Recognition by Nonaromatic and Stereochemical Subunit‐Containing Polyamides of the Four Watson–Crick Base Pairs in the DNA Minor Groove

In order to develop an optimal subunit as a T‐recognition element in hairpin polyamides, 15 novel chirality‐modified polyamides containing ( R )‐α,β‐diaminopropionic acid ( R β   α‐NH   2), ( S )‐α,β‐diaminopropionic acid ( S β   α‐NH   2), (1 R ,3 S )‐3‐aminocyclopentanecarboxylic acid ( RS Cp), (1 S ,3 R )‐3‐amino‐cyclopentanecarboxylic acid ( RS Cp), (1 R ,3 R )‐3‐aminocyclopentanecarboxylic acid ( RR Cp) and (1 S ,3 S )‐3‐amino‐cyclopentanecarboxylic acid ( SS Cp) residues were synthesized. Their binding characteristics to DNA sequences 5′‐TGC N CAT‐3′/3′‐ACG N′ GTA‐5′ ( N⋅N′ =A ⋅ T, T ⋅ A, G ⋅ C and C ⋅ G) were systemically studied by surface plasmon resonance (SPR) and molecular simulation (MSim) techniques. SPR showed that polyamide 4 , AcIm‐ S β   α‐NH   2‐ImPy‐γ‐ImPy‐β‐Py‐βDp (β/ S β   α‐NH   2pair), bound to a DNA sequence containing a core binding site of 5′‐TGC A CAT‐3′ with a dissociation equilibrium constant ( K D ) of 4.5×10 −8   m. This was a tenfold improvement in specificity over 5′‐TGCTCAT‐3′ ( K D =4.5×10 −7   M ). MSim studies supported the SPR results. More importantly, for the first time, we found that chiral 3‐aminocyclopentanecarboxylic acids in polyamides can be employed as base readers with only a small decrease in binding affinity to DNA. In particular, SPR showed that polyamide 9 ( RR Cp/β pair) had a 15‐fold binding preference for 5′‐TGCTCAT‐3′ over 5′‐TGCACAT‐3′. A large difference in standard free energy change for A ⋅ T over T ⋅ A was determined (ΔΔ G o =5.9 kJ mol −1 ), as was a twofold decrease in interaction energy by MSim. Moreover, a 1:1 stoichiometry ( 9 to 5′‐TGC T CAT‐3′/3′‐ACG A GTA‐5′) was shown by MSim to be optimal for the chiral five‐membered cycle to fit the minor groove. Collectively, the study suggests that the ( S )‐α‐amino‐β‐aminopropionic acid and (1 R ,3 R )‐3‐aminocyclopentanecarboxylic acid can serve as a T‐recognition element, and the stereochemistry and the nature of these subunits significantly influence binding properties in these recognition events. Subunit (1 R ,3 R )‐3‐aminocyclopentanecarboxylic acid broadens our scope to design novel polyamides.