We present the development of , a structurally novel PROTAC targeting the CREB-binding protein (CBP) and E1A-associated protein (EP300)-two homologous multidomain enzymes crucial for enhancer-mediated transcription. The design of was based on the crystal structure of an in-house bromodomain (BRD) inhibitor featuring a 3-methyl-cinnoline acetyl-lysine mimic acetyl-lysine mimic discovered by high-throughput fragment docking. Our study shows that, despite its modest binding affinity to CBP/EP300-BRD, 's remarkable protein degradation activity stems from its good cooperativity, which we demonstrate by the characterization of its ternary complex formation both and .
View Article and Find Full Text PDFCannabidiol (CBD) is garnering increasing interest due to its significant biological activity. This natural compound is one of the major cannabinoids in Cannabis sativa L. In this work, we describe the encapsulation of CBD in solid and hollow pH-sensitive poly(4-vinylpyridine) (solid@p4VP and hollow@p4VP) nanoparticles, and temperature-sensitive poly(N-isopropylacrylamide) (solid@pNIPAM and hollow@pNIPAM) nanoparticles for transport and release CBD in a controlled manner.
View Article and Find Full Text PDFThe 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.
View Article and Find Full Text PDFProteolysis 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.
View Article and Find Full Text PDFAn 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 β-aryl and β-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.
View Article and Find Full Text PDFAn electrochemically driven nickel-catalyzed enantioselective reductive cross-coupling of aryl aziridines with alkenyl bromides has been developed, affording enantioenriched β-aryl homoallylic amines with excellent -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.
View Article and Find Full Text PDFThe 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.
View Article and Find Full Text PDFAntibody-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.
View Article and Find Full Text PDFThe bengamides comprise an interesting family of natural products isolated from sponges belonging to the prolific 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 and .
View Article and Find Full Text PDFSmall 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.
View Article and Find Full Text PDFThe 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 family, were explored and investigated as a new option to improve CRC treatment. To this end, two potent bengamide analogues, Ben I () and Ben V (), were selected for this study, for which they were synthesized according to a new synthetic strategy recently developed in our laboratories.
View Article and Find Full Text PDFEncouraged 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.
View Article and Find Full Text PDFMarine 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.
View Article and Find Full Text PDFGlycolipids 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.
View Article and Find Full Text PDFNew 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.
View Article and Find Full Text PDFA 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.
View Article and Find Full Text PDFThe 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.
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