ABSTRACT
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.
Subject(s)
Radiation Tolerance , Telomerase , Animals , Mice , Cellular Senescence/drug effects , DNA Damage/drug effects , Radiation Tolerance/drug effects , Telomerase/antagonists & inhibitors , Telomerase/metabolism , TelomereABSTRACT
[This corrects the article DOI: 10.1039/C9SC00302A.].
ABSTRACT
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.
Subject(s)
Carboxylic Acids/chemistry , Ketones/chemistry , Ketones/chemical synthesis , Methane/analogs & derivatives , Photochemical Processes , Catalysis , Chemistry Techniques, Synthetic , Heterocyclic Compounds/chemistry , Methane/chemistry , Oxidation-ReductionABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemistry , DNA-Binding Proteins/chemistry , Diterpenes/chemistry , Enzyme Inhibitors/chemistry , Telomerase/antagonists & inhibitors , Amino Acid Sequence , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Catalysis , Cell Line, Tumor , Cell Proliferation/drug effects , Cycloaddition Reaction , DNA Damage/drug effects , Diterpenes/pharmacology , Drug Screening Assays, Antitumor , Enzyme Inhibitors/pharmacology , Humans , Models, Molecular , Molecular Structure , Protein Binding , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Carbon/chemistry , Enzymes/metabolism , Hydrogen/chemistry , Light , Catalysis , Cytochrome P-450 Enzyme System/metabolism , Hydroxylation , Oxidation-Reduction , StereoisomerismABSTRACT
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.
ABSTRACT
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.
ABSTRACT
Increased cancer cell motility constitutes a root cause of end organ destruction and mortality, but its complex regulation represents a barrier to precision targeting. We use the unique characteristics of small molecules to probe and selectively modulate cell motility. By coupling efficient chemical synthesis routes to multiple upfront in parallel phenotypic screens, we identify that KBU2046 inhibits cell motility and cell invasion in vitro. Across three different murine models of human prostate and breast cancer, KBU2046 inhibits metastasis, decreases bone destruction, and prolongs survival at nanomolar blood concentrations after oral administration. Comprehensive molecular, cellular and systemic-level assays all support a high level of selectivity. KBU2046 binds chaperone heterocomplexes, selectively alters binding of client proteins that regulate motility, and lacks all the hallmarks of classical chaperone inhibitors, including toxicity. We identify a unique cell motility regulatory mechanism and synthesize a targeted therapeutic, providing a platform to pursue studies in humans.
Subject(s)
Cell Movement/drug effects , Flavones/therapeutic use , Molecular Probe Techniques , Molecular Probes/therapeutic use , Neoplasms, Experimental/drug therapy , Animals , Cell Line, Tumor , Drug Screening Assays, Antitumor , Female , Flavones/pharmacology , Humans , Male , Membrane Glycoproteins/drug effects , Mice , Molecular Probes/pharmacologyABSTRACT
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.
Subject(s)
Pyrans/chemical synthesis , Benzoquinones/chemical synthesis , Benzoquinones/chemistry , Catalysis , Esters/chemical synthesis , Esters/chemistry , Ethers/chemical synthesis , Ethers/chemistry , Lewis Acids/chemical synthesis , Lewis Acids/chemistry , Models, Molecular , Oxidation-Reduction , Pyrans/chemistry , StereoisomerismABSTRACT
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.
