Long-range charge transfer is mediated by the DNA base paired stack. Metal complexes whose ligands have an extended "aromatic surface" for intercalation in DNA can function as electron donors (red) and acceptors (ye I I ow) to pro be p ho toi nd u ced electron transfer t h rough the DNA base stack.The major target of oxidative damage of nucleic acid within the cell is guanine (G). Metal intercalators which are strong photooxidants and attached to the DNA at a well-defined separation from a GG doublet can initiate selective oxidation of 5guanine from a distance. RE,VIEWCharge Transfer through the DNA Base Stack R. Erik Holmlin, Peter J. Dandliker, and Jacqueline K. Barton* -\ Whether the DNA base pair stack might serve as a medium for efficient, long-range charge transfer has been debated almost since the first proposal of the double-helical structure of DNA. The consequences of long-range radical migration through DNA are important with respect to understanding carcinogenesis and mutagenesis. Double-helical DNA has in its core a stacked array of aromatic heterocyclic base pairs, and this molecular x stack represents a unique system in which to explore the chemistry of electron transfer. We designed a family of metal complexes which bind to DNA by intercalative stacking within the helix; these metallointercalators may be usefully applied in probing DNA-mediated electron transfer. Here we describe a range of electron transfer reactions we carried out which are mediated by the DNA base paired stack. In some cases, DNA serves as a bridge, and spectroscopic analyses permit us to probe how the JC stack couples DNAbound donors and acceptors. These studies point to the sensitivity of coupling to DNA intercalation. However, if the DNA n stack effectively bridges donors and acceptors, the base-pair stack itself might serve not only as a conduit for electron transfer in DNA, but also in reactions initiated from a remote position. We carried out a series of reactions involving oxidative damage to DNA arising from the remotely positioned oxidant on the helix. The implications of long-range charge migration through DNA to effect damage are substantial. As in other DNA-mediated charge transfers, these reactions are highly dependent on DNA intercalation and the integrity of the intervening base-pair stack, but not on molecular distance. Furthermore, a physiologically important DNA lesion, the thymine dimers, can be reversed in a reaction initiated by electron transfer. This repair reaction can also be promoted from a distance as a result of long-range charge migration through the DNA base pair stack.
Pharmacological activation of the STING (stimulator of interferon genes)–controlled innate immune pathway is a promising therapeutic strategy for cancer. Here we report the identification of MSA-2, an orally available non-nucleotide human STING agonist. In syngeneic mouse tumor models, subcutaneous and oral MSA-2 regimens were well tolerated and stimulated interferon-β secretion in tumors, induced tumor regression with durable antitumor immunity, and synergized with anti–PD-1 therapy. Experimental and theoretical analyses showed that MSA-2 exists as interconverting monomers and dimers in solution, but only dimers bind and activate STING. This model was validated by using synthetic covalent MSA-2 dimers, which were potent agonists. Cellular potency of MSA-2 increased upon extracellular acidification, which mimics the tumor microenvironment. These properties appear to underpin the favorable activity and tolerability profiles of effective systemic administration of MSA-2.
The metallointercalator Rh(phi)2DMB3+ (phi, 9,10-phenanthrenequinone diimine; DMB, 4,4'-dimethyl-2,2'-bipyridine) catalyzed the repair of a thymine dimer incorporated site-specifically in a 16-base pair DNA duplex by means of visible light. This repair could be accomplished with rhodium noncovalently bound to the duplex and at long range (16 to 26 angstroms), with the rhodium intercalator tethered to either end of the duplex assembly. This long-range repair was mediated by the DNA helix. Repair efficiency did not decrease with increasing distance between intercalated rhodium and the thymine dimer, but it diminished with disruption of the intervening pi-stack.
Most drugs are developed through iterative rounds of chemical synthesis and biochemical testing to optimize the affinity of a particular compound for a protein target of therapeutic interest. This process is challenging because candidate molecules must be selected from a chemical space of more than 10 drug-like possibilities , and a single reaction used to synthesize each molecule has more than 10 plausible permutations of catalysts, ligands, additives and other parameters . The merger of a method for high-throughput chemical synthesis with a biochemical assay would facilitate the exploration of this enormous search space and streamline the hunt for new drugs and chemical probes. Miniaturized high-throughput chemical synthesis has enabled rapid evaluation of reaction space, but so far the merger of such syntheses with bioassays has been achieved with only low-density reaction arrays, which analyse only a handful of analogues prepared under a single reaction condition. High-density chemical synthesis approaches that have been coupled to bioassays, including on-bead , on-surface , on-DNA and mass-encoding technologies , greatly reduce material requirements, but they require the covalent linkage of substrates to a potentially reactive support, must be performed under high dilution and must operate in a mixture format. These reaction attributes limit the application of transition-metal catalysts, which are easily poisoned by the many functional groups present in a complex mixture, and of transformations for which the kinetics require a high concentration of reactant. Here we couple high-throughput nanomole-scale synthesis with a label-free affinity-selection mass spectrometry bioassay. Each reaction is performed at a 0.1-molar concentration in a discrete well to enable transition-metal catalysis while consuming less than 0.05 milligrams of substrate per reaction. The affinity-selection mass spectrometry bioassay is then used to rank the affinity of the reaction products to target proteins, removing the need for time-intensive reaction purification. This method enables the primary synthesis and testing steps that are critical to the invention of protein inhibitors to be performed rapidly and with minimal consumption of starting materials.
Strong through‐space interactions with the dendritic shell surrounding the chromophore are at the root of the unusual redox properties of the porphyrin unit in 1. Compound 1, measuring approximately 4 nm in diameter with a molecular weight of over 19 kDa, represents a new class of synthetic, densely packed, globular electrontransfer protein mimics. R NHC[CH2OCH2CH2CONH‐(CH2OCH2CH2CO2CH3)3]3.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.