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The development of novel strategies to rapidly construct complex chiral molecules from readily available feedstocks is a long-term pursuit in the chemistry community. Radical-mediated alkene difunctionalizations represent an excellent platform towards this goal. However, asymmetric versions remain highly challenging, and more importantly, examples featuring simple hydrocarbons as reaction partners are elusive. Here we report an asymmetric three-component alkene dicarbofunctionalization capitalizing on the direct activation of C(sp 3)-H bonds through the combination of photocatalysed hydrogen atom transfer and nickel catalysis. This protocol provides an efficient platform for installing two vicinal carbon-carbon bonds across alkenes in an atom-economic fashion, providing a wide array of high-value chiral α-aryl/alkenyl carbonyls and phosphonates, as well as 1,1-diarylalkanes from ubiquitous alkane, ether and alcohol feedstocks. This method exhibits operational simplicity, broad substrate scope and excellent regioselectivity, chemoselectivity and enantioselectivity. The compatibility with bioactive motifs and expedient synthesis of pharmaceutically relevant molecules highlight the synthetic potential of this protocol.
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Proteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that simultaneously bind an E3 ligase and a protein of interest, inducing degradation of the latter via the ubiquitin-proteasome system. Here we present the development of degraders targeting CREB-binding protein (CBP) and E1A-associated protein (EP300)-two homologous multidomain enzymes crucial for enhancer-mediated transcription. Our PROTAC campaign focused on CPI-1612, a reported inhibitor of the histone acetyltransferase (HAT) domain of these two proteins. A novel asymmetric synthesis of this ligand was devised, while PROTAC-SAR was explored by measuring degradation, target engagement, and ternary complex formation in cellulo. Our study demonstrates that engagement of Cereblon (CRBN) and a sufficiently long linker between the E3 and CBP/EP300 binders (≥21 atoms) are required for PROTAC-mediated degradation using CPI-1612 resulting in a new active PROTAC dCE-1. Lessons learned from this campaign, particularly the importance of cell-based assays to understand the reasons underlying PROTAC performance, are likely applicable to other targets to assist the development of degraders.
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An asymmetric three-component carbosulfonylation of alkenes is presented here. The reaction, involving the simultaneous formation of a C-C and a C-S bond across the π-system, uses a dual nickel/photoredox catalytic system to produce both ß-aryl and ß-alkenyl sulfones in high yields and with excellent levels of stereocontrol (up to 99:1 er). This protocol exhibits a broad substrate scope and excellent functional group tolerance and its synthetic potential has been demonstrated by successful applications toward pharmacologically relevant molecules. A broad array of control experiments supports the involvement of a secondary alkyl radical intermediate generated through radical addition of a sulfonyl radical to the double bond. Moreover, stoichiometric and cross-over experiments further suggest an underlying Ni(0)/Ni(I)/Ni(III) pathway operative in these transformations.
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An electrochemically driven nickel-catalyzed enantioselective reductive cross-coupling of aryl aziridines with alkenyl bromides has been developed, affording enantioenriched ß-aryl homoallylic amines with excellent E-selectivity. This electroreductive strategy proceeds in the absence of heterogeneous metal reductants and sacrificial anodes by employing constant current electrolysis in an undivided cell with triethylamine as a terminal reductant. The reaction features mild conditions, remarkable stereocontrol, broad substrate scope, and excellent functional group compatibility, which was illustrated by the late-stage functionalization of bioactive molecules. Mechanistic studies indicate that this transformation conforms with a stereoconvergent mechanism in which the aziridine is activated through a nucleophilic halide ring-opening process.
