RESUMEN
We developed a transition metal-free methodology for the construction of pyrazoloquinazolinone derivatives. The strategy involves a one-pot reaction wherein the N-tosylhydrazone and its corresponding diazo derivative are generated in situ, followed by an intramolecular 1,3-dipolar cycloaddition-ring expansion to provide the pyrazolo-[1,5-c]quinazolinone motif. This approach enables straightforward access to a diverse range of highly functionalized N-heterocyclic compounds in good yields (up to 92%).
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BACKGROUND: Despite the current therapeutic treatments including surgery, chemotherapy, radiotherapy and more recently immunotherapy, the mortality rate of lung cancer stays high. Regarding lung cancer, epigenetic modifications altering cell cycle, angiogenesis and programmed cancer cell death are therapeutic targets to combine with immunotherapy to improve treatment success. In a recent study, we uncovered that a molecule called QAPHA ((E)-3-(5-((2-cyanoquinolin-4-yl)(methyl)amino)-2-methoxyphenyl)-N-hydroxyacrylamide) has a dual function as both a tubulin polymerization and HDAC inhibitors. Here, we investigate the impact of this novel dual inhibitor on the immune response to lung cancer. METHODS: To elucidate the mechanism of action of QAPHA, we conducted a chemical proteomics analysis. Using an in vivo mouse model of lung cancer (TC-1 tumor cells), we assessed the effects of QAPHA on tumor regression. Tumor infiltrating immune cells were characterized by flow cytometry. RESULTS: In this study, we first showed that QAPHA effectively inhibited histone deacetylase 6, leading to upregulation of HSP90, cytochrome C and caspases, as revealed by proteomic analysis. We confirmed that QAPHA induces immunogenic cell death (ICD) by expressing calreticulin at cell surface in vitro and demonstrated its efficacy as a vaccine in vivo. Remarkably, even at a low concentration (0.5 mg/kg), QAPHA achieved complete tumor regression in approximately 60% of mice treated intratumorally, establishing a long-lasting anticancer immune response. Additionally, QAPHA treatment promoted the infiltration of M1-polarized macrophages in treated mice, indicating the induction of a pro-inflammatory environment within the tumor. Very interestingly, our findings also revealed that QAPHA upregulated major histocompatibility complex class II (MHC-II) expression on TC-1 tumor cells both in vitro and in vivo, facilitating the recruitment of cytotoxic CD4+T cells (CD4+CTL) expressing CD4+, NKG2D+, CRTAM+, and Perforin+. Finally, we showed that tumor regression strongly correlates to MHC-II expression level on tumor cell and CD4+ CTL infiltrate. CONCLUSION: Collectively, our findings shed light on the discovery of a new multitarget inhibitor able to induce ICD and MHC-II upregulation in TC-1 tumor cell. These two processes participate in enhancing a specific CD4+ cytotoxic T cell-mediated antitumor response in vivo in our model of lung cancer. This breakthrough suggests the potential of QAPHA as a promising agent for cancer treatment.
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Antineoplásicos , Neoplasias Pulmonares , Animales , Ratones , Neoplasias Pulmonares/tratamiento farmacológico , Proteómica , Regulación hacia Arriba , Antígenos de Histocompatibilidad Clase II , Linfocitos T CD4-PositivosRESUMEN
This study evaluated the potential of isoCoQ-Carbazole, a diheterocyclic analog of isoCA-4, as an anti-tumor agent. To overcome its low aqueous solubility, liposomes were developed as a delivery system for the compound. In vitro experiments showed that loaded liposomes exhibited similar activity to the free form on multiple human tumor cell lines. In vivo experiments using a palliative intratumoral injection chemotherapy approach further demonstrated that isoCoQ-Carbazole loaded liposomes significantly reduced tumor growth in a CA-4-resistant HT29â cell model, without inducing any observable toxicity or weight loss in the treated mice. These findings suggest that liposomal isoCoQ-Carbazole may hold promise as a potential therapeutic agent for the treatment of inoperable, radiation-insensitive cancers.
