DNA intercalation optimized by two-step molecular lock mechanism

Abstract

The diverse properties of DNA intercalators, varying in affinity and kinetics over several orders of magnitude, provide a wide range of applications for DNA-ligand assemblies. Unconventional intercalation mechanisms may exhibit high affinity and slow kinetics, properties desired for potential therapeutics. We used single-molecule force spectroscopy to probe the free energy landscape for an unconventional intercalator that binds DNA through a novel two-step mechanism in which the intermediate and final states bind DNA through the same mono-intercalating moiety. During this process, DNA undergoes significant structural rearrangements, first lengthening before relaxing to a shorter DNA-ligand complex in the intermediate state to form a molecular lock. To reach the final bound state, the molecular length must increase again as the ligand threads between disrupted DNA base pairs. This unusual binding mechanism results in an unprecedented optimized combination of high DNA binding affinity and slow kinetics, suggesting a new paradigm for rational design of DNA intercalators.

DNA Intercalation Facilitates Efficient DNA-Targeted Covalent Binding of Phenanthriplatin

“…Moreover, the reversible DNA elongation rates for phenanthriplatin and trans -phenanthriplatin are comparable to those observed for previously reported DNA intercalators, including the observation of one or two phase dissociation kinetics. 12, 20–21, 27–30 Notably, the measured DNA equilibrium elongation by trans -phenanthriplatin binding provides an insightful estimate of the force-dependent equilibrium dissociation constant K d . For an exponential force dependence of DNA elongation 12, 20 (see Supporting Information, section III), we estimate the zero-force equilibrium dissociation constant K d to be 10 to 30 µM, which is consistent with previously reported values of K d for DNA intercalation by phenanthridinium derivatives.…”

Turning intercalators into groove binders: synthesis, photophysics and DNA binding properties of tetracationic mononuclear ruthenium(ii)-based chromophore–quencher complexes

“…Whilst dinuclear complexes of tpphz are established 45 to be non-intercalating groove binders, 37,38 this is due to coordination of metal centres at both ends of the ligand preventing all but threading intercalation; similarly, the more extended [µ-bidppz (bipy) 4 Ru 2 ] 4+ system, which incorporates the Òface-to-face dppz bridging ligand, bidppz (11,11Õ-bis(di-50 pyrido[3,2-a :2Õ,3Õ-c]phenazinyl), initially groove binds to duplex DNA. 39,40,41,42 As seen from the crystal structure, the terminal bipyridyldiylium group of the quaternized tpphz ligand does include a Òpropeller twistedÓ ethylene group that produces a slight deviation from complete planarity, but the steric demand of 55 this structure is low and many conventional intercalators, such as ethidium bromide, ellipticine, and amasacrine, have bulkier groups attached to their intercalating surface. Indeed, given that they contain a large extended planar ligand, in many respects both 3 4+ and 4 4+ fulfil all the apparent structural prerequisites for 60 classical intercalators.…”

General Synthesis of 1-Aryl-6-azaisocytosines and Their Utilization for the Preparation of Related Condensed 1,2,4-Triazines

“…Many of the prepared compounds (especially condensed derivatives 9 – 12 ) can serve as model compounds that have the potential for intercalation with DNA. These compounds may exhibit biological activity, not only through intercalation, as is the case with a number of isocyclic condensed aromatics [23,24,25,26], but also through forming intermolecular hydrogen bonds via the acidic NH groups.…”