RESUMO
A concise asymmetric synthesis of clickable enantiomeric pyrrolidines was achieved using Crabbé-Ma allenation. The synthesized iminosugars were grafted by copper-free strain-promoted alkyne-azide cycloaddition onto phosphorus dendrimers. The hexavalent and dodecavalent pyrrolidines were evaluated as ß-glucocerebrosidase inhibitors. The level of inhibition suggests that monofluorocyclooctatriazole group may contribute to the affinity for the protein leading to potent multivalent inhibitors. Docking studies were carried out to rationalize these results. Then, the iminosugars clusters were evaluated as pharmacological chaperones in Gaucher patients' fibroblasts. An increase in ß-glucocerebrosidase activity was observed with hexavalent and dodecavalent pyrrolidines at concentrations as low as 1 µM and 0.1 µM, respectively. These iminosugar clusters constitute the first example of multivalent pyrrolidines acting as pharmacological chaperones against Gaucher disease.
Assuntos
Doença de Gaucher , Imino Açúcares , Humanos , Doença de Gaucher/tratamento farmacológico , Glucosilceramidase , Pirrolidinas/farmacologia , Inibidores Enzimáticos/farmacologiaRESUMO
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a worldwide scourge with more than 10 million people affected yearly. Among the proteins essential for the survival of Mtb, InhA has been and is still clinically validated as a therapeutic target. A new family of direct diaryl ether inhibitors, not requiring prior activation by the catalase peroxidase enzyme KatG, has been designed with the ambition of fully occupying the InhA substrate-binding site. Thus, eleven compounds, featuring three pharmacophores within the same molecule, were synthesized. One of them, 5-(((4-(2-hydroxyphenoxy)benzyl)(octyl)amino)methyl)-2-phenoxyphenol (compound 21), showed good inhibitory activity against InhA with IC50 of 0.70 µM. The crystal structure of compound 21 in complex with InhA/NAD+ showed how the molecule fills the substrate-binding site as well as the minor portal of InhA. This study represents a further step towards the design of new inhibitors of InhA.
Assuntos
Antituberculosos , Imidazóis , Mycobacterium tuberculosis , Sulfonamidas , Tiofenos , Humanos , Antituberculosos/farmacologia , Antituberculosos/química , Éter , Éteres , Sítios de Ligação , Etil-Éteres , Proteínas de Bactérias/metabolismoRESUMO
Tuberculosis is a serious public health problem worldwide. The search for new antibiotics has become a priority, especially with the emergence of resistant strains. A new family of imidazoquinoline derivatives, structurally analogous to triazolophthalazines, which had previously shown good antituberculosis activity, were designed to inhibit InhA, an essential enzyme for Mycobacterium tuberculosis survival. Over twenty molecules were synthesized and the results showed modest inhibitory efficacy against the protein. Docking experiments were carried out to show how these molecules could interact with the protein's substrate binding site. Disappointingly, unlike triazolophthlazines, these imidazoquinoline derivatives showed an absence of inhibition on mycobacterial growth.
Assuntos
Antituberculosos , Proteínas de Bactérias , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis , Oxirredutases , Quinolinas , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/efeitos dos fármacos , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Oxirredutases/antagonistas & inibidores , Oxirredutases/metabolismo , Antituberculosos/farmacologia , Antituberculosos/química , Antituberculosos/síntese química , Quinolinas/química , Quinolinas/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Relação Estrutura-Atividade , Testes de Sensibilidade Microbiana , Sítios de Ligação , Estrutura MolecularRESUMO
Indoleamine 2,3-dioxygenase (IDO1) and tryptophane 2,3-dioxygenase (TDO) are two heme-containing enzymes which catalyze the conversion of tryptophan to N-formylkynurenine. Both enzymes are well establish therapeutic targets as important factors in the tumor immune evasion mechanism. A number of analogues of the marine pyrroloquinoline alkaloids tsitsikammamines or wakayin have been synthesized, two of them were synthesized using an original method to build the bispyrroloquinone framework. All the derivatives were evaluated in a cellular assay for their capacity to inhibit the enzymes. Six compounds have shown a significant potency on HEK 293-EBNA cell lines expressing hIDO1 or hTDO.