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Antineoplásicos , Carbazoles , Liposomas , Solubilidad , Humanos , Liposomas/química , Carbazoles/química , Carbazoles/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Animales , Ratones , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
Functionalized 4-aryl-4H-benzo[d][1,3]oxazines are synthesized under transition-metal-free conditions using ortho-amide-N-tosylhydrazones. This synthetic method uses readily available N-tosylhydrazones as the diazo compound precursors and involves an intramolecular ring closure reaction mediated by a protic polar additive (iPrOH). A wide range of functionalized oxazines are obtained by this straightforward method in good to excellent yields. Furthermore, the viability of our strategy is illustrated by the gram-scale elaboration of a bromo-substituted 4H-benzo[d][1,3]oxazine and its post-functionalization by palladium-catalyzed cross-couplings.
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Amidas , Oxazinas , Ciclización , Catálisis , PaladioRESUMEN
A series of quinoline and quinazoline analogs were designed and synthesized as new tubulin polymerization (TP) and histone deacetylases (HDAC) inhibitors. Compounds 12a and 12d showed the best cytotoxicity activities against a panel of human cancer cell lines with an averaged IC50 value of 0.6 and 0.7 nM, respectively. Furthermore, these lead compounds showed good activities against CA-4-resistant colon-carcinoma and multidrug-resistant leukemia cells. In addition, compounds 12a and 12d induced HT29 cell cycle arrest in the G2/M phase and produced caspase-induced apoptosis of HT29 cells through mitochondrial dysfunction. Also, 12a and 12d inhibited HDAC8, 6, and 11 activities. Furthermore, lead compound 12a exhibited higher metabolic stability than isoCA-4 and was highly potent in suppressing tumor growth in the fibrosarcoma MCA205 tumor model. Collectively, these studies suggest that 12a represents a new dual inhibitor of TP and HDAC activities, which makes it a suitable candidate for further investigations in clinical development.
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Antineoplásicos , Quinolinas , Línea Celular Tumoral , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Humanos , Ácidos Hidroxámicos/farmacología , Polimerizacion , Quinolinas/farmacología , Proteínas Represoras , Tubulina (Proteína)/metabolismoRESUMEN
Imidazopyridines constitute one of the most important scaffolds in medicinal chemistry, as their skeleton could be found in a myriad of biologically active molecules. Although numerous strategies were elaborated for imidazopyridine preparation in the 2010s, novel eco-compatible synthetic approaches have emerged, conscious of climate change concerns. In this framework, photochemical methods have been promoted to conceive this heterocyclic motif over the last decade. This review covers the recently published works on synthesizing highly functionalized imidazopyridines by light induction.
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Imidazoles , Piridinas , Química Farmacéutica , Imidazoles/química , Piridinas/químicaRESUMEN
Inhibiting receptor tyrosine kinases is commonly achieved by two main strategies targeting either the intracellular kinase domain by low molecular weight compounds or the extracellular ligand-binding domain by monoclonal antibodies. Identifying small molecules able to inhibit RTKs at the extracellular level would be highly desirable to gain exquisite selectivity but is believed to be challenging owing to the size of RTK endogenous ligands (cytokines, growth factors) and the topology of RTK extracellular domains. We here report the high-throughput screening of the French Chemical Library (48K compounds) for extracellular inhibitors of the Fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase, by a homogeneous time-resolved fluorescence competition assay. A total of 679 small molecular weight ligands (1.4%) were confirmed to strongly inhibit (>75%) the binding of the fluorescent labeled FLT3 ligand (FL cytokine) to FLT3 overexpressed in HEK-293 cells, at two different concentrations (5 and 20 µM). Concentration-response curves, obtained for 111 lead-like molecules, confirmed the unexpected tolerance of the FLT3 extracellular domain for low molecular weight druggable inhibitors exhibiting submicromolar potencies, chemical diversity, and promising pharmacokinetic properties. Further investigation of one hit confirmed inhibitory properties in dorsal root ganglia neurons and in a mouse model of neuropathic pain.
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Ensayos Analíticos de Alto Rendimiento , Tirosina Quinasa 3 Similar a fms , Animales , Células HEK293 , Humanos , Ligandos , RatonesRESUMEN
This study shows that various di- and tri-substituted alkenes with high chemoselectivity were obtained in good to high yields by coupling N-tosylhydrazones (NTHs) with benzylic phosphates as electrophilic partners. The obtained new catalytic system consisted of PdCl2(CH3CN)2/dppp, LiOtBu as a base, and cyclopentyl methyl ether as a green solvent. In addition, we performed a gram-scale transformation using NTH derivatives and benzylic phosphates having a C sp2-Cl bond. The latter was used as a starting point for further postfunctionalization of the key intermediates.
