Abstract
We review the preparation of new compounds with good solution and cell uptake properties that can selectively recognize mixed A·T and G·C bp sequences of DNA. Our underlying aim is to show that these new compounds provide important new biotechnology reagents as well as a new class of therapeutic candidates with better properties and development potential than other currently available agents. In this review, entirely different ways to recognize mixed sequences of DNA by modifying AT selective heterocyclic cations are described. To selectively recognize a G·C base pair an H-bond acceptor must be incorporated with AT recognizing groups as with netropsin. We have used pyridine, azabenzimidazole and thiophene-N-methylbenzimidazole GC recognition units in modules crafted with both rational design and empirical optimization. These modules can selectively and strongly recognize a single G·C base pair in an AT sequence context. In some cases, a relatively simple change in substituents can convert a heterocyclic module from AT to GC recognition selectivity. Synthesis and DNA interaction results for initial example lead modules are described for single G·C base pair recognition compounds. The review concludes with a description of the initial efforts to prepare larger compounds to recognize sequences of DNA with more than one G·C base pairs. The challenges and initial successes are described along with future directions.
Highlights
Overview of DNA and RNA Targeting ChallengesThe interaction of designed, synthetic, small organic molecules with macromolecules is a fascinating and important current research area for both biophysical studies and for the design of new reagents for selective binding applications as well as for therapeutic development
G·C bps sequence at the minor groove provide a rational explanation for the observed two Description of the design, preparation and biophysical testing of entirely new types of heterocyclic amidine compounds with good solution and cell uptake properties that selectively recognize mixed A·T and G·C bp sequences of DNA is described in this report
These compounds are the first example of a series of rationally-designed agents for mixed sequence DNA recognition and they provide very different biotechnology reagents and new therapeutic candidates compared with those previously reported
Summary
Overview of DNA and RNA Targeting Challenges. The interaction of designed, synthetic, small organic molecules with macromolecules is a fascinating and important current research area for both biophysical studies and for the design of new reagents for selective binding applications as well as for therapeutic development. Compounds that bind to proteins have become important molecular probes and account for many of our most active current drugs [1,2,3]. The design of agents that selectively target sequences or structures of DNA or RNA has progressed more slowly due to their more repetitive structures and properties [4,5,6,7,8]. The generally repetitive duplex structure of DNA as well as duplex sections of RNA makes selective targeting more of a challenge.
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