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1.
Chem Rec ; 20(2): 120-141, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31250972

RESUMO

Fluorine-containing organic scaffolds are of significant interest in medicinal chemistry. The incorporation of fluorine into biomolecules can lead to remarkable changes in their physical, chemical, and biological properties. There are already many drugs on the market, which contain at least one fluorine atom. Saturated functionalized azaheterocycles as bioactive substances have gained increasing attention in pharmaceutical chemistry. Due to the high biorelevance of organofluorine molecules and the importance of N-heterocyclic compounds, selective stereocontrolled procedures to the access of new fluorine-containing saturated N-heterocycles are considered to be a hot research topic. This account summarizes the synthesis of functionalized and fluorine-containing saturated azaheterocycles starting from functionalized cycloalkenes and based on oxidative ring cleavage of diol intermediates followed by ring expansion with reductive amination.


Assuntos
Compostos Aza/química , Compostos Heterocíclicos/química , Aldeídos/química , Azepinas/síntese química , Azepinas/química , Ciclização , Flúor/química , Compostos Heterocíclicos/síntese química , Oxirredução , Estereoisomerismo
2.
Eur J Med Chem ; 183: 111726, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31585275

RESUMO

Multidrug resistance (MDR) is a main cause of chemotherapy failure and patient death. This situation usually involves a glycoprotein (P-gp) mediated drug efflux, resulting in a low cellular drug concentration and insensitivity. Here we report the design, synthesis and evaluation of novel (+/-)-securinine bivalents as P-gp inhibitors in vitro and in vivo. MTT assays reflected that bivalent mimetics of securinine particularly the virosecurinine bivalent mimetic 8C showed promissing MDR reversal potential in both P-gp highly expressed cell line HepG2/DOX and MCF-7/ADM. At a 10 µM concentration, 8C can entirely reverse the resistance of HepG2/DOX to doxorubicin (DOX), and is more effective than the positive control verapamil (VRP). Fluorescence, flow cytometry, and DOX efflux assays demonstrated that 8C can facilitate the accumulation and diminish the efflux of intracellular DOX. Molecular docking analysis and western blot assays indicated that 8C accomplished this by competitively inhibiting the activity of P-gp rather than by affecting its expression. Compound 8C was also observed to reverse drug resistance effectively in xenograft models when combined with DOX. This study lays a foundation for the discovery of (+/-)-securinine ramifications as P-gp inhibitors and provides a promising lead compound 8C as a P-gp mediated MDR reversal agent.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Alcaloides , Antineoplásicos , Azepinas , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Lactonas , Piperidinas , Alcaloides/química , Alcaloides/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Azepinas/química , Azepinas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Compostos Heterocíclicos de Anel em Ponte/química , Compostos Heterocíclicos de Anel em Ponte/farmacologia , Humanos , Lactonas/química , Lactonas/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Piperidinas/química , Piperidinas/farmacologia , Verapamil/farmacologia
3.
Molecules ; 24(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540496

RESUMO

Crohn's disease (CD) and ulcerative colitis (UC), collectively referred to as inflammatory bowel disease (IBD), are autoimmune diseases characterized by chronic inflammation within the gastrointestinal tract. Debromohymenialdisine is an active pyrrole alkaloid that is well known to serve as a stable and effective inhibitor of Chk2. In the present study, we attempted to investigate the anti-inflammatory properties of (10Z)-debromohymenialdisine (1) isolated from marine sponge Stylissa species using an intestinal in vitro model with a transwell co-culture system. The treatment with 1 attenuated the production and gene expression of lipopolysaccharide (LPS)-induced Interleukin (IL)-6, IL-1ß, prostaglandin E2 (PGE2), and tumor necrosis factor-α in co-cultured THP-1 macrophages at a concentration range of 1-5 µM. The protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 were down-regulated in response to the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) translocation into the nucleus in cells. In addition, we observed that 1 markedly promoted the nuclear translocation of nuclear factor erythroid 2 related factor 2 (Nrf2) and subsequent increase of heme oxygenase-1 (HO-1) expression. These findings suggest the potential use of 1 as a pharmaceutical lead in the treatment of inflammation-related diseases including IBD.


