RESUMO
Glioblastoma (GBM) is the most aggressive and treatment-refractory malignant adult brain cancer. After standard of care therapy, the overall median survival for GBM is only â¼6 months with a 5-year survival <10%. Although some patients initially respond to the DNA alkylating agent temozolomide (TMZ), unfortunately most patients become resistant to therapy and brain tumors eventually recur. We previously found that knockout of BRG1 or treatment with PFI-3, a small molecule inhibitor of the BRG1 bromodomain, enhances sensitivity of GBM cells to temozolomide in vitro and in vivo GBM animal models. Those results demonstrated that the BRG1 catalytic subunit of the SWI/SNF chromatin remodeling complex appears to play a critical role in regulating TMZ-sensitivity. In the present study we designed and synthesized Structurally Related Analogs of PFI-3 (SRAPs) and tested their bioactivity in vitro. Among of the SRAPs, 9f and 11d show better efficacy than PFI-3 in sensitizing GBM cells to the antiproliferative and cell death inducing effects of temozolomide in vitro, as well as enhancing the inhibitor effect of temozolomide on the growth of subcutaneous GBM tumors.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Compostos Azabicíclicos/farmacologia , DNA Helicases/antagonistas & inibidores , Glioblastoma/tratamento farmacológico , Proteínas Nucleares/antagonistas & inibidores , Piridinas/farmacologia , Temozolomida/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Animais , Antineoplásicos Alquilantes/química , Compostos Azabicíclicos/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , DNA Helicases/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos NOD , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Proteínas Nucleares/metabolismo , Piridinas/química , Relação Estrutura-Atividade , Temozolomida/química , Fatores de Transcrição/metabolismoRESUMO
Thousands of known alkaloids contain a nitrogen (N) heterocycle. While five-, six- and seven-membered N-heterocycles (ie: pyrroles, imidazoles, indoles, pyridines and azepines and their saturated variants) are common, those with an eight-membered N-heterocycle are comparatively rare. This review discusses the structure and bioactivity of alkaloids that contain an azocine (or saturated azocane) ring, and the array of sources whence they originate.
Assuntos
Alcaloides/farmacologia , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Antimaláricos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Inseticidas/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Antimaláricos/química , Antimaláricos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Compostos Azabicíclicos/química , Compostos Azabicíclicos/isolamento & purificação , Compostos Azabicíclicos/farmacologia , Azocinas/química , Azocinas/isolamento & purificação , Azocinas/farmacologia , Humanos , Inseticidas/química , Inseticidas/isolamento & purificação , Estrutura MolecularRESUMO
Pyclen-dipicolinate chelates proved to be very efficient chelators for the radiolabeling with ß--emitters such as 90Y. In this study, a pyclen-dipicolinate ligand functionalized with additional C12 alkyl chains was synthesized. The radiolabeling with 90Y proved that the addition of saturated carbon chains does not affect the efficiency of the radiolabeling, whereas a notable increase in lipophilicity of the resulting 90Y radiocomplex was observed. As a result, the compound could be extracted in Lipiodol® and encapsulated in biodegrable pegylated poly(malic acid) nanoparticles demonstrating the potential of lipophilic pyclen-dipicolinate derivatives as platforms for the design of radiopharmaceuticals for the treatment of liver or brain cancers by internal radiotherapy.
Assuntos
Compostos Azabicíclicos/química , Compostos Radiofarmacêuticos/química , Radioterapia/métodos , Radioisótopos de Ítrio/química , Óleo Etiodado/química , Ligantes , Ácidos Picolínicos/químicaRESUMO
Helicobacter pylori is one of the main causal risk factor in the generation of chronic gastritis, gastroduodenal ulcers and gastric carcinoma. Thus, the eradication of H. pylori infection is an important way for preventing and managing the gastric diseases. Multiple-therapy with several antibacterial agents is used for the eradication of H. pylori infections; however the increase of resistance to H. pylori strains has resulted in unsatisfactory eradication and unsuccessful treatment. Furthermore, the combination therapy with high dosing leads to the disruption of intestinal microbial flora and undesired side effects. Therefore, the search for new therapeutic agents with high selectivity against H. pylori is a field of current interest. In recent years, diverse compounds originating from natural sources or synthetic drug design programs were evaluated and tried to optimize for applying against H. pylori. In this review, we have described various classes of anti-H. pylori compounds, their structure-activity relationship studies, and mechanism of actions, which could be useful for the development of new drugs for the treatment of H. pylori infections.