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The inhibition of sustained angiogenesis is an attractive approach for the treatment of cancer, blindness and other angiogenesis-dependent diseases. Encouraged by our previous finding that toluquinol, a methyl hydroquinone isolated from a marine fungus, exhibited an interesting antiangiogenic activity, we further explored structural modifications of this natural compound in order to develop improved drug candidates. Our results indicate that although the methyl group plays a relevant role in the cytotoxic activity of toluquinol, some derivatives in which this methyl was replaced by another substituent, could keep the antiangiogenic activity, whereas exhibiting a lower cytotoxicity in vitro. This is the case of (E)- 2-(3-methoxyprop-1-en-1-yl) benzene-1,4-diol, which exhibits a decreased toxicity, whereas maintaining or even improving the antiangiogenic activity of toluquinol, as demonstrated by a number of in vitro (endothelial cells proliferation, migration and tube formation) and in vivo (chick embryo chrorioallantoic membrane vascularization and murine corneal neovascularization) experimental approaches. Our results point to a mechanism of action that could be related to an induction of apoptosis, as well as to an increase in the reactive oxygen species levels, a reduction of the redox capacity and the inhibition of the VEGFR2, Akt and ERK phosphorylation in VEGF-activated endothelial cells. The biological activity of this new angiogenesis inhibitor, along with its lower undesired toxicity, suggests that it is a promising drug candidate with improved potential for the treatment of angiogenesis-related diseases.
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Inhibidores de la Angiogénesis , Hidroquinonas , Embrión de Pollo , Animales , Ratones , Humanos , Inhibidores de la Angiogénesis/uso terapéutico , Hidroquinonas/farmacología , Hidroquinonas/uso terapéutico , Factor A de Crecimiento Endotelial Vascular , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células Endoteliales/metabolismo , Especies Reactivas de Oxígeno , Benceno , Transducción de Señal , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Proliferación Celular , Células Endoteliales de la Vena Umbilical Humana/metabolismoRESUMEN
Antibody-drug conjugates (ADCs) are an important class of therapeutics for the treatment of cancer. Structurally, an ADC comprises an antibody, which serves as the delivery system, a payload drug that is a potent cytotoxin that kills cancer cells, and a chemical linker that connects the payload with the antibody. Unlike conventional chemotherapy methods, an ADC couples the selective targeting and pharmacokinetic characteristics related to the antibody with the potent cytotoxicity of the payload. This results in high specificity and potency by reducing off-target toxicities in patients by limiting the exposure of healthy tissues to the cytotoxic drug. As a consequence of these outstanding features, significant research efforts have been devoted to the design, synthesis, and development of ADCs, and several ADCs have been approved for clinical use. The ADC field not only relies upon biology and biochemistry (antibody) but also upon organic chemistry (linker and payload). In the latter, total synthesis of natural and designed cytotoxic compounds, together with the development of novel synthetic strategies, have been key aspects of the consecution of clinical ADCs. In the case of payloads from marine origin, impressive structural architectures and biological properties are observed, thus making them prime targets for chemical synthesis and the development of ADCs. In this review, we explore the molecular and biological diversity of ADCs, with particular emphasis on those containing marine cytotoxic drugs as the payload.
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Antineoplásicos , Inmunoconjugados , Neoplasias , Antineoplásicos/química , Antineoplásicos/farmacología , Citotoxinas , Humanos , Inmunoconjugados/química , Inmunoconjugados/farmacología , Neoplasias/tratamiento farmacológicoRESUMEN
The bengamides comprise an interesting family of natural products isolated from sponges belonging to the prolific Jaspidae family. Their outstanding antitumor properties, coupled with their unique mechanism of action and unprecedented molecular structures, have prompted an intense research activity directed towards their total syntheses, analogue design, and biological evaluations for their development as new anticancer agents. Together with these biological studies in cancer research, in recent years, the bengamides have been identified as potential antibiotics by their impressive biological activities against various drug-resistant bacteria such as Mycobacterium tuberculosis and Staphylococcus aureus. This review reports on the new advances in the chemistry and biology of the bengamides during the last years, paying special attention to their development as promising new antibiotics. Thus, the evolution of the bengamides from their initial exploration as antitumor agents up to their current status as antibiotics is described in detail, highlighting the manifold value of these marine natural products as valid hits in medicinal chemistry.
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Antineoplásicos , Productos Biológicos , Mycobacterium tuberculosis , Antibacterianos/química , Antibacterianos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Productos Biológicos/química , Productos Biológicos/farmacología , Estructura MolecularRESUMEN
Small molecule ligand binding to the ATAD2 bromodomain is investigated here through the synergistic combination of molecular dynamics and protein crystallography. A previously unexplored conformation of the binding pocket upon rearrangement of the gatekeeper residue Ile1074 has been found. Further, our investigations reveal how minor structural differences in the ligands result in binding with different plasticity of the ZA loop for this difficult-to-drug bromodomain.