Assuntos
Organismos Aquáticos/química , Azepinas/farmacologia , Colite Ulcerativa , Doença de Crohn , Intestinos/patologia , Poríferos/química , Pirróis/farmacologia , Animais , Azepinas/química , Células CACO-2 , Técnicas de Cocultura , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Dinoprostona/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Pirróis/química , Células THP-1
4.
Chem Commun (Camb) ; 55(82): 12348-12351, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31559401

RESUMO

A multimeric MRI contrast agent based on the closo-borane motif is reported. Twelve copies of a modified AAZTA chelate with an alkyne end group are appended on an azide-functionalized closo-borane motif using Cu(i) catalyzed click chemistry. The presence of two water molecules on the Gd-bound AAZTA chelate results in high relaxivity for the closomer in vitro/in vivo.


Assuntos
Acetatos/química , Azepinas/química , Boranos/química , Quelantes/química , Meios de Contraste/química , Complexos de Coordenação/química , Imagem por Ressonância Magnética , Acetatos/síntese química , Azepinas/síntese química , Boranos/síntese química , Quelantes/síntese química , Meios de Contraste/síntese química , Complexos de Coordenação/síntese química , Estrutura Molecular
5.
Eur J Med Chem ; 182: 111633, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31461688

RESUMO

Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1 at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.


Assuntos
Azepinas/química , Descoberta de Drogas , Proteínas/antagonistas & inibidores , Pirazóis/química , Animais , Azepinas/síntese química , Azepinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Domínios Proteicos , Proteínas/metabolismo , Pirazóis/síntese química , Pirazóis/farmacologia , Relação Estrutura-Atividade
6.
Chem Pharm Bull (Tokyo) ; 67(7): 620-631, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257316

RESUMO

Natural products are still rich sources of clinically used medicines and lead compounds for them. This review summarizes chemical studies carried out by the author on natural products of microorganism origin, many of which were discovered at the Institute of Microbial Chemistry (BIKAKEN). Caprazamycin B is a liponucleoside antibiotic from which CPZEN-45, an antituberculosis agent with a unique mode of action, was developed. Intervenolin and leucinostatin A exert antiproliferative activity toward tumor cells in the presence of the corresponding stromal cells, which implies that the primary molecular targets of these molecules should be related to growth signals from normal (stromal) cells. Details of the endeavors to establish efficient synthetic routes to these compounds which accelerated structure-activity relationship studies and further evaluation of biological activity are described.


Assuntos
Anti-Infecciosos/química , Antineoplásicos/química , Produtos Biológicos/química , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Peptídeos Catiônicos Antimicrobianos , Antineoplásicos/farmacologia , Azepinas/química , Azepinas/farmacologia , Produtos Biológicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Peptídeos/química , Peptídeos/farmacologia , Relação Estrutura-Atividade
7.
Org Biomol Chem ; 17(24): 5951-5961, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31166343

RESUMO

The syntheses of conduramine B-2, ent-conduramine F-2, aminocyclopentitol and trihydroxyazepane were accomplished from a common precursor, through a divergent approach using ring closing metathesis (RCM) as the key step. Tri-O-benzyl-d-glucal was converted to 3,4,6-tri-O-benzyl-1,2-dideoxy-2-iodo-1-p-toluenesulfonamido-α-d-mannose. Exposure to NaBH4 in MeOH resulted in a facile 1,2-transposition of the -NHTs group with concomitant glycosylation to give methyl 3,4,6-tri-O-benzyl-2-deoxy-2-p-toluenesulfonamido-ß-d-glucoside, which was converted into methyl 6-deoxy-6-iodo-glucoside in three steps. Zinc-mediated Vasella's rearrangement proceeded smoothly to give the pluripotent formyl-olefin, possessing both electrophilic and nucleophilic sites, which was used as a common precursor in our diversity-oriented approach. Vinylation of the carbonyl group followed by RCM and subsequent deprotection resulted in the successful synthesis of conduramine B-2 and ent-conduramine F-2 for the first time. On the other hand, the Wittig reaction of the formyl-olefin affords the diene that undergoes Grubbs' I catalyzed RCM and deprotection/reduction to provide 3-amino-cyclopentan-1,2-diol. Utilizing the nucleophilic site at the nitrogen of the common precursor, base mediated N-allylation was carried out to obtain the corresponding diene that underwent a smooth RCM to afford trihydroxyazepane.