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Alquenos , Paladio , Catálisis , FosfatosRESUMEN
This review concerns the synthesis and biological activities of pyrazino[1,2-a]indoles and pyrazino[1,2-a]indol-1-ones reported since 1997 and the discovery of biological activity of pyrazinoindole derivatives. In the first part, we first presented the synthetic routes that have been reported from a methodological point of view to access the pyrazinoindole unit according to cyclization reactions using or not using metal catalysts. Then, syntheses and neuropsychiatric, auto-immune, anti-infectious and anti-cancer properties of pyrazinoindoles were detailed. In the second part, we first reported the main accesses to pyrazinoindol-1-one substrates according to Michael reactions, metal-catalyzed and metal-free cyclization reactions. The syntheses and anti-cancer, anti-infectious, anti-allergenic and neuropsychiatric properties of pyrazinoindolones were next described and discussed.
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This review brings together the various pathways to the oxazino[4,3-a]indole motif over the last decades. Representative examples showing the scope of these processes will illustrate the synthetic pathways and the biological activity of the synthesized oxazinoindoles will be mentioned wherever possible.
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Indoles/síntesis química , Humanos , Estructura Molecular , EstereoisomerismoRESUMEN
In this study, a variety of original ligands related to Combretastatin A-4 and isoCombretastatin A-4, able to inhibit the tubulin polymerization into microtubules, was designed, synthesized, and evaluated. Our lead compound 15d having a quinazoline as A-ring and a 2-substituted indole as B-ring separated by a N-methyl linker displayed a remarkable sub-nanomolar level of cytotoxicity (IC50 < 1 nM) against 9 human cancer cell lines.
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Antineoplásicos/farmacología , Indoles/química , Estilbenos/química , Moduladores de Tubulina/química , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Sitios de Unión , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Estabilidad de Medicamentos , Humanos , Indoles/metabolismo , Indoles/farmacología , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Ratas , Estilbenos/metabolismo , Estilbenos/farmacología , Relación Estructura-Actividad , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/farmacologíaRESUMEN
A new methodology to synthesize sulfonyl-N-phenylaniline derivatives via the trapping of bromo-sulfone derivatives generated from N-tosylhydrazones (NTHs) with amines is described. The reaction proved successful for a wide range of NTHs and amines and tolerated various functional groups on either coupling partner (35 examples). The mechanism was studied, and we showed that the sulfone formation does not follow a radical pathway.
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The pyrido[1,2-a]indole unit found in many organic compounds such as natural products, pharmaceuticals, and materials, has intensively stimulated the research of new synthetic pathways giving access to this heterocyclic nucleus in very recent years. In this review, the synthesis of pyrido[1,2-a]indoles will be divided into two parts, which concern accesses to this skeleton using or not metal catalysis.
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In this work, a series of cyclic bridged analogs of isocombretastatin A-4 (isoCA-4) with phenyl or pyridine linkers were designed and synthesized. The synthesis of the desired analogs was performed by the formation of nitro-vinyl intermediates, followed by a Cadogan cyclization. Structure activity relationship (SAR) study demonstrates the critical role of the combination of quinaldine as ring A, pyridine as the linker, and indole as ring B in the same molecule, for the cytotoxic activity. Among all tested compounds, compound 42 showed the highest antiproliferative activity against a panel of cancer cell lines with average IC50 values of 5.6 nM. Also, compound 42 showed high antiproliferative activity against the MDR1-overexpressing K562R cell line; thus, it was 1.5- and 12-fold more active than the reference compounds, isoCA-4 and CA-4, respectively. Moreover, 42 displayed a strong antiproliferative activity against the colon-carcinoma cells (HT-29), which are resistant to combretastatin A-4 and isoCA-4, and it was found to be 8000-fold more active than natural CA-4. Compound 42 also effectively inhibited tubulin polymerization both in vitro and in cells, and induced cell cycle arrest in G2/M phase. Next, we demonstrated that compound 42 dose-dependently caused caspase-induced apoptosis of K562 cells through mitochondrial dysfunction. Finally, we evaluated the effect of compound 42 in human no cancer cells compared to the reference compound. We demonstrated that 42 was 73 times less cytotoxic than isoCA-4 in quiescent peripheral blood lymphocytes (PBLs). In summary, these results suggest that compound 42 represents a promising tubulin inhibitor worthy of further investigation.