Assuntos
Alcaloides/síntese química , Inibidores Enzimáticos/síntese química , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Pirroliminoquinonas/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Triptofano Oxigenase/antagonistas & inibidores , Alcaloides/metabolismo , Organismos Aquáticos/química , Inibidores Enzimáticos/metabolismo , Células HEK293 , Humanos , Alcaloides Indólicos/química , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Pirróis/química , Pirroliminoquinonas/metabolismo , Quinolinas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Relação Estrutura-AtividadeRESUMO
Dysregulation of the ceramide transport protein CERT is associated to diseases such as cancer. In search for new CERT START domain ligands, N-dodecyl-deoxynojirimycin (N-dodecyl-DNJ) iminosugar was found to display, as a ceramide mimic, significant protein recognition. To reinforce the lipophilic interactions and strengthen this protein binding, a docking study was carried out in order to select the optimal position on which to introduce an additional O-alkyl chain on N-dodecyl-DNJ. Analysis of the calculated poses for three different regioisomers indicated an optimal calculated interaction pattern for N,O3-didodecyl-DNJ. The two most promising regioisomers were prepared by a divergent route and their binding to the CERT START domain was evaluated with fluorescence intensity (FLINT) binding assay. N,O3-didodecyl-DNJ was confirmed to be a new binder prototype with level of protein recognition in the FLINT assay comparable to the best known ligands from the alkylated HPA-12 series. This work opens promising perspectives for the development of new inhibitors of CERT-mediated ceramide trafficking.
Assuntos
Glucosamina/análogos & derivados , Proteínas Serina-Treonina Quinases/química , 1-Desoxinojirimicina/química , 1-Desoxinojirimicina/metabolismo , Sítios de Ligação , Ceramidas/metabolismo , Glucosamina/química , Glucosamina/metabolismo , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/metabolismo , Humanos , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica , Domínios Proteicos , Proteínas Serina-Treonina Quinases/metabolismo , Estereoisomerismo , TermodinâmicaRESUMO
A concise and asymmetric synthesis of the enantiomeric pyrrolidines 2 and ent-2 are herein reported. Both enantiomers were assessed as ß-GCase inhibitors. While compound ent-2 acted as a poor competitive inhibitor, its enantiomer 2 proved to be a potent non-competitive inhibitor. Docking studies were carried out to substantiate their respective protein binding mode. Both pyrrolidines were also able to enhance lysosomal ß-GCase residual activity in N370S homozygous Gaucher fibroblasts. Notably, the non-competitive inhibitor 2 displayed an enzyme activity enhancement comparable to that of reference compounds IFG and NN-DNJ. This work highlights the impact of inhibitors chirality on their protein binding mode and shows that, beyond competitive inhibitors, the study of non-competitive ones can lead to the identification of new relevant parmacological chaperones.
Assuntos
Doença de GaucherRESUMO
Two macrocyclic derivatives based on the triclosan frame were designed and synthesized as inhibitors of Mycobacterium tuberculosis InhA enzyme. One of the two molecules M02 displayed promising inhibitory activity against InhA enzyme with an IC50 of 4.7 µM. Molecular docking studies of these two compounds were performed and confirmed that M02 was more efficient as inhibitor of InhA activity. These molecules are the first macrocyclic direct inhibitors of InhA enzyme able to bind into the substrate pocket. Furthermore, these biaryl ether compounds exhibited antitubercular activities comparable to that of triclosan against M. tuberculosis H37Rv strain.
Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Compostos Macrocíclicos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Triclosan/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Proteínas de Bactérias/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Oxirredutases/metabolismo , Relação Estrutura-Atividade , Triclosan/síntese química , Triclosan/químicaRESUMO
A series of simple C-alkyl pyrrolidines already known as cytotoxic inhibitors of ceramide glucosylation in melanoma cells can be converted into their corresponding 6-membered analogues by means of a simple ring expansion. This study illustrated how an isomerisation from iminosugar pyrrolidine toward piperidine could invert their targeting from glucosylceramide (GlcCer) formation toward GlcCer hydrolysis. Thus, we found that the 5-membered ring derivatives did not inhibit the hydrolysis reaction of GlcCer catalysed by lysosomal ß-glucocerebrosidase (GBA). On the other hand, the ring-expanded C-alkyl piperidine isomers, non-cytotoxic and inactive regarding ceramide glucosylation, revealed to be potent inhibitors of GBA. A molecular docking study showed that the positions of the piperidine ring of the compound 6b and its analogous 2-O-heptyl DIX 8 were similar to that of isofagomine. Furthermore, compound 6b promoted mutant GBA enhancements over 3-fold equivalent to that of the related O-Hept DIX 8 belonging to one of the most potent iminosugar-based pharmacological chaperone series reported to date.
Assuntos
Ceramidas/química , Inibidores Enzimáticos/química , Glucosilceramidase/antagonistas & inibidores , Imino Açúcares/química , Animais , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Glucosilceramidase/metabolismo , Humanos , Hidrólise , Imino Piranoses/química , Isomerismo , Lisossomos , Melanoma Experimental , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperidinas/química , Ligação Proteica , Pirrolidinas/química , Relação Estrutura-AtividadeRESUMO
The enigmatical dichotomy between the two CERT/GPBP protein isoforms, their vast panel of biological implications and the scarcity of known antagonist series call for new ligand chemotypes identification. We report the design of iminosugar-based ceramide mimics for the development of new START domain ligands potentially targeting either protein isoforms. Strategic choice of (i) an iminoxylitol core structure and (ii) the positioning of two dodecyl residues led to an extent of protein binding comparable to that of the natural cargo lipid ceramide or the archetypical inhibitor HPA-12. Molecular docking study evidenced a possible mode of protein binding fully coherent with the one observed in crystalline co-structures of known ligands. The present study thus paves the way for cellular CERT inhibition studies en route to the development of pharmacological tools aiming at deciphering the respective function and therapeutic potential of the two CERT/GPBP protein isoforms.
Assuntos
Imino Açúcares/química , Mimetismo Molecular , Isoformas de Proteínas/metabolismo , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Desenho de Fármacos , Imino Açúcares/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
A series of 12 analogues of the Cer transfer protein (CERT) antagonist HPA-12 with long aliphatic chains were prepared as their (1R,3S)-syn and (1R,3R)-anti stereoisomers from pivotal chiral oxoamino acids. The enantioselective access to these intermediates as well as their ensuing transformation relied on a practical crystallization-induced asymmetric transformation (CIAT) process. Sonogashira coupling followed by triple bond reduction and thiophene ring hydrodesulfurization (HDS) into the corresponding alkane moieties was then implemented to complete the synthetic routes delivering the targeted HPA-12 analogues in concise 4- to 6-step reaction sequences. Ten compounds were evaluated regarding their ability to bind to the CERT START domain by using the recently developed time-resolved FRET-based homogeneous (HTR-FRET) binding assay. The introduction of a lipophilic appendage on the phenyl moiety led to an overall 10- to 1000-fold enhancement of the protein binding, with the highest effect being observed for a n-hexyl residue in the meta position. The importance of the phenyl ring for the activity was indicated by the reduced potency of the 3-deoxyphytoceramide aliphatic analogues. The 1,3-syn stereoisomers were systematically more potent than their 1,3-anti analogues. In silico studies were used to rationalized these trends, leading to a model of protein recognition coherent with the stronger binding of (1R,3S)-syn HPAs.