Assuntos
Azepinas/síntese química , Cicloexanóis/síntese química , Cicloexilaminas/síntese química , Ciclopentanos/síntese química , Azepinas/química , Cicloexanóis/química , Cicloexilaminas/química , Ciclopentanos/química , Glicosilação , Estrutura Molecular
8.
Eur J Med Chem ; 177: 414-424, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158754

RESUMO

Due to the role of butyrylcholinesterase (BChE) in acetylcholine hydrolysis in the late stages of the Alzheimer's disease (AD), inhibitors of butyrylcholinesterase (BChE) have been recently envisaged, besides acetylcholinesterase (AChE) inhibitors, as candidates for treating mild-to-moderate AD. Herein, synthesis and AChE/BChE inhibition activity of some twenty derivatives of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (HHAI) is reported. Most of the newly synthesized HHAI derivatives achieved the inhibition of both ChE isoforms with IC50s in the micromolar range, with a structure-dependent selectivity toward BChE. Apparently, molecular volume and lipophilicity do increase selectivity toward BChE, and indeed the N2-(4-phenylbutyl) HHAI derivative 15d, which behaves as a mixed-type inhibitor, resulted the most potent (IC50 0.17 µM) and selective (>100-fold) inhibitor toward either horse serum and human BChE. Moreover, 15d inhibited in vitro self-induced aggregation of neurotoxic amyloid-ß (Aß) peptide and displayed neuroprotective effects in neuroblastoma SH-SY5Y cell line, significantly recovering (P < 0.001) cell viability when impaired by Aß1-42 and hydrogen peroxide insults. Overall, this study highlighted HHAI as useful and versatile scaffold for developing new small molecules targeting some enzymes and biochemical pathways involved in the pathogenesis of AD.


Assuntos
Azepinas/farmacologia , Inibidores da Colinesterase/farmacologia , Indóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Peptídeos beta-Amiloides/metabolismo , Azepinas/síntese química , Azepinas/química , Azepinas/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Relação Dose-Resposta a Droga , Desenho de Drogas , Depuradores de Radicais Livres/síntese química , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/metabolismo , Depuradores de Radicais Livres/farmacologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fragmentos de Peptídeos/metabolismo , Ligação Proteica/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
9.
Comput Biol Chem ; 80: 433-440, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31146119

RESUMO

High production cost, instability, low tumor penetration are some of the shortcomings that have characterized and undermined the use of antibodies as a target for Cytotoxic T-lymphocytes associated protein 4 (CTLA-4). Design and discovery of small molecule inhibitors have therefore become a sine qua non in targeting immune proteins implicated in immune disorders. In this study, we utilized a drug repositioning approach to explore the characteristic feature of unrelated proteins to have similar binding sites and the promiscuity of drugs to repurpose an existing drug to target CTLA-4. CTLA-4 and Kallikrein-7 were found to have similar binding sites, we therefore used 1, 3, 6-trisubstituted 1, 4-diazepane-7-ones (TDSO) which is an inhibitor of Kallikrein-7 as our lead compound. High throughput screening using TDSO as a lead compound resulted in 9 hits with ZINC04515726 and ZINC08985213 having the highest binding score. We went ahead to investigate the interaction of these compounds with CTLA-4 by conducting a molecular dynamic simulation. Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) estimations revealed that TDSO had the highest binding energy value of -28.51Kcal/mol, with ZINC04515726 and ZINC08985213 having -23.76Kcal/mol and -21.03Kcal/mol respectively. The per-residue decomposition highlighted Tyr24, Ala25, Gly28, Ala30, Tyr53 and Asn72 as having significantly high electrostatic energy contributions and the main contributing residues to the binding of TDSO, ZINC04515726 and ZINC08985213 to Cytotoxic T lymphocytes CTLA-4. Summarily, from the results gathered, we proposed that TDSO can be an effective immune check point small molecule inhibitor against the suppression of T-cell activation, proliferation, and tumor cell eradication.