Assuntos
Antibacterianos/farmacologia , Helicobacter pylori/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêuticoRESUMO
A family of three picolinate pyclen-based ligands, previously investigated for the complexation of Y3+ and some lanthanide ions (Gd3+, Eu3+), was studied with 161Tb and 177Lu in view of potential radiotherapeutic applications. The set of six Tb3+ and Lu3+ complexes was synthesized and fully characterized. The coordination properties in the solid state and in solution were thoroughly studied. Potentiometric titrations, supported by density functional theory (DFT) calculations, showed the very high stability constants of the Tb3+ and Lu3+ complexes, associated with remarkable kinetic inertness for up to 30 days in 1 M HCl. A complete radiolabeling study performed with both 161Tb and 177Lu radionuclides, including experiments with regard to the stability with and without scavengers and kinetic inertness using challenging agents, proved that the ligands could reasonably compete with the DOTA analogue. To conclude, the potential of using the same ligand for both radiotherapy and optical imaging was highlighted for the first time.
Assuntos
Compostos Azabicíclicos/química , Quelantes/química , Elementos da Série dos Lantanídeos/química , Ácidos Picolínicos/química , Medicina de Precisão , Ligantes , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
The 1-azabicyclo[3.1.0]hexane ring is a key moiety in natural products for biological activities against bacteria, fungi, and tumor through DNA alkylation. Ficellomycin is a dipeptide that consists of l-valine and a non-proteinogenic amino acid with the 1-azabicyclo[3.1.0]hexane ring structure. Although the biosynthetic gene cluster of ficellomycin has been identified, the biosynthetic pathway currently remains unclear. We herein report the final stage of ficellomycin biosynthesis involving ring modifications and successive dipeptide formation. After the ring is formed, the hydroxy group of the ring is converted into the guanidyl unit by three enzymes, which include an aminotransferase with a novel inter ω-ω amino-transferring activity. In the last step, the resulting 1-azabicyclo[3.1.0]hexane ring-containing amino acid is connected with l-valine by an amino acid ligase to yield ficellomycin. The present study revealed a new machinery that expands the structural and biological diversities of natural products.
Assuntos
Compostos Azabicíclicos/química , Guanidina/química , Hexanos/química , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Relação Estrutura-AtividadeRESUMO
In addition to the already described ligand L4a, two pyclen-based lanthanide chelators, L4b and L4c, bearing two specific picolinate two-photon antennas (tailor-made for each targeted metal) and one acetate arm arranged in a dissymmetrical manner, have been synthesized, to form a complete family of lanthanide luminescent bioprobes: [EuL4a], [SmL4a], [YbL4b], [TbL4c], and [DyL4c]. Additionally, the symmetrically arranged regioisomer L4a' was also synthesized as well as its [EuL4a'] complex to highlight the astonishing positive impact of the dissymmetrical N-distribution of the functional chelating arms. The investigation clearly shows the high performance of each bioprobe, which, depending on the complexed lanthanide, could be used in various applications. Each presents high brightness, quantum yields, and lifetimes. Staining of the complexes into living human breast cancer cells was observed. In addition, in vivo two-photon microscopy was performed for the first time on a living zebrafish model with [EuL4a]. No apparent toxicity was detected on the growth of the zebrafish, and images of high quality were obtained.
Assuntos
Compostos Azabicíclicos/química , Complexos de Coordenação/química , Elementos da Série dos Lantanídeos/química , Substâncias Luminescentes/química , Imagem Óptica , Fótons , Animais , Complexos de Coordenação/síntese química , Humanos , Ligantes , Substâncias Luminescentes/síntese química , Células MCF-7 , Estrutura Molecular , Peixe-Zebra/embriologiaRESUMO
The first NIR fluorescent mitochondria-targeting K+ sensor, denoted as TAC-Rh, was developed. The produced sensor consists of a rhodamine analog as the fluorophore and triazacryptand (TAC) as the K+ recognition unit. Compared to the K+ sensors reported previously, TAC-Rh exhibits two unique optical properties: the largest Stokes shifts (120 nm) and the longest emission peak wavelength (720 nm). With the assistance of this novel sensor, real-time changes of K+ concentrations in mitochondria during apoptosis were monitored for the first time. Moreover, it was also the first time that the relationship between mitochondrial K+ flux and apoptosis was investigated in real time using fluorescence imaging.