Assuntos
Amidas/química , Ceramidas/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Tiofenos/química , Amidas/metabolismo , Transporte Biológico , Ceramidas/metabolismo , Ligantes , Modelos Moleculares , Ligação Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The first unified synthetic route to the four enantiopure HPA-12 stereoisomers in multi-gram scale is reported based on Crystallization-Induced Asymmetric Transformation (CIAT) technology. This preparative stereoselective synthesis allowed the unprecedented comparative evaluation of HPA-12 stereoisomers regarding their interaction with the CERT START domain. In vitro binding assay coupled to in silico docking approach indicate a possible interaction for the four derivatives. The first TR-FRET homogeneous-phase assay was developed to quantify their binding to the START domain, allowing complete determination of HPA-12 EC50. Results indicate that not only the (1R,3S) lead to the strongest binding, but that both 1R and 3S stereocenters similarly contribute to extent of recognition This automated homogenous assay further opens up promising prospect for the identification of novel potential CERT antagonist by means of high throughput screening.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Amidas/química , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The two marine alkaloids granulatimide and isogranulatimide have been shown to inhibit the checkpoint kinase 1 (Chk1), a promising target for cancer treatment. A molecular docking study allowing the design of new potential Chk1 inhibitors based on the natural products skeleton and the synthetic work to an amino-target platform to prepare them are described.
Assuntos
Alcaloides/farmacologia , Desenho de Fármacos , Imidazóis/farmacologia , Indóis/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Alcaloides/síntese química , Alcaloides/química , Quinase 1 do Ponto de Checagem , Relação Dose-Resposta a Droga , Imidazóis/síntese química , Imidazóis/química , Indóis/síntese química , Indóis/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) affects 10 million people each year and the emergence of resistant TB augurs for a growing incidence. In the last 60 years, only three new drugs were approved for TB treatment, for which resistances are already emerging. Therefore, there is a crucial need for new chemotherapeutic agents capable of eradicating TB. Enzymes belonging to the type II fatty acid synthase system (FAS-II) are involved in the biosynthesis of mycolic acids, cell envelope components essential for mycobacterial survival. Among them, InhA is the primary target of isoniazid (INH), one of the most effective compounds to treat TB. INH acts as a prodrug requiring activation by the catalase-peroxidase KatG, whose mutations are the major cause for INH resistance. Herein, a new series of direct InhA inhibitors were designed based on a molecular hybridization approach. They exhibit potent inhibitory activities of InhA and, for some of them, good antitubercular activities. Moreover, they display a low toxicity on human cells. A study of the mechanism of action of the most effective molecules shows that they inhibit the biosynthesis of mycolic acids. The X-ray structures of two InhA/NAD+/inhibitor complexes have been obtained showing a binding mode of a part of the molecule in the minor portal, rarely seen in the InhA structures reported so far.
Assuntos
Antituberculosos , Mycobacterium tuberculosis , Humanos , Antituberculosos/farmacologia , Antituberculosos/química , Proteínas de Bactérias/metabolismo , Éter , Éteres/farmacologia , Etil-Éteres/farmacologia , Isoniazida/farmacologia , Mutação , Ácidos MicólicosRESUMO
A series of 25 chiral anti-cancer lipidic alkynylcarbinols (LACs) were devised by introducing an (hetero)aromatic ring between the aliphatic chain and the dialkynylcarbinol warhead. The resulting phenyl-dialkynylcarbinols (PACs) exhibit enhanced stability, while retaining cytotoxicity against HCT116 and U2OS cell lines with IC50 down to 40 nM for resolved eutomers. A clickable probe was used to confirm the PAC prodrug behavior: upon enantiospecific bio-oxidation of the carbinol by the HSD17B11 short-chain dehydrogenase/reductase (SDR), the resulting ynones covalently modify cellular proteins, leading to endoplasmic reticulum stress, ubiquitin-proteasome system inhibition, and apoptosis. Insights into the design of LAC prodrugs specifically bioactivated by HSD17B11 vs its paralogue HSD17B13 were obtained. The HSD17B11/HSD17B13-dependent cytotoxicity of PACs was exploited to develop a cellular assay to identify specific inhibitors of these enzymes. A docking study was performed with the HSD17B11 AlphaFold model, providing a molecular basis of the SDR substrates mimicry by PACs. The safety profile of a representative PAC was established in mice.