Assuntos
Azepinas/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/metabolismo , Reposicionamento de Medicamentos , Polifarmacologia , Sequência de Aminoácidos , Azepinas/química , Azepinas/farmacocinética , Sítios de Ligação , Antígeno CTLA-4/química , Ensaios de Triagem em Larga Escala , Humanos , Calicreínas/química , Simulação de Dinâmica Molecular , Ligação Proteica
10.
Int J Med Microbiol ; 309(5): 319-324, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31138496

RESUMO

Cell wall biosynthesis represents a valid target for antibacterial action but only a limited number of chemical structure classes selectively interact with specific enzymes or protein structures like transporters of the cell envelope. The integral membrane protein MraY translocase is essential for peptidoglycan biosynthesis catalysing the transfer of the peptidoglycan precursor phospho-MurNAc-pentapeptide to the lipid carrier undecaprenyl phosphate, thereby generating the cell wall intermediate lipid I. Not present in eukaryotic cells, MraY is a member of the superfamily of yet not well-understood integral membrane enzymes which involve proteins for bacterial lipopolysaccharide and teichoic acid or eukaryotic N-linked saccharides biosynthesis. Different natural nucleoside antibiotics as inhibitors of MraY translocase have been discovered comprising a glycosylated heterocyclic pyrimidin base among other potential lipid-, peptidic- or sugar moieties. Caprazamycins are liponucleoside antibiotics isolated from Streptomyces sp. MK730-62F2. They possess activity in vitro against Gram-positive bacteria, in particular against the genus Mycobacterium including M. intracellulare, M. avium and M. tuberculosis. Structural elucidation revealed the (+)-caprazol core skeleton as a unique moiety, the caprazamycins share with other MraY inhibitors such as the liposidomycins, A-90289 and the muraminomicins. They also share structural features such as uridyl-, aminoribosyl- and fatty acyl-moieties with other MraY translocase inhibitors like FR-900493 and the muraymycins. Intensive studies on their biosynthesis during the last decade identified not only common initial biosynthetic steps, but also revealed possible branching points towards individual biosynthesis of the respective compound. Structural diversity of caprazamycins was generated by feeding experiments, genetic engineering of the biosynthetic gene clusters and chemical synthesis for structure activity relationship studies with its target, MraY translocase.


Assuntos
Antibacterianos/química , Azepinas/química , Proteínas de Bactérias/antagonistas & inibidores , Nucleosídeos/química , Streptomyces/química , Transferases/antagonistas & inibidores , Antibacterianos/farmacologia , Vias Biossintéticas , Estrutura Molecular , Família Multigênica , Mycobacterium/efeitos dos fármacos , Relação Estrutura-Atividade
11.
Biochem Pharmacol ; 164: 237-251, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30991051

RESUMO

The persistence of latent human immunodeficiency virus type 1 (HIV-1) reservoirs remains a major hurdle for HIV-1 eradication. The "shock and kill" strategy relies on the drug-mediated reversion of HIV-1 latency and the subsequent death of HIV-producing cells. Unfortunately, none of the agents currently in use possess a sufficient potency to reactivate latent virus or eliminate the latent HIV-1 reservoir in vivo. Here, we demonstrated that a promising specific bromodomain and extraterminal domain inhibitor, CPI-203, could potently reactivate latent HIV-1 in different latently infected cell lines with minimal cytotoxicity by activating the positive transcription elongation factor b signaling pathway. Notably, CPI-203 exhibited synergism in latent HIV-1 reactivation and alleviated the HIV-1-induced "cytokine storm" when used in combination with the protein kinase C (PKC) agonist prostratin. These findings highlight that CPI-203 shows promise as a novel, safe candidate for the design of targeted strategies to "shock and kill" HIV-1 and thus represents a potential functional cure.


Assuntos
Acetamidas/farmacologia , Azepinas/farmacologia , HIV-1/efeitos dos fármacos , Fator B de Elongação Transcricional Positiva/metabolismo , Ativação Viral/efeitos dos fármacos , Latência Viral/efeitos dos fármacos , Acetamidas/química , Adulto , Animais , Azepinas/química , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T CD4-Positivos/virologia , Feminino , HIV-1/fisiologia , Humanos , Células Jurkat , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Domínios Proteicos/efeitos dos fármacos , Domínios Proteicos/fisiologia , Ativação Viral/fisiologia , Latência Viral/fisiologia
12.
Eur J Med Chem ; 171: 462-474, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30933853