Assuntos
Apoptose/fisiologia , Corantes Fluorescentes/química , Mitocôndrias/metabolismo , Potássio/análise , Compostos Azabicíclicos/química , Linhagem Celular Tumoral , Humanos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Potássio/metabolismo , Rodaminas/químicaRESUMO
PURPOSE: Imipenem/cilastatin/relebactam has shown efficacy in complicated intra-abdominal and urinary tract infections in the RESTORE IMI-1 study, and it was recently approved by the US Food and Drug Administration. A press release announced that another Phase III study (RESTORE IMI-2) in patients with hospital-acquired and ventilator-associated pneumonia has met the primary end point. Critically ill patients with multidrug-resistant infections are expected to receive several pharmaceutical intravenous drugs while admitted in hospitals, warranting the need for Y-site compatibility studies. This study was conducted to evaluate the physical compatibility of imipenem/cilastatin/relebactam for injection during Y-site administration with common injectable intravenous medications. METHODS: Imipenem/cilastatin/relebactam was prepared to the concentration of 5 mg/mL, and other intravenous tested drugs were reconstituted as per the package inserts. Y-site was simulated as a 2-drug combination by mixing 5 mL of each in a glass tube, with reversing of the order of mixing; physical characteristics were recorded, and pH changes and turbidity were measured at time intervals. FINDINGS: Imipenem/cilastatin/relebactam was found to be compatible with a wide range of intravenous medications, facilitating co-administration with various IV medications. IMPLICATIONS: The compatibility reported is limited to a 2-h observation period in this study to adequately cover imipenem/cilastatin/relebactam infusion time. In addition, it is based on the measured turbidity with no chemical assay of the components of the admixture.
Assuntos
Compostos Azabicíclicos/química , Cilastatina/química , Imipenem/química , Combinação de Medicamentos , Nefelometria e TurbidimetriaRESUMO
The chemokine system plays an important role in mediating a proinflammatory microenvironment for tumor growth in hepatocellular carcinoma (HCC). The CXCR6 receptor and its natural ligand CXCL16 are expressed at high levels in HCC cell lines and tumor tissues and receptor expression correlates with increased neutrophils in these tissues contributing to poor prognosis in patients. Availability of pharmacologcal tools targeting the CXCR6/CXCL16 axis are needed to elucidate the mechanism whereby neutrophils are affected in the tumor environment. We report the discovery of a series of small molecules with an exo-[3.3.1]azabicyclononane core. Our lead compound 81 is a potent (EC50 = 40 nM) and selective orally bioavailable small molecule antagonist of human CXCR6 receptor signaling that significantly decreases tumor growth in a 30-day mouse xenograft model of HCC.
Assuntos
Receptores CXCR6/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Animais , Compostos Azabicíclicos/química , Compostos Azabicíclicos/metabolismo , Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Concentração Inibidora 50 , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores CXCR6/metabolismo , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
Relebactam, a potent ß-lactamase inhibitor, in combination with Primaxin is an FDA-approved (Recarbrio) treatment for serious and antibiotic-resistant bacterial infections. An efficient synthesis of key chiral piperidine intermediate 1 suitable for large-scale preparation of relebactam is described. The key steps include a unique highly diastereoselective FeCl3·6H2O/NaBH4 reduction of a chiral oxime ether and chemoselective amidation of the resulting unprotected pipecolic acid. Nuclear magnetic resonance studies and density functional theory calculations were carried out on the substrate-Fe(III) complexes, which shed light on diastereoselective reduction.
Assuntos
Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/farmacologia , Boroidretos/química , Cloretos/química , Compostos Férricos/química , Oximas/química , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/farmacologia , Compostos Azabicíclicos/química , Éteres/química , Estrutura Molecular , Oxirredução , Análise Espectral/métodos , Estereoisomerismo , Água/químicaRESUMO
The biosynthesis of the azinomycins involves the conversion of glutamic acid to an aziridino[1,2-a]pyrrolidine moiety, which together with the epoxide moiety imparts anticancer activity to these agents. The mechanism of azabicycle formation is complex and involves at least 14 enzymatic steps. Previous research has identified N-acetyl-glutamate 5-semialdehyde as a key intermediate, which originates from protection of the amino terminus of glutamic acid and subsequent reduction of the γ-carboxylate. This study reports on the seminal discovery of a thiamin-dependent transketolase responsible for the formation of 2-acetamido-5,6-dihydroxy-6-oxoheptanoic acid, which accounts for the two-carbon extension needed to complete the carbon framework of the azabicycle moiety.
