RESUMO
DNA-encoded libraries have proven their tremendous value in the identification of new lead compounds for drug discovery. To access libraries in new chemical space, many methods have emerged to transpose traditional mol-scale reactivity to nmol-scale, on-DNA chemistry. However, procedures to access libraries with a greater fraction of C(sp3) content are still limited, and the need to "escape from flatland" more readily on-DNA remains. Herein, we report a Giese addition to install highly functionalized bicyclo[1.1.1]pentanes (BCPs) using tricyclo[1.1.1.01,3]pentane (TCP) as a radical linchpin, as well as other diverse alkyl groups, on-DNA from the corresponding organohalides as non-stabilized radical precursors. Telescoped procedures allow extension of the substrate pool by at least an order of magnitude to ubiquitous alcohols and carboxylic acids, allowing us to "upcycle" these abundant feedstocks to afford non-traditional libraries with different physicochemical properties for the small-molecule products (i.e., non-peptide libraries with acids). This approach is amenable to library production, as a DNA damage assessment revealed good PCR amplifiability and only 6% mutated sequences for a full-length DNA tag.
Assuntos
Pentanos , Bibliotecas de Moléculas Pequenas , DNA/química , Biblioteca Gênica , Halogênios , Bibliotecas de Moléculas Pequenas/químicaRESUMO
To identify new potential therapeutic targets for neurodegenerative diseases, we initiated activity-based protein profiling studies with withanolide A (WitA), a known neuritogenic constituent of Withania somnifera root with unknown mechanism of action. Molecular probes were designed and synthesized, and led to the discovery of the glucocorticoid receptor (GR) as potential target. Molecular modeling calculations using the VirtualToxLab predicted a weak binding affinity of WitA for GR. Neurite outgrowth experiments in human neuroblastoma SH-SY5Y cells further supported a glucocorticoid-dependent mechanism, finding that WitA was able to reverse the outgrowth inhibition mediated by dexamethasone (Dex). However, further GR binding and transactivation assays found no direct interference of WitA. Further molecular modeling analysis suggested that WitA, although forming several contacts with residues in the GR binding pocket, is lacking key stabilizing interactions as observed for Dex. Taken together, the data suggest that WitA-dependent induction of neurite outgrowth is not through a direct effect on GR, but might be mediated through a closely related pathway. Further experiments should evaluate a possible role of GR modulators and/or related signaling pathways such as ERK, Akt, NF-κB, TRα, or Hsp90 as potential targets in the WitA-mediated neuromodulatory effects.
Assuntos
Receptores de Glucocorticoides/metabolismo , Vitanolídeos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dexametasona/química , Dexametasona/metabolismo , Dexametasona/farmacologia , Glucocorticoides/química , Glucocorticoides/metabolismo , Glucocorticoides/farmacologia , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Neuritos/efeitos dos fármacos , Neuritos/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Ligação Proteica , Estrutura Terciária de Proteína , Receptores de Glucocorticoides/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Vitanolídeos/farmacologia , Vitanolídeos/uso terapêuticoRESUMO
An enantioselective cross-dehydrogenative coupling (CDC) reaction to access tetrahydropyrans has been developed. This process combines in situ Lewis acid activation of a nucleophile in concert with the oxidative formation of a transient oxocarbenium electrophile, leading to a productive and highly enantioselective CDC. These advances represent one of the first successful applications of CDC for the enantioselective couplings of unfunctionalized ethers. This system provides efficient access to valuable tetrahydropyran motifs found in many natural products and bioactive small molecules.
Assuntos
Piranos/síntese química , Benzoquinonas/síntese química , Benzoquinonas/química , Catálise , Ésteres/síntese química , Ésteres/química , Éteres/síntese química , Éteres/química , Ácidos de Lewis/síntese química , Ácidos de Lewis/química , Modelos Moleculares , Oxirredução , Piranos/química , EstereoisomerismoRESUMO
Natural products have had an immense influence on science and have directly led to the introduction of many drugs. Organic chemistry, and its unique ability to tailor natural products through synthesis, provides an extraordinary approach to unlock the full potential of natural products. In this Review, an approach based on natural product derived fragments is presented that can successfully address some of the current challenges in drug discovery. These fragments often display significantly reduced molecular weights, reduced structural complexity, a reduced number of synthetic steps, while retaining or even improving key biological parameters such as potency or selectivity. Examples from various stages of the drug development process up to the clinic are presented. In addition, this process can be leveraged by recent developments such as genome mining, antibody-drug conjugates, and computational approaches. All these concepts have the potential to identify the next generation of drug candidates inspired by natural products.
