Hydrogen bonded amide activity

Peptide Synthesis. The salt reacts with a carboxylic acid (preferably the alkali salt) in an alkaline medium to form an active ester, shown to have structure (2). This structure is more stable than (b) mainly because of the intramolecular hydrogen bond. These active esters react with amines to form amides... 

Fig. 8. Rephcation. The amino adenosine X and the pentafluorophenyl ester Y form a hydrogen-bonded dimer XY, prior to reaction between the amine and the activated ester groups (shown in the circle). The reaction product is a <7 -amide conformer cis-Z that isomeri2es to the more stable trans- acnide Z. The rephcative process is cataly2ed by the reaction product Z (also referred to as the template). First, a termolecular complex XYZ is formed from X, Y, and Z.

Coleman et al. have performed a preliminary structure/activity study for a series of analogues of 77 [149]. They found that removal of the naphthoate moiety (88 Scheme 11.11) dramatically reduced the yield of DNA alkylation, while replacement of the NH2 group with O-benzyl (89 and 90) abolished DNA alkylation completely. Compound 91 alkylated DNA with reduced efficiency, so this effect is not simply due to a requirement for a hydrogen bond donor at this position. Perhaps the amide is required at this position to increase the ability of the C=0 to act as a hydrogen bond acceptor. Importantly, they found a strong correlation between the extent of in vitro DNA alkylation and cell culture cytotoxicity. 

In 1990 Rebek reported an interesting self-replicating systems based on the Kemp s triacid derivative 82 (see Scheme 43) [112-114]. By a combination of hydrogen bonding and tt-tt stacking interactions, diamine 83 forms a binary complex with 82. In such a complex, the amine is ideally positioned to react with the activated ester in 82 yielding the ds-amide complex 84. 

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