Assuntos
Compostos Azabicíclicos/química , Compostos Azabicíclicos/metabolismo , Transcetolase/metabolismo , Humanos , Modelos Moleculares , Conformação Proteica , Transcetolase/químicaRESUMO
We designed the synthesis of a small library of 3-substituted-3,6-diazabicyclo[3.1.1]heptanes whose affinity on neuronal nicotinic receptors (nAChRs) was evaluated. Among the synthesized compounds, the 5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-N-(2-fluorophenyl)nicotinamide 43 proved to be the most interesting compound with α4ß2Ki value of 10 pM and a very high α7/α4ß2 selectivity. Furthermore, compounds 35, 39 and 43 elicited a selective partial agonist activity for α4ß2 nAChR subtype. Finally, in this paper we also report the conclusions on the 3,6-diazabicyclo[3.1.1]heptanes as ligands for nAChRs, resulting from our consolidated structure activity relationship (SAR) studies on this template.
Assuntos
Compostos Azabicíclicos/farmacologia , Neurônios/efeitos dos fármacos , Niacinamida/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/metabolismo , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/química , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Neurônios/metabolismo , Niacinamida/síntese química , Niacinamida/química , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/química , Relação Estrutura-AtividadeRESUMO
OBJECTIVES: To develop a multifunctional adjuvant molecule that can rescue ß-lactam antibiotics and ß-lactam/ß-lactamase inhibitor combinations from resistance in carbapenem-resistant Pseudomonas aeruginosa clinical isolates. METHODS: Preparation of adjuvant was guided by structure-activity relationships, following standard protocols. Susceptibility and chequerboard studies were assessed using serial 2-fold dilution assays. Toxicity was evaluated against porcine erythrocytes, human embryonic kidney (HEK293) cells and liver carcinoma (HepG2) cells via MTS assay. Preliminary in vivo efficacy was evaluated using a Galleria mellonella infection model. RESULTS: Conjugation of tobramycin and cyclam abrogates the ribosomal effects of tobramycin but confers a potent adjuvant property that restores full antibiotic activity of meropenem and aztreonam against carbapenem-resistant P. aeruginosa. Therapeutic levels of susceptibility, as determined by CLSI susceptibility breakpoints, were attained in several MDR clinical isolates, and time-kill assays revealed a synergistic dose-dependent pharmacodynamic relationship. A triple combination of the adjuvant with ceftazidime/avibactam (approved), aztreonam/avibactam (Phase III) and meropenem/avibactam enhances the efficacies of ß-lactam/ß-lactamase inhibitors against recalcitrant strains, suggesting rapid access of the combination to their periplasmic targets. The newly developed adjuvants, and their combinations, were non-haemolytic and non-cytotoxic, and preliminary in vivo evaluation in G. mellonella suggests therapeutic potential for the double and triple combinations. CONCLUSIONS: Non-ribosomal tobramycin-cyclam conjugate mitigates the effect of OprD/OprF porin loss in P. aeruginosa and potentiates ß-lactam/ß-lactamase inhibitors against carbapenem-resistant clinical isolates, highlighting the complexity of resistance to ß-lactam antibiotics. Our strategy presents an avenue to further preserve the therapeutic utility of ß-lactam antibiotics.