RESUMO

The present status of antibiotic resistant requires an urgent invention of novel agents that act on clinically unexplored antibacterial targets. The enzyme MraY (phospho-MurNAc-pentapeptide translocase), essential for bacterial cell wall synthesis, fulfils this criterion as it has not been explored as a target in a clinical context. Specifically, the enzyme is involved in the lipid-linked cycle of peptidoglycan biosynthesis and is reportedly targeted by naturally-occurring nucleoside antibiotics. The antimicrobial 'caprazamycin' class of nucleoside antibiotics targets Mycobacterium tuberculosis and clinically relevant Gram-negative bacteria such as Pseudomonas aeruginosa besides various drug resistant strains and is therefore an eligible starting point for the development of novel agents. In this review, we aim to summarise the structure-activity relationships of the natural, semi-synthetic as well as synthetic analogues of nucleoside antibiotic caprazamycins. This review highlights caprazamycins as promising lead structures for development of potent and selective antimicrobial agents that target MraY, the bacterial enzyme involved in the first membrane-dependent step in bacterial peptidoglycan assembly.


Assuntos
Antibacterianos/farmacologia , Azepinas/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Produtos Biológicos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Transferases/antagonistas & inibidores , Uridina/análogos & derivados , Antibacterianos/química , Azepinas/química , Proteínas de Bactérias/metabolismo , Produtos Biológicos/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Relação Estrutura-Atividade , Transferases/metabolismo , Uridina/química , Uridina/farmacologia
13.
Molecules ; 24(3)2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30743991

RESUMO

A one-pot synthesis of triazolobenzodiazepine-containing polycyclic compounds is introduced. The reaction process involves a decarboxylative three-component [3 + 2] cycloaddition of nonstabilized azomethine ylides, N-propargylation, and intramolecular click reactions.


Assuntos
Azepinas/química , Compostos Azo/química , Química Click , Cobre/química , Reação de Cicloadição , Tiossemicarbazonas/química , Triazóis/química , Azepinas/síntese química , Estrutura Molecular , Estereoisomerismo
14.
Biol Pharm Bull ; 42(2): 261-267, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30713256

RESUMO

A series of tetraethyl 2,4,8,10-tetramethyl-6,12-diaryl-3,9-dioxahexacyclo[6.4.0.02,7.04,11.05,10]dodecane-1,5,7,11-tetracarboxylates (simplified as 3,9-dioxatetraasteranes) with C2-symmetric structural characteristics were synthesized through the [2 + 2] photocycloaddition of the diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylates. Besides, their anti-human immunodeficiency virus (HIV)-1 activities were evaluated by enzyme-linked immunosorbent assay (ELISA) assay against HIV-1 (IIIB) replication in MT-4 cell culture. The result showed that the tested compounds exhibited potential activates with IC50 values less than 110 nM. Furthermore, docking study was carried out to study the binding mode of these compounds. The results indicated that the overall orientation of the inhibitors in the active site were similar to that of the cyclic urea AHA001 and a hydrogen bond with the protein residues might play a crucial role in their anti-HIV-1 activities. Such results will provide a theoretical foundation for further investigations on the biological activity of 3,9-dioxatetraasteranes.


Assuntos
Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Urease/química , Urease/farmacologia , Azepinas/química , Azepinas/farmacologia , Protease de HIV/metabolismo , Inibidores da Protease de HIV/síntese química , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química , Ureia/farmacologia , Urease/síntese química
15.
BMC Bioinformatics ; 19(Suppl 13): 342, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30717648

RESUMO

BACKGROUND: (-)-Balanol is an ATP-mimicking inhibitor that non-selectively targets protein kinase C (PKC) isozymes and cAMP-dependent protein kinase (PKA). While PKA constantly shows tumor promoting activities, PKC isozymes can ambiguously be tumor promoters or suppressors. In particular, PKCε is frequently implicated in tumorigenesis and a potential target for anticancer drugs. We recently reported that the C5(S)-fluorinated balanol analogue (balanoid 1c) had improved binding affinity and selectivity for PKCε but not to the other novel PKC isozymes, which share a highly similar ATP site. The underlying basis for this fluorine-based selectivity is not entirely comprehended and needs to be investigated further for the development of ATP mimic inhibitors specific for PKCε. RESULTS: Using molecular dynamics (MD) simulations assisted by homology modelling and sequence analysis, we have studied the fluorine-based selectivity in the highly similar ATP sites of novel PKC (nPKC) isozymes. The study suggests that every nPKC isozyme has different dynamics behaviour in both apo and 1c-bound forms. Interestingly, the apo form of PKCε, where 1c binds strongly, shows the highest degree of flexibility which dramatically decreases after binding 1c. CONCLUSIONS: For the first time to the best of our knowledge, we found that the origin of 1c selectivity for PKCε comes from the unique dynamics feature of each PKC isozyme. Fluorine conformational control in 1c can synergize with and lock down the dynamics of PKCε, which optimize binding interactions with the ATP site residues of the enzyme, particularly the invariant Lys437. This finding has implications for further rational design of balanol-based PKCε inhibitors for cancer drug development.


