RESUMO
Beyond synthesizing telomere repeats, the telomerase reverse transcriptase (TERT) also serves multiple other roles supporting cancer growth. Blocking telomerase to drive telomere erosion appears impractical, but TERT's non-canonical activities have yet to be fully explored as cancer targets. Here, we used an irreversible TERT inhibitor, NU-1, to examine impacts on resistance to conventional cancer therapies. In vitro, inhibiting TERT sensitized cells to chemotherapy and radiation. NU-1 delayed repair of double-strand breaks, resulting in persistent DNA damage signaling and cellular senescence. Although NU-1 alone did not impact growth of syngeneic CT26 tumors in BALB/c mice, it dramatically enhanced the effects of radiation, leading to immune-dependent tumor elimination. Tumors displayed persistent DNA damage, suppressed proliferation, and increased activated immune infiltrate. Our studies confirm TERT's role in limiting genotoxic effects of conventional therapy but also implicate TERT as a determinant of immune evasion and therapy resistance.
Assuntos
Tolerância a Radiação , Telomerase , Animais , Camundongos , Senescência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Tolerância a Radiação/efeitos dos fármacos , Telomerase/antagonistas & inibidores , Telomerase/metabolismo , TelômeroRESUMO
[This corrects the article DOI: 10.1039/C9SC00302A.].
RESUMO
As a key element in the construction of complex organic scaffolds, the formation of C-C bonds remains a challenge in the field of synthetic organic chemistry. Recent advancements in single-electron chemistry have enabled new methods for the formation of various C-C bonds. Disclosed herein is the development of a novel single-electron reduction of acyl azoliums for the formation of ketones from carboxylic acids. Facile construction of the acyl azolium in situ followed by a radical-radical coupling was made possible merging N-heterocyclic carbene (NHC) and photoredox catalysis. The utility of this protocol in synthesis was showcased in the late-stage functionalization of a variety of pharmaceutical compounds. Preliminary investigations using chiral NHCs demonstrate that enantioselectivity can be achieved, showcasing the advantages of this protocol over alternative methodologies.
Assuntos
Ácidos Carboxílicos/química , Cetonas/química , Cetonas/síntese química , Metano/análogos & derivados , Processos Fotoquímicos , Catálise , Técnicas de Química Sintética , Compostos Heterocíclicos/química , Metano/química , OxirreduçãoRESUMO
Telomerase is a ribonuceloprotein complex responsible for maintaining telomeres and protecting chromosomal integrity. The human telomerase reverse transcriptase (hTERT) is expressed in â¼90% of cancer cells where it confers the capacity for limitless proliferation. Along with its established role in telomere lengthening, telomerase also serves noncanonical extra-telomeric roles in oncogenic signaling, resistance to apoptosis, and enhanced DNA damage response. We report a new class of natural-product-inspired covalent inhibitors of telomerase that target the catalytic active site.
Assuntos
Antineoplásicos/química , Proteínas de Ligação a DNA/química , Diterpenos/química , Inibidores Enzimáticos/química , Telomerase/antagonistas & inibidores , Sequência de Aminoácidos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Catálise , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Reação de Cicloadição , Dano ao DNA/efeitos dos fármacos , Diterpenos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacologia , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-AtividadeRESUMO
Chemical transformations that install heteroatoms into C-H bonds are of significant interest because they streamline the construction of value-added small molecules. Direct C-H oxyfunctionalization, or the one step conversion of a C-H bond to a C-O bond, could be a highly enabling transformation due to the prevalence of the resulting enantioenriched alcohols in pharmaceuticals and natural products,. Here we report a single-flask photoredox/enzymatic process for direct C-H hydroxylation that proceeds with broad reactivity, chemoselectivity and enantioselectivity. This unified strategy advances general photoredox and enzymatic catalysis synergy and enables chemoenzymatic processes for powerful and selective oxidative transformations.
Assuntos
Carbono/química , Enzimas/metabolismo , Hidrogênio/química , Luz , Catálise , Sistema Enzimático do Citocromo P-450/metabolismo , Hidroxilação , Oxirredução , EstereoisomerismoRESUMO
A cooperative Lewis acid/photocatalytic reduction of salicylaldehyde-derived arylidene malonates provides access to a versatile, stabilized radical anion enolate. Using these unusual umpolung operators, we have developed a novel route to access densely functionalized carbo- and heterocycles through a radical annulation addition pathway.
RESUMO
A strategy with arylidene malonates provides access to ß-umpolung single-electron species. Reported here is the utilization of these operators in intermolecular radical-radical arylations, while avoiding conjugate addition/dimerization reactivity that is commonly encountered in enone-based photoredox chemistry. This reactivity relies on tertiary amines that serve to both activate the arylidene malonate for single-electron reduction by a proton-coupled electron transfer mechanism as well as serve as a terminal reductant. This photoredox catalysis pathway demonstrates the versatility of stabilized radicals for unique bond-forming reactions.
RESUMO
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
A novel biocatalytic system to access a wide variety of ß-hydroxydioxinones from ß-ketodioxinones employing commercial engineered ketoreductases has been developed. This practical system provides a remarkably straightforward solution to limitations in accessing certain chemical scaffolds common in ß-hydroxydioxinones that are of great interest due to their diversification capabilities. A few highlights of this system are that it is high yielding, highly enantioselective, and chromatography-free. We have demonstrated both a wide substrate scope and a high degree of scalability.