Abstract
Cyclam was attached to 1-, 2- and 3-pyrrole lexitropsins for the first time through a synthetically facile copper-catalyzed “click” reaction. The corresponding copper and zinc complexes were synthesized and characterized. The ligand and its complexes bound AT-rich DNA selectively over GC-rich DNA, and the thermodynamic profile of the binding was evaluated by isothermal titration calorimetry. The metal, encapsulated in a scorpion azamacrocyclic complex, did not affect the binding, which was dominated by the organic tail.
Highlights
We have previously demonstrated that it is possible to influence an azamacrocycle’s interaction with DNA by changing the nature of an amino acid appended to the macrocycle,[75] and created a metal complex whose primary coordination environment changes in response to the binding of a protein.[76]
It was noted that intermediates in the synthesis of 1 containing deprotected amines decomposed after a few hours at room temperature, and were typically used immediately after isolation
The magnitude and selectivity of the binding exhibited by these cyclam-polyamide compounds is gratifying for the reasons detailed above
Summary
Many naturally-occurring small molecules are known to bind DNA with sequence selectivity, most notably the polyamide class of minor groove binders that includes distamycin and netropsin, known generically as the lexitropsins.[8,9,10,11,12] Distamycin and netropsin selectively bind AT-rich regions of DNA, sequences that are important for example because of the widespread occurrence of the TATA box transcription factor binding site in the genome.[13] Lexitropsins are structurally simple molecules possessing features that are well-suited for minor groove binding: they are curved ( this is not an absolute requirement[14]), flat and contain well-positioned hydrogen bonding groups, positively charged end groups and strategically placed van der Waals contacts.[15,16]. With such a well-evolved scaffold for interaction with DNA, it is unsurprising that there has been a great deal of interest in tailoring the basic design to build in greater sequence-selectivity and adapt these structures to develop new types of drugs.[17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36] Much has been learned about how to modify lexitropsin structures to achieve binding to bespoke DNA sequences[9,37,38,39,40,41,42] or to improve physicochemical and pharmacokinetic properties.[26,43,44,45,46,47]
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