Assuntos
Antibacterianos/uso terapêutico , Compostos Heterocíclicos/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Tobramicina/uso terapêutico , Inibidores de beta-Lactamases/uso terapêutico , Adjuvantes Farmacêuticos/química , Adjuvantes Farmacêuticos/uso terapêutico , Animais , Antibacterianos/química , Compostos Azabicíclicos/química , Compostos Azabicíclicos/uso terapêutico , Carbapenêmicos/química , Carbapenêmicos/uso terapêutico , Ceftazidima/química , Ceftazidima/uso terapêutico , Combinação de Medicamentos , Eritrócitos , Células HEK293 , Compostos Heterocíclicos/química , Humanos , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/enzimologia , Suínos , Tobramicina/química , Inibidores de beta-Lactamases/químicaRESUMO
Mycobacterium tuberculosis (Mtb), the main causative agent of tuberculosis (TB), is naturally resistant to ß-lactam antibiotics due to the production of the extended spectrum ß-lactamase BlaC. ß-Lactam/ß-lactamase inhibitor combination therapies can circumvent the BlaC-mediated resistance of Mtb and are promising treatment options against TB. However, still little is known of the exact mechanism of BlaC inhibition by the ß-lactamase inhibitors currently approved for clinical use, clavulanic acid, sulbactam, tazobactam, and avibactam. Here, we present the X-ray diffraction crystal structures of the acyl-enzyme adducts of wild-type BlaC with the four inhibitors. The +70 Da adduct derived from clavulanate and the trans-enamine acylation adducts of sulbactam and tazobactam are reported. BlaC in complex with avibactam revealed two inhibitor conformations. Preacylation binding could not be observed because inhibitor binding was not detected in BlaC variants carrying a substitution of the active site serine 70 to either alanine or cysteine, by crystallography, ITC or NMR. These results suggest that the catalytic serine 70 is necessary not only for enzyme acylation but also for increasing BlaC affinity for inhibitors in the preacylation state. The structure of BlaC with the serine to cysteine mutation showed a covalent linkage of the cysteine 70 Sγ atom to the nearby amino group of lysine 73. The differences of adduct conformations between BlaC and other ß-lactamases are discussed.
Assuntos
Inibidores de beta-Lactamases/química , beta-Lactamases/química , Acilação , Aldeídos/química , Substituição de Aminoácidos , Compostos Azabicíclicos/química , Compostos Azabicíclicos/metabolismo , Compostos Azabicíclicos/farmacologia , Domínio Catalítico , Ácido Clavulânico/química , Ácido Clavulânico/metabolismo , Cristalografia por Raios X , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Conformação Proteica , Serina/genética , Serina/metabolismo , Sulbactam/química , Sulbactam/metabolismo , Tazobactam/química , Tazobactam/metabolismo , Tazobactam/farmacologia , Inibidores de beta-Lactamases/metabolismo , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/genética , beta-Lactamases/metabolismoRESUMO
AIM: Colon cancer is the third leading cause of death worldwide; therefore, there is a need for an effective therapy with lower side effects. METHODS: A series of 8-alkyl-2,4-bisbenzylidene-3-nortropinones 3 & 14-39 was prepared via Claisen-Schmidt condensation of 8-alkyl-3-nortropinones 11-13 with different aromatic aldehydes. The target compounds were screened for their antiproliferative activity. RESULTS: Most of the prepared compounds showed promising antiproliferative activity against many of 60 National Cancer Institute cell lines at 10 µM. Furthermore, 8-ethyl-2,4-bis(3,4-dimethoxybenzylidene)-8-nortropin-3-one 29 and its 3,4,5-trimethoxy analog 30 were the most active compounds against HCT116 cell line with IC50 values 0.01 and 0.46 µM, respectively. Using CODESSA-Pro software, a significant 2D-quantitative structure-activity relationship (QSAR) model was obtained. CONCLUSION: The 8-Alkyl-2,4-bisbenzylidene-8-azabicyclo[3.2.1]octan-3-one represents an interesting core for further structural optimization to obtain more promising hits.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos de Benzilideno/química , Compostos de Benzilideno/farmacologia , Proliferação de Células/efeitos dos fármacos , Alquilação , Antineoplásicos/síntese química , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Compostos de Benzilideno/síntese química , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Relação Quantitativa Estrutura-AtividadeRESUMO
Covering: up to 2018 Thioester reductase domains catalyze two- and four-electron reductions to release natural products following assembly on nonribosomal peptide synthetases, polyketide synthases, and their hybrid biosynthetic complexes. This reductive off-loading of a natural product yields an aldehyde or alcohol, can initiate the formation of a macrocyclic imine, and contributes to important intermediates in a variety of biosyntheses, including those for polyketide alkaloids and pyrrolobenzodiazepines. Compounds that arise from reductase-terminated biosynthetic gene clusters are often reactive and exhibit biological activity. Biomedically important examples include the cancer therapeutic Yondelis (ecteinascidin 743), peptide aldehydes that inspired the first therapeutic proteasome inhibitor bortezomib, and numerous synthetic derivatives and antibody drug conjugates of the pyrrolobenzodiazepines. Recent advances in microbial genomics, metabolomics, bioinformatics, and reactivity-based labeling have facilitated the detection of these compounds for targeted isolation. Herein, we summarize known natural products arising from this important category, highlighting their occurrence in Nature, biosyntheses, biological activities, and the technologies used for their detection and identification. Additionally, we review publicly available genomic data to highlight the remaining potential for novel reductively tailored compounds and drug leads from microorganisms. This thorough retrospective highlights various molecular families with especially privileged bioactivity while illuminating challenges and prospects toward accelerating the discovery of new, high value natural products.