Assuntos
Azepinas/metabolismo , Halogenação , Hidroxibenzoatos/metabolismo , Proteína Quinase C-épsilon/metabolismo , Trifosfato de Adenosina/metabolismo , Azepinas/química , Análise por Conglomerados , Humanos , Hidroxibenzoatos/química , Isoenzimas/metabolismo , Simulação de Dinâmica Molecular , Fosforilação , Conformação Proteica , Proteína Quinase C-épsilon/química , Ribose/química , Alinhamento de Sequência , Eletricidade Estática , Especificidade por Substrato
16.
J Enzyme Inhib Med Chem ; 34(1): 361-374, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30734603

RESUMO

Phosphoinositide-dependent protein kinase-1 (PDK1) is an important protein in mediating the PI3K-AKT pathway and is thus identified as a promising target. The catalytic activity of PDK1 is tightly regulated by allosteric modulators, which bind to the PDK1 Interacting Fragment (PIF) pocket of the kinase domain that is topographically distinct from the orthosteric, ATP binding site. Allosteric modulators by attaching to the less conserved PIF-pocket have remarkable advantages such as higher selectivity, less side effect, and lower toxicity. Targeting allosteric PIF-pocket of PDK1 has become the focus of recent attention. In this review, we summarise the current advances in the structure-based discovery of PDK1 allosteric modulators. We will first present the three-dimensional structure of PDK1 and illustrate the allosteric regulatory mechanism of PDK1 through the modulation of the PIF-pocket. Then, the recent advances of PDK1 allosteric modulators targeting the PIF-pocket will be recapitulated detailly according to the structural similarity of allosteric modulators.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Descoberta de Drogas , Proteínas Serina-Treonina Quinases/metabolismo , Alcaloides/química , Alcaloides/farmacologia , Azepinas/química , Azepinas/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Dissulfetos/química , Dissulfetos/farmacologia , Humanos , Sulfonamidas/química , Sulfonamidas/farmacologia
17.
Arch Pharm (Weinheim) ; 352(3): e1800298, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30648282

RESUMO

The synthesis of inhibitors of SphK2 with novel structural scaffolds is reported. These compounds were designed from a molecular modeling study, in which the molecular interactions stabilizing the different complexes were taken into account. Particularly interesting is that 7-bromo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine, which is a selective inhibitor of SphK2, does not exert any cytotoxic effects and has a potent anti-inflammatory effect. It was found to inhibit mononuclear cell adhesion to the dysfunctional endothelium with minimal impact on neutrophil-endothelial cell interactions. The information obtained from our theoretical and experimental study can be useful in the search for inhibitors of SphK2 that play a prominent role in different diseases, especially in inflammatory and cardiovascular disorders.


Assuntos
Anti-Inflamatórios/síntese química , Azepinas/síntese química , Inibidores Enzimáticos/síntese química , Compostos de Epóxi/síntese química , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/toxicidade , Azepinas/química , Azepinas/farmacologia , Adesão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desenho de Drogas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/toxicidade , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Simulação de Acoplamento Molecular , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Ligação Proteica , Relação Estrutura-Atividade
18.
Biomed Chromatogr ; 33(6): e4489, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30652327

RESUMO

Knowledge and understanding of the stability profile of a drug is important as it affects its safety and efficacy. In the present work, besifloxacin, a new, fourth-generation fluoroquinolone antibiotic, was subjected to different forced-degradation conditions as per International Conference on Harmonization (ICH) guidelines such as hydrolysis (acid, base and neutral), oxidation, thermal and photolysis. The drug degraded under acidic, basic, oxidative and photolytic conditions while it was found to be stable under dry heat and neutral hydrolytic conditions. In total, five degradation products (DPs) were formed under different conditions-DP1 and DP2 (photolysis), DP3 (oxidation), DP4 (acidic), DP3 and DP5 (basic). The chromatographic separation of besifloxacin and its degradation products was achieved on a Sunfire C18 (250 mm × 4.6 mm, 5 µm) column with 0.1% aqueous formic acid-acetonitrile as a mobile phase. The gradient RP-HPLC method was developed and validated as per ICH guidelines. The degradation products were characterized with the help of LC-ESI-QTOF mass spectrometric studies and the most likely degradation pathway of the drug was proposed. In silico toxicity assessment of the drug and its degradation products was carried out, which indicated that DP3 and DP4 carry a mutagenicity alert.


