimiocina CXCL1 , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Modelos Animais de Doenças , Leucócitos/imunologia , Lipopolissacarídeos , Masculino , Camundongos , Neuroproteção/fisiologia , Nociceptividade/fisiologia , Peptidil Dipeptidase A/metabolismoRESUMO
Understanding the interplay between molecules and lipid membranes is fundamental when studying cellular and biotechnological phenomena. Partition between aqueous media and lipid membranes is key to the mechanism of action of many biomolecules and drugs. Quantifying membrane partition, through adequate and robust parameters, is thus essential. Surface Plasmon Resonance (SPR) is a powerful technique for studying 1:1 stoichiometric interactions but has limited application to lipid membrane partition data. We have developed and applied a novel mathematical model for SPR data treatment that enables determination of kinetic and equilibrium partition constants. The method uses two complementary fitting models for association and dissociation sensorgram data. The SPR partition data obtained for the antibody fragment F63, the HIV fusion inhibitor enfuvirtide, and the endogenous drug kyotorphin towards POPC membranes were compared against data from independent techniques. The comprehensive kinetic and partition models were applied to the membrane interaction data of HRC4, a measles virus entry inhibitor peptide, revealing its increased affinity for, and retention in, cholesterol-rich membranes. Overall, our work extends the application of SPR beyond the realm of 1:1 stoichiometric ligand-receptor binding into a new and immense field of applications: the interaction of solutes such as biomolecules and drugs with lipids.
Assuntos
Bicamadas Lipídicas/química , Lipídeos de Membrana/química , Ressonância de Plasmônio de Superfície , Endorfinas/química , Enfuvirtida , Proteína gp41 do Envelope de HIV/química , Cinética , Modelos Biológicos , Fragmentos de Peptídeos/química , Propriedades de SuperfícieRESUMO
Kyotorphin (KTP) is an endogenous peptide with analgesic properties when administered into the central nervous system (CNS). Its amidated form (l-Tyr-l-Arg-NH2; KTP-NH2) has improved analgesic efficacy after systemic administration, suggesting blood-brain barrier (BBB) crossing. KTP-NH2 also has anti-inflammatory action impacting on microcirculation. In this work, selected derivatives of KTP-NH2 were synthesized to improve lipophilicity and resistance to enzymatic degradation while introducing only minor changes in the chemical structure: N-terminal methylation and/or use of d amino acid residues. Intravital microscopy data show that KTP-NH2 having a d-Tyr residue, KTP-NH2-DL, efficiently decreases the number of leukocyte rolling in a murine model of inflammation induced by bacterial lipopolysaccharide (LPS): down to 46% after 30 min with 96 µM KTP-NH2-DL. The same molecule has lower ability to permeate membranes (relative permeability of 0.38) and no significant activity in a behavioral test which evaluates thermal nociception (hot-plate test). On the contrary, methylated isomers at 96 µM increase leukocyte rolling up to nearly 5-fold after 30 min, suggesting a proinflammatory activity. They have maximal ability to permeate membranes (relative permeability of 0.8) and induce long-lasting antinociception.
Assuntos
Analgésicos/farmacologia , Dipeptidases/farmacologia , Endorfinas/química , Endotélio/efeitos dos fármacos , Microcirculação/efeitos dos fármacos , Animais , Anti-Inflamatórios , Barreira Hematoencefálica , Dipeptidases/síntese química , Dipeptidases/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Endorfinas/farmacologia , Hiperalgesia/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Ratos , Fatores de TempoRESUMO
Chronic brain ischemia is a prominent risk factor for neurological dysfunction and progression for dementias, including Alzheimer's disease (AD). In rats, permanent bilateral common carotid artery occlusion (2VO) causes a progressive neurodegeneration in the hippocampus, learning deficits and memory loss as it occurs in AD. Kyotorphin (KTP) is an endogenous antinociceptive dipeptide whose role as neuromodulator/neuroprotector has been suggested. Recently, we designed two analgesic KTP-derivatives, KTP-amide (KTP-NH2) and KTP-NH2 linked to ibuprofen (IbKTP-NH2) to improve KTP brain targeting. This study investigated the effects of KTP-derivatives on cognitive/behavioral functions (motor/spatial memory/nociception) and hippocampal pathology of female rats in chronic cerebral hypoperfusion (2VO-rat model). 2VO-animals were treated with KTP-NH2 or IbKTP-NH2 for 7 days at weeks 2 and 5 post-surgery. After behavioral testing (week 6), coronal sections of hippocampus were H&E-stained or immunolabeled for the cellular markers GFAP (astrocytes) and NFL (neurons). Our findings show that KTP-derivatives, mainly IbKTP-NH2, enhanced cognitive impairment of 2VO-animals and prevented neuronal damage in hippocampal CA1 subfield, suggesting their potential usefulness for the treatment of dementia.
RESUMO
Lyngbouilloside and the related macrolides lyngbyaloside, lyngbyaloside B and lyngbyaloside C have attracted a lot of attention over the past decade due to their intriguing architecture, their natural scarcity and their potential biological activities. This review aims to showcase the various strategies that have been used to access these natural products.
Assuntos
Cianobactérias/metabolismo , Macrolídeos/síntese química , Espectroscopia de Ressonância MagnéticaRESUMO
The first enantioselective total synthesis of the originally assigned structure of lyngbouilloside aglycon has been achieved using a particularly flexible route featuring an acylketene macrolactonization of a tertiary methyl carbinol as the key step. Comparison of the C13 chemical shifts of our synthetic aglycon with the ones pertaining to natural lyngbouilloside and lyngbyaloside C resulted in a possible stereochemical reassignment of the C11 stereogenic center.
Assuntos
Lactonas/síntese química , Macrolídeos/síntese química , Estrutura Molecular , EstereoisomerismoRESUMO
The enantioselective total synthesis of the dual-specificity phosphatase inhibitor (-)-bitungolide F has been achieved using two convergent routes. Both strategies feature an asymmetric boron-mediated pentenylation, a stereoselective aldol, and a hydroxyl-directed 1,3-anti-reduction in order to control the stereogenic centers at C4, C5, C9, and C11. Whereas the first total synthesis was achieved in 11 steps and 14.6% overall yield using an Evans-type asymmetric alkylation, the second was completed in 9 steps and 11.4% overall yield using a highly enantioselective organocatalytic Michael addition as a key step and a protecting group free strategy.
Assuntos
Alcenos/síntese química , Pironas/síntese química , Alquilação , Estrutura Molecular , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , EstereoisomerismoRESUMO
A simple and straightforward methodology toward the synthesis of novel 2,6-disubstituted-4-alkoxypyrimidine derivatives of type 16 and 19 has been developed. This methodology, initially developed in solution, can be perfectly adapted to the solid support under analogous conditions, taking full advantage of automated parallel synthesis systems. This successful methodology benefits from the key role played by the thioether linkage placed at the 2-position in 3, 9, or 13 in a double manner: on one side, the steric effect exerted by the thioether linkage is likely to be responsible for the very high observed selectivity toward the formation of the O-alkylation products. On the other side, this sulfur linkage can serve not only as a robust point of attachment for the heterocycle, stable to a number of reaction conditions, but also as a means of introducing a new element of diversity through activation to the corresponding sulfone (safety-catch linker concept) and subsequent ipso-substitution reaction with a variety of different N-nucleophiles.