Design, synthesis, and cyclization of 4-aminobutyric acid derivatives: potential candidates as self-immolative spacers?

Organic & Biomolecular Chemistry Pub Date: 2011-01-26 DOI: 10.1039/C0OB00890G

Abstract

Self-immolative spacers have gained significant interest in recent years due to their utility in numerous prodrug, sensor and drug delivery systems. However, there are a very limited number of spacers that are capable of undergoing spontaneous and rapid reactions under mild conditions. To address this need, 4-aminobutyric acid derivatives were explored as a potential class of self-immolative spacers. Using a modular approach, eleven N- and α-substituted derivatives of 4-aminobutyric acid were synthesized, and their intramolecular cyclizations to γ-lactams were studied. Kinetics experiments were carried out at physiological pH and temperature, and the observed half-lives for the spacers ranged from 2 to 39 s, depending on the molecular structure. In addition, the pH dependence of the cyclization rate was also explored and it was found that cyclization still occurred rapidly at mildly acidic pH. Therefore, this class of compounds exhibits promise for incorporation into a variety of self-immolative systems where rapid cyclization reactions are desired.

Graphical abstract: Design, synthesis, and cyclization of 4-aminobutyric acid derivatives: potential candidates as self-immolative spacers
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