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The limited success and side effects of the current chemotherapeutic strategies against colorectal cancer (CRC), the third most common cancer worldwide, demand an assay with new drugs. The prominent antitumor activities displayed by the bengamides (Ben), a family of natural products isolated from marine sponges of the Jaspidae family, were explored and investigated as a new option to improve CRC treatment. To this end, two potent bengamide analogues, Ben I (5) and Ben V (10), were selected for this study, for which they were synthesized according to a new synthetic strategy recently developed in our laboratories. Their antitumor effects were analyzed in human and mouse colon cell lines, using cell cycle analysis and antiproliferative assays. In addition, the toxicity of the selected analogues was tested in human blood cells. These biological studies revealed that Ben I and V produced a significant decrease in CRC cell proliferation and induced a significant cell cycle alteration with a greater antiproliferative effect on tumor cell lines than normal cells. Interestingly, no toxicity effects were detected in blood cells for both compounds. All these biological results render the bengamide analogues Ben I and Ben V as promising antitumoral agents for the treatment of CRC.
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Antineoplásicos/farmacología , Azepinas/farmacología , Neoplasias del Colon/tratamiento farmacológico , Poríferos , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Azepinas/química , Azepinas/uso terapéutico , Línea Celular Tumoral/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Relación Estructura-ActividadRESUMEN
Ultraviolet radiation (UVR; 280-400 nm) has a great impact on aquatic ecosystems by affecting ecophysiological and biogeochemical processes as a consequence of the global change scenario generated by anthropogenic activities. We studied the effect of PAR (P)+UVA (A)+UVB (B) i.e. PAB, on the molecular physiology of the unicellular green alga Dunaliella tertiolecta for six days. We assessed the relationship between the triggered UVR stress response and metacaspases and caspase-like (CL)activities, which are proteases denoted to participate in cell death (CD) in phytoplankton. UVR inhibited cell growth and in vivo chlorophyll a fluorescence but did not cause cell death. Western blot analyses reflected that Type-II metacaspases (MCs) are present and appear to be involved in UVR induced-cell stress but not in dark-induced CD in D. tertiolecta. Enzyme kinetics revealed that cleavage of the MCs-reporter substrates RVRR, QRR, GRR, LKR, HEK, and VLK was 10-fold higher than WEHD, DEVD, IETD, and LETD CLs-substrates. The lowest apparent Michaelis-Menten constants (KM ap) corresponded to RVRRase (37.5 µM) indicating a high affinity by the RVRR substrate. The inhibition of enzymatic activities by using inhibitors with different target sites for hydrolyses demonstrated that from all of the R/ Kase activities only RVRRase was a potential candidate for being a metacaspase. In parallel, zymograms and peptide-mass fingerprinting analyses revealed the identities of such Rase activities suggesting an indirect evidence of possible natural physiological substrates of MCs. We present evidence of type II-MCs not being involved in CD in D. tertiolecta, but rather in survival strategies under the stressful irradiance conditions applied in this study.
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Encouraged by the promising antitumoral, antiangiogenic, and antilymphangiogenic properties of toluquinol, a set of analogues of this natural product of marine origin was synthesized to explore and evaluate the effects of structural modifications on their cytotoxic activity. We decided to investigate the effects of the substitution of the methyl group by other groups, the introduction of a second substituent, the relative position of the substituents, and the oxidation state. A set of analogues of 2-substituted, 2,3-disubstituted, and 2,6-disubstituted derived from hydroquinone were synthesized. The results revealed that the cytotoxic activity of this family of compounds could rely on the hydroquinone/benzoquinone part of the molecule, whereas the substituents might modulate the interaction of the molecule with their targets, changing either its activity or its selectivity. The methyl group is relevant for the cytotoxicity of toluquinol, since its replacement by other groups resulted in a significant loss of activity, and in general the introduction of a second substituent, preferentially in the para position with respect to the methyl group, was well tolerated. These findings provide guidance for the design of new toluquinol analogues with potentially better pharmacological properties.