Assuntos
Produtos Biológicos/metabolismo , Peptídeo Sintases/metabolismo , Policetídeo Sintases/metabolismo , Alcaloides/biossíntese , Alcaloides/química , Compostos Azabicíclicos/química , Compostos Azabicíclicos/metabolismo , Benzodiazepinonas/química , Benzodiazepinonas/metabolismo , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Vias Biossintéticas/genética , Ciclização , Depsipeptídeos/química , Depsipeptídeos/metabolismo , Dipeptídeos/química , Dipeptídeos/metabolismo , Indóis/química , Indóis/metabolismo , Lactamas/química , Lactamas/metabolismo , Leupeptinas/química , Leupeptinas/metabolismo , Lisina/análogos & derivados , Lisina/química , Lisina/metabolismo , Família Multigênica , Peptídeo Sintases/genética , Policetídeo Sintases/genética , Domínios ProteicosRESUMO
The first pyclen based ligand bearing two picolinate intra-ligand charge transfer transition antennae and one acetate arm organized in a dissymmetric manner was synthesized for Eu(iii) and Sm(iii) complexation. The europium complex presents an excellent brightness and biphotonic imaging of T24-cells has been performed using Eu(iii) and the less common Sm(iii) bioprobes.
Assuntos
Compostos Azabicíclicos/química , Complexos de Coordenação/química , Európio/química , Substâncias Luminescentes/química , Samário/química , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/efeitos da radiação , Técnicas Biossensoriais/métodos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/efeitos da radiação , Humanos , Ligantes , Luz , Substâncias Luminescentes/síntese química , Substâncias Luminescentes/efeitos da radiação , Estrutura Molecular , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/química , Ácidos Picolínicos/efeitos da radiaçãoRESUMO
Identification of a new class of antitumor agent capable to induce apoptosis without triggering necrotic cell death event is challenging. The present communication describes the multicomponent synthesis of seven new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro antiproliferative activity on cervical cancer cell line (CaSki), breast cancer cell line (MDA-MB231), lung cancer cell line (SK-Lu-1) and human lymphocytes. Among the synthesized dithiocarbamates, compound 9e displayed significant antiproliferative activity without inducing any necrotic cell death (both on tumour cells and lymphocytes) and induced apoptosis in tumor cells by the caspase dependent apoptotic pathway. The compound 9e also exhibited greater tumor selectivity than human lymphocytes. In silico ADME predictions revealed that compound 9e has the potential to be developed as a drug candidate. Rapid chemical modifications of this lead are thus highly necessary for further investigation as a drug like safer antitumor candidate and also to achieve compounds with better activity profile.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Azabicíclicos/farmacologia , Tiocarbamatos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tiocarbamatos/síntese química , Tiocarbamatos/químicaRESUMO
Multidrug-resistant (MDR) bacterial infections are a serious threat to public health. Among the most alarming resistance trends is the rapid rise in the number and diversity of ß-lactamases, enzymes that inactivate ß-lactams, a class of antibiotics that has been a therapeutic mainstay for decades. Although several new ß-lactamase inhibitors have been approved or are in clinical trials, their spectra of activity do not address MDR pathogens such as Acinetobacter baumannii. This report describes the rational design and characterization of expanded-spectrum serine ß-lactamase inhibitors that potently inhibit clinically relevant class A, C and D ß-lactamases and penicillin-binding proteins, resulting in intrinsic antibacterial activity against Enterobacteriaceae and restoration of ß-lactam activity in a broad range of MDR Gram-negative pathogens. One of the most promising combinations is sulbactam-ETX2514, whose potent antibacterial activity, in vivo efficacy against MDR A. baumannii infections and promising preclinical safety demonstrate its potential to address this significant unmet medical need.