Assuntos
Azepinas , Cromatografia Líquida de Alta Pressão/métodos , Fluoroquinolonas , Espectrometria de Massas por Ionização por Electrospray/métodos , Animais , Azepinas/análise , Azepinas/química , Azepinas/toxicidade , Bactérias/efeitos dos fármacos , Linhagem Celular , Simulação por Computador , Fluoroquinolonas/análise , Fluoroquinolonas/química , Fluoroquinolonas/toxicidade , Humanos , Modelos Lineares , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/métodos , Testes de Toxicidade
19.
J Pharm Biomed Anal ; 163: 17-23, 2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30273837

RESUMO

As a PAC-1 derivative, SM-1 exhibts a promising antitumour property. To better understand the relationship between the drug concentrations and pharmacological effects, both liquid chromatography coupled with tandem mass spectrometry and high performance liquid chromatography methods were developed and validated in the work. Those methods were then applied to the pharmacokinetics (PK), tissue distribution and plasma protein binding (PPB) studies of SM-1. As a results, the proposed methods were demonstrated to be accurate, precise and stable for the analysis of the SM-1 in plasma and tissue samples. Meanwhile, the PK parameters of SM-1 showed that SM-1 had good PK properties. SM-1 had good absorption in the body, with 59.01% of the absolute bioavailability in rats and 55.63% of that in dogs. SM-1 rapidly distributed to all tissues, with the highest distribution in the lung and less in the brain and muscle. The PPB rates in rat plasma, dog plasma, and human plasma were 91.1%, 91.2%, and 90.7%, respectively. These good PK properties will contribute SM-1 to be a promising anti-tumour candidate. These results also provide insights into the further pharmacological investigation of SM-1.


Assuntos
Azepinas/farmacocinética , Proteínas Sanguíneas/metabolismo , Hidrazonas/farmacocinética , Absorção Fisico-Química , Animais , Azepinas/química , Disponibilidade Biológica , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Cães , Ensaios de Seleção de Medicamentos Antitumorais/instrumentação , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Humanos , Hidrazonas/química , Pulmão/metabolismo , Masculino , Músculos/metabolismo , Piperazinas/química , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos , Distribuição Tecidual
20.
J Med Chem ; 62(1): 288-305, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29620897

RESUMO

An impaired signaling capacity of the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) has been implicated in the neurobehavioral processes that promote relapse vulnerability in cocaine use disorder (CUD). Restoration of the diminished 5-HT2CR signaling through positive allosteric modulation presents a novel therapeutic approach. Several new molecules with the 4-alkylpiperidine-2-carboxamide scaffold were designed, synthesized, and pharmacologically evaluated, leading to the discovery of selective 5-HT2CR positive allosteric modulators (PAMs). Compound 16 (CYD-1-79) potentiated 5-HT-evoked intracellular calcium release in cells stably expressing the human 5-HT2CR but not the 5-HT2AR cells. A topographically distinct allosteric site was identified based on the newly solved 5-HT2CR structure. Compound 16 modulated 5-HT2CR-mediated spontaneous ambulation, partially substituted for the training dose of the 5-HT2CR agonist WAY163909, synergized with a low dose of WAY163909 to substitute fully for the stimulus effects of WAY163909, and attenuated relapse vulnerability as assessed in a rodent self-administration model, indicating its therapeutic promise for CUD.


Assuntos
Amidas/química , Desenho de Drogas , Receptor 5-HT2C de Serotonina/química , Regulação Alostérica , Sítio Alostérico , Amidas/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Azepinas/química , Células CHO , Cálcio/metabolismo , Cricetinae , Cricetulus , Meia-Vida , Indóis/química , Locomoção/efeitos dos fármacos , Simulação de Acoplamento Molecular , Piperidinas/química , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Ratos , Receptor 5-HT2C de Serotonina/genética , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/química , Relação Estrutura-Atividade
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