Assuntos
Alcinos , Antineoplásicos , Camundongos , Animais , Alcinos/farmacologia , Alcinos/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Acetileno , Estrutura Molecular , Lipídeos/química , Linhagem Celular TumoralRESUMO
Zearalenone (ZEN) is a non-steroid estrogen mycotoxin produced by numerous strains of Fusarium which commonly contaminate cereals. After oral administration, ZEN is reduced via intestinal and hepatic metabolism to α- and ß-zearalenol (αZEL and ßZEL). These reduced metabolites possess estrogenic properties, αZEL showing the highest affinity for ERs. ZEN and reduced metabolites cause hormonal effects in animals, such as abnormalities in the development of the reproductive tract and mammary gland in female offspring, suggesting a fetal exposure to these contaminants. In our previous work, we have suggested the potential impact of ZEN on placental cells considering this organ as a potential target of xenobiotics. In this work, we first compared the in vitro effects of αZEL and ßΖΕL on cell differentiation to their parental molecule on human trophoblast (BeWo cells). Secondly, we investigated their molecular mechanisms of action by investigating the expression of main differentiation biomarkers and the implication of nuclear receptor by docking prediction. Conversely to ZEN, reduced metabolites did not induce trophoblast differentiation. They also induced significant changes in ABC transporter expression by potential interaction with nuclear receptors (LXR, PXR, PR) that could modify the transport function of placental cells. Finally, the mechanism of ZEN differentiation induction seemed not to involve nuclear receptor commonly involved in the differentiation process (PPARγ). Our results demonstrated that in spite of structure similarities between ZEN, αZEL and ßZEL, toxicological effects and toxicity mechanisms were significantly different for the three molecules.
Assuntos
Estrogênios não Esteroides/toxicidade , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Trofoblastos/efeitos dos fármacos , Zearalenona/toxicidade , Zeranol/análogos & derivados , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Humanos , Receptores Citoplasmáticos e Nucleares/metabolismo , Relação Estrutura-Atividade , Trofoblastos/metabolismo , Zeranol/toxicidadeRESUMO
A sexual enhancer dietary supplement in pre-commercialization phase was analyzed. It contained the two phosphodiesterase-5 inhibitors (PDE-5i) sildenafil and methisosildenafil as major adulterants. Fourteen more sildenafil derivatives were detected and after isolation, their structures were elucidated thanks to NMR, high resolution and tandem mass spectrometry, and UV spectroscopy. Ten of them were never described. All these compounds are probably by-products of different reaction steps during the synthesis of the two PDE-5i that were not properly eliminated during the purification procedure. The total amount of sildenafil-related compounds was estimated at 68â¯mg per capsule, sildenafil and methisosildenafil accounting for 20â¯mg and 38â¯mg respectively.
Assuntos
Contaminação de Medicamentos , Inibidores da Fosfodiesterase 5 , Suplementos Nutricionais/análise , Citrato de Sildenafila , Espectrometria de Massas em TandemRESUMO
Preeclampsia (PE) is a leading cause of pregnancy complications, affecting 3-7% of pregnant women worldwide. The pathophysiology of preeclampsia involves a redox imbalance, oxidative stress and a reduced nitric oxide (NO) bioavailability. The molecular and cellular mechanisms leading to the dysfunction of the placental endothelial NO synthase (eNOS) are not clarified. This study was designed to investigate whether aldehydes generated by lipid peroxidation products (LPP), may contribute to placental eNOS dysfunction in PE. The analysis of placentas from PE-affected patients and normal pregnancies, showed a significant increase in protein carbonyl content, indicative of oxidative stress-induced protein modification, as shown by the accumulation of acrolein, 4-hydroxynonenal (HNE), and 4-oxo-2(E)-nonenal (ONE) adducts in PE placentas. In contrast, the levels of these LPP-adducts were low in placentas from normal pregnancies. Immunofluorescence and confocal experiments pointed out a colocalization of eNOS with ONE-Lys adducts, whereas eNOS was not modified in normal placentas. LC-MS/MS analysis of recombinant eNOS preincubated with ONE, allowed to identify several ONE-modified Lys-containing peptides, confirming that eNOS may undergo post-translational modification by LPP. The preincubation of HTR-8/SVneo human trophoblasts (HTR8) with ONE, resulted in ONE-Lys modification of eNOS and a reduced generation of NO. ONE inhibited the migration of HTR8 trophoblasts in the wound closure model, and this was partly restored by the NO donor, NOC-18, which confirmed the important role of NO in the invasive potential of trophoblasts. In conclusion, placental eNOS is modified by ONE in PE placentas, which emphasizes the sensitivity of this protein to oxidative stress in the disturbed redox environment of preeclamptic pregnancies.