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Antineoplásicos/farmacología , Diseño de Fármacos , Hidroquinonas/farmacología , Antineoplásicos/síntesis química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hidroquinonas/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Marine sponges are a prolific source of bioactive compounds. In this work, the putative antiangiogenic potential of a series of synthetic precursors of Solomonamide A, a cyclic peptide isolated from a marine sponge, was evaluated. By means of an in vitro screening, based on the inhibitory activity of endothelial tube formation, the compound Solo F-OH was selected for a deeper characterization of its antiangiogenic potential. Our results indicate that Solo F-OH is able to inhibit some key steps of the angiogenic process, including the proliferation, migration, and invasion of endothelial cells, as well as diminish their capability to degrade the extracellular matrix proteins. The antiangiogenic potential of Solo F-OH was confirmed by means of two different in vivo models: the chorioallantoic membrane (CAM) and the zebrafish yolk membrane (ZFYM) assays. The reduction in ERK1/2 and Akt phosphorylation in endothelial cells treated with Solo F-OH denotes that this compound could target the upstream components that are common to both pathways. Taken together, our results show a new and interesting biological activity of Solo F-OH as an inhibitor of the persistent and deregulated angiogenesis that characterizes cancer and other pathologies.
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Inhibidores de la Angiogénesis/farmacología , Péptidos Cíclicos/farmacología , Inhibidores de la Angiogénesis/química , Animales , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Membrana Corioalantoides , Células Endoteliales/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Estructura Molecular , Proteína Oncogénica v-akt/metabolismo , Fragmentos de Péptidos/metabolismo , Péptidos Cíclicos/química , Transducción de Señal/efectos de los fármacos , Pez CebraRESUMEN
Glycolipids represent a broad class of natural products structurally featured by a glycosidic fragment linked to a lipidic molecule. Despite the large structural variety of these glycoconjugates, they can be classified into three main groups, i.e., glycosphingolipids, glycoglycerolipids, and atypical glycolipids. In the particular case of glycolipids derived from marine sources, an impressive variety in their structural features and biological properties is observed, thus making them prime targets for chemical synthesis. In the present review, we explore the chemistry and biology of this class of compounds.
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Organismos Acuáticos/metabolismo , Productos Biológicos/química , Glucolípidos/química , Animales , Organismos Acuáticos/química , Productos Biológicos/farmacología , Glucolípidos/farmacología , Estructura Molecular , Océanos y Mares , Relación Estructura-ActividadRESUMEN
New synthetic strategies directed toward the novel cyclopeptides solomonamides have been explored utilizing an olefin metathesis as the key reaction. In the various strategies investigated, we worked on minimally oxidized systems, and the olefin metathesis reaction demonstrated efficiency and validity for the construction of the macrocyclic core. The described synthetic strategies toward the solomonamides are well suited for the subsequent access to the natural products and represent flexible and diversity-oriented routes that allow for the generation of a variety of analogues via oxidative transformations. In addition, preliminary biological evaluations of the generated solomonamide precursors revealed antitumor activity against various tumor cell lines.
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Antineoplásicos/farmacología , Péptidos Cíclicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclización , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Conformación Molecular , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/química , Relación Estructura-ActividadRESUMEN
A new total synthesis of the natural product (-)-depudecin, a unique and unexplored histone deacetylase (HDAC) inhibitor, is reported. A key feature of the synthesis is the utilization of an olefin cross-metathesis strategy, which provides for an efficient and improved access to natural depudecin, compared with our previous linear synthesis. Featured by its brevity and convergency, our developed synthetic strategy was applied to the preparation of the 10-epi derivative and the enantiomer of depudecin, which represent interesting stereoisomeric analogues for structure-activity relationship studies.
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The total synthesis of the natural product depudecin, an antiangiogenic microbial polyketide with inhibitory activity against histone deacetylases, is reported. Characterized by a highly oxidized 11-carbon chain containing two epoxides conjugated through a trans-disubstituted olefin, its total synthesis was efficiently accomplished by a novel asymmetric methodology of epoxide formation based on a new class of chiral sulfonium salts, allowing for the construction of the oxirane rings in an efficient and stereoselective fashion.