Assuntos
Produtos Biológicos/farmacologia , Animais , Produtos Biológicos/síntese química , Produtos Biológicos/química , Descoberta de Drogas , HumanosRESUMO
DNA-encoded library (DEL) screens have significantly impacted new lead compound identification efforts within drug discovery. An advantage of DELs compared to traditional screening methods is that an exponentially broader chemical space can be effectively screened using only nmol quantities of billions of DNA-tagged, drug-like molecules. The synthesis of DELs containing diverse, sp3-rich spirocycles, an important class of molecules in drug discovery, has not been previously reported. Herein, we demonstrate the synthesis of complex and novel spirocyclic cores via an on-DNA, visible light-mediated intermolecular [2 + 2] cycloaddition of olefins with heterocycles, including indoles, azaindoles, benzofurans, and coumarins. The DNA-tagged exo-methylenecyclobutane substrates were prepared from easily accessible alkyl iodides and styrene derivatives. Broad reactivity with many other DNA-conjugated alkene substrates was observed, including unactivated and activated alkenes, and the process is tolerant of various heterocycles. The cycloaddition was successfully scaled from 10 to 100 nmol without diminished yield, indicative of this reaction's suitability for DNA-encoded library production. Evaluation of DNA compatibility with the developed reaction in a mock-library format showed that the DNA barcode was maintained with high fidelity, with <1% mutated sequences and >99% amplifiable DNA from quantitative polymerase chain reaction (PCR) and next generation sequencing (NGS).
RESUMO
Azaspiro[3.3]heptanes are valuable synthetic targets for drug discovery programs. The challenges associated with the preparation and diversification of this moiety as compared to other small, saturated rings have led to limited applications of compounds containing this spirocycle. In this regard, important advances in the field of synthetic photochemistry have exploited the biradical nature of the triplet excited state of 2-isoxazoline-3-carboxylates, engaging these species in intermolecular coupling reactions under visible light irradiation. As a continuation of our program preparing F(sp3)-rich, structurally complex molecules for DNA-encoded library technology (DELT) applications via photocatalysis, we disclose herein the incorporation of unique and densely functionalized 2-oxa-1-azabicyclo[3.2.0]heptanes via [2+2] cycloaddition energy transfer sensitization, providing access to an unexplored library of azaspiro compounds, many of which include additional synthetic handles important for further functionalization of the DNA-conjugated products and for library production.
Assuntos
Heptanos , Luz , Transferência de Energia , Catálise , DNARESUMO
Prins-type macrocyclizations have recently emerged as a successful strategy in the synthesis of polyketide-derived natural products. This reaction provides a concise and selective means to form tetrahydropyran-containing macrocyclic rings of varying size. A high degree of functionality within the macrocycle is tolerated and the yields for these transformations are typically good to excellent. Since the initial report of a Prins macrocyclization reaction in 1979, examples of this approach did not re-emerge until 2008. However, the use of this method in natural product synthesis has rapidly gained momentum in the synthetic community, with multiple examples of this macrocyclization tactic reported in the recent literature.
Assuntos
Produtos Biológicos/síntese química , Produtos Biológicos/química , Briostatinas/síntese química , Briostatinas/química , Ciclização , Dissacarídeos/síntese química , Dissacarídeos/química , Compostos Macrocíclicos/química , Macrolídeos/síntese química , Macrolídeos/química , Piranos/química , Rifabutina/análogos & derivados , Rifabutina/síntese química , Rifabutina/química , EstereoisomerismoRESUMO
Evaluation of the importance of C18/C19 stereochemistry of azinomycin A/B epoxyamide partial structures with respect to DNA alkylation sequence selectivity is reported using a unique assay with a DNA oligomer containing imbedded normal (5'-GGC-3'/3'-CCG-5') and inverted (5'-CGG-3'/3'-GCC-5') azinomycin consensus cross-linking sequences. Both species were found to have unique selectivity profiles and alkylate DNA in a manner distinct from azinomycin B. Computational docking experiments support altered binding modes for the enantiomers.
Assuntos
DNA/química , Compostos de Epóxi/síntese química , Compostos de Epóxi/toxicidade , Glicopeptídeos/química , Glicopeptídeos/toxicidade , Naftalenos/síntese química , Naftalenos/toxicidade , Peptídeos/química , Peptídeos/toxicidade , Alquilação , Compostos Azabicíclicos , Sequência de Bases , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dipeptídeos , Compostos de Epóxi/química , Glicopeptídeos/síntese química , Guanina/química , Humanos , Ligação de Hidrogênio , Peptídeos e Proteínas de Sinalização Intercelular , Naftalenos/química , Conformação de Ácido Nucleico , Peptídeos/síntese química , EstereoisomerismoRESUMO
A Brønsted acid-catalyzed Prins-type cyclization sequence to construct spirooxindole pyrans in high yields and excellent diastereoselectivity has been developed. The combination of a ß-hydroxy dioxinone fragment and isatin dimethyl acetal generate oxa-spirooxindoles efficiently. These compounds are diversifiable scaffolds that tap into the rich chemistry of dioxinones.