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Diseño de Fármacos , Estilbenos/química , Estilbenos/farmacología , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclización , Humanos , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Estilbenos/síntesis química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis químicaRESUMEN
A divergent and efficient one-pot sequence allowing direct access to 3-arylbenzofuran derivatives has been developed. The process, involving N-tosylhydrazones and bromophenols, proceeds via a palladium-catalyzed Barluenga-Valdés cross-coupling, followed by an aerobic, copper-catalyzed, radical cyclization to form Csp2-Csp2 and O-Csp2 bonds. 3-Arylated benzofurans bearing various substituents were obtained with good to excellent yields (up to 90%). Mechanistic investigation strongly supports a radical process for the cyclization step.
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The use of sulfinic acids and their salts continues to be extensively developed in organic chemistry. This is attributable to their dual capacity for acting as nucleophilic or electrophilic reagents, as well as their ease of preparation and stability on storage. This report highlights the research accomplished since 2015 on this topic, updating a previous review published by our team in 2014.
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In this work, unique flavopiridol analogs bearing thiosugars, amino acids and heterocyclic moieties tethered to the flavopiridol via thioether and amine bonds mainly on its C ring have been prepared. The analogs bearing thioether-benzimidazoles as substituents have demonstrated high cytotoxic activity in vitro against up to seven cancer cell lines. Their cytotoxic effects are comparable to those of flavopiridol. The most active compound 13c resulting from a structure-activity relationship (SAR) study and in silico docking showed the best antiproliferative activity and was more efficient than the reference compound. In addition, compound 13c showed significant nanomolar inhibition against CDK9, CDK10, and GSK3ß protein kinases.
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Antineoplásicos/farmacología , Flavonoides/farmacología , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Flavonoides/síntesis química , Flavonoides/química , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
More than 160 arginine analogues modified on the C-terminus via either an amide bond or a heterocyclic moiety (1,2,4-oxadiazole, 1,3,4-oxadiazole and 1,2,4-triazole) were prepared as potential inhibitors of NO synthases (NOS). A methodology involving formation of a thiocitrulline intermediate linked through its side-chain on a solid support followed by modification of its carboxylate group was developed. Finally, the side-chain thiourea group was either let unchanged, S-alkylated (Me, Et) or guanidinylated (Me, Et) to yield respectively after TFA treatment the corresponding thiocitrulline, S-Me/Et-isothiocitrulline and N-Me/Et-arginine substrate analogues. They all were tested against three recombinant NOS isoforms. Several compounds containing a S-Et- or a S-Me-Itc moiety and mainly belonging to both the dipeptide-like and 1,2,4-oxadiazole series were shown to inhibit nNOS and iNOS with IC50 in the 1-50â µM range. Spectral studies confirmed that these new compounds interacted at the heme active site. The more active compounds were found to inhibit intra-cellular iNOS expressed in RAW264.7 and INS-1 cells with similar efficiency than the reference compounds L-NIL and SEIT.
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Dipéptidos/farmacología , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Técnicas de Síntesis en Fase Sólida , Animales , Bovinos , Línea Celular , Dipéptidos/síntesis química , Dipéptidos/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Ratones , Óxido Nítrico Sintasa/metabolismo , RatasRESUMEN
Combretastatin A-4 (CA-4) is a natural anti-cancer agent isolated in 1989 from the African willow tree, Combretum caffrum. Due to its chemical simplicity, this (Z)-stilbene has been the subject of many structural modifications mainly to improve its chemical and metabolic stability. Beside a large number of synthetic analogues, isoCombretastatin A-4 (isoCA-4), has proved to be a solution of choice since this non-natural isomer of CA-4 is stable, easier to synthesize and has equivalent antitumor properties as CA-4. In this review, we will present the structure-activity relationships (SARs) around isoCA-4 since its discovery in 2007. In a first part, we will describe some alternatives to replace the phenol B-ring of isoCA-4, then we will focus on the variations made on the 1,1-ethylene double bond and then, we will evocate very recent exiting results concerning the possible replacements of the 3,4,5-trimethoxyphenyl A-ring of isoCA-4 by suitable heterocycles.