Assuntos
Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico/metabolismo , Pré-Eclâmpsia/tratamento farmacológico , Acroleína/antagonistas & inibidores , Acroleína/metabolismo , Adulto , Aldeídos/antagonistas & inibidores , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida , Feminino , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Óxido Nítrico/genética , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Placenta/efeitos dos fármacos , Placenta/patologia , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Gravidez , Espectrometria de Massas em Tandem , Trofoblastos/efeitos dos fármacos , Trofoblastos/patologiaRESUMO
The natural product ferutinin was shown to act as an agonist to estrogen receptor ERα and agonist/antagonist to ERß featuring a weak antiproliferative activity toward breast cancer cells. To enhance this activity, ferutinin analogues were synthesized by esterification of jaeschkenadiol with different acids. These compounds were assayed for their in vitro antiproliferative activity against estrogen-dependent (MCF-7) and estrogen-independent (MDA-MB-231) breast cancer cell lines. Among the compounds, 3c' exhibited a potent inhibitory selective activity against MCF-7 with IC50 value of 1 µM. Docking simulation of 3c' in the ligand binding domain of the ERs indicated a potential antagonism interaction with both ER subtypes. Functional assay showed that 3c' binds as an antagonist to ERα protein while ferutinin acts as an agonist.
Assuntos
Benzoatos/metabolismo , Cicloeptanos/metabolismo , Sesquiterpenos/metabolismo , Compostos Bicíclicos com Pontes/metabolismo , Linhagem Celular Tumoral , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Simulação de Acoplamento Molecular , Espectrofotometria InfravermelhoRESUMO
A series of GEQ analogues bearing pyrrolidinone or pyrrolidine cores were synthesized and evaluated against InhA, essential target for Mycobacterium tuberculosis (M.tb) survival. The compounds were also evaluated against M.tb H37Rv growth. Interestingly, some of the compounds, not efficient as InhA inhibitors, are active against M.tb with MICs up to 1.4 µM. In particular, compound 4b was screened with different M.tb mutated strains in order to identify the cellular target, but without success, suggesting a new possible mode of action.
Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Desenho de Fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Pirrolidinas/química , Pirrolidinas/farmacologia , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Antituberculosos/química , Antituberculosos/metabolismo , Antituberculosos/farmacologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Proteínas de Membrana Transportadoras/metabolismo , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/metabolismo , Oxirredutases/química , Oxirredutases/metabolismo , Conformação Proteica , Pirrolidinas/metabolismo , Pirrolidinonas/metabolismo , Relação Estrutura-AtividadeRESUMO
Marine organisms have proven to be a promising source of new compounds with activity against tumor cell lines. Granulatimide and isogranulatimide are marine alkaloids that have been shown to inhibit checkpoint kinase 1 (Chk1), a key protein in the DNA damage response and an emerging target for anticancer therapeutics. Here, we describe the synthesis and preliminary evaluation of amido and amino analogues of isogranulatimide. The new derivatives were prepared in three steps from 2-imidazol-1-yl-1H-indol-5-ylamine. Two of the compounds synthesized exhibited more potent in vitro antiproliferative activity (single-digit micromolar concentration range), by at least one log of magnitude, than the natural product isogranulatimide when evaluated in six human tumor cell lines: non-small-cell lung cancer (A549), colon cancer (LoVo), breast cancer (MCF7), oligodendroglioma (Hs683), glioblastoma (U373), and melanoma (SKMEL28). The mechanism of action of these derivatives remains to be elucidated, given that they did not significantly inhibit Chk1, however these compounds are easily synthesized and exhibit potent anticancer activity and are thus worthy of further study.