Prodrug Strategies Based on Intramolecular Cyclization Reactions

Abstract

Several new prodrug systems for amines, alcohols, and peptides are reviewed. The design of these new prodrug systems takes advantage of several facile intramolecular cyclization reactions, that permit separate manipulation of the release kinetics independent of the structural features of the drug moiety. Such systems can be used for the preparation of esterase-, phosphatase-, and redox-sensitive prodrugs of amines and alcohols and esterase-sensitive cyclic prodrugs of peptides and peptide mimetics.

Cyclization-activated Prodrugs

“…Dipeptides have been thus proposed as drug carriers to deliver the parent drug through enzyme-independent processes, namely, via DKP formation. Further, dipeptides are readily accessible carriers that can be easily modified to optimize the rate of release of the parent drug [63].…”

“…Lactonization of o-hydroxyhydrocinnamic acids 21; the "trimethyl lock" (R 1 =R 2 =Me) is depicted inside the dashed rectangle [75]. This has been exploited by medicinal chemists, especially by Borchardt and co-workers, to develop two-step activation prodrugs [6]. Thus, these authors carried out covalent attachment of model drugs to the carboxyl group of the hydrocinnamic acid moiety while masking the o-hydroxyl substituent as a precursor structure sensitive to either reductases [76][77][78], esterases [79][80][81] or phosphatases [82].…”

“…Scheme 14. Application of the "trimethyl lock" concept by Borchardt and co-workers for the design of two-step prodrugs (X=RCOO or PO 2 O; R 1 =H, OH) [6,[76][77][78][79][80][81][82]. In what concerns similar esterase-sensitive pro-prodrugs of anisidine as model amine, half-lives determined at 37 ºC in different media were as follows: 4030 min in phosphate buffer (pH 7.4), 11.9 min in the same buffer containing porcine liver esterase, 53.7 min in plasma and 475 min in plasma containing diisopropylfluorophosphate.…”

“…The present work is a brief overview of research on cyclization-activated prodrugs over the past two decades. Reviews addressing this particular issue have previously been published by Shan et al [6], Testa & Mayer [7] and by Wang et al [8], in the late 1990s, and more recently by Vinšová and Imramovský [9]. Another interesting review on anticancer prodrugs selectively activated by elimination and cyclization pathways was published by Papot et al [10] in 2002.…”

Cyclization-activated prodrugs. Synthesis, reactivity and toxicity of dipeptide esters of paracetamol

“…Dipeptide esters and amides (2, X = O or NH, Scheme 1) can deliver the parent drug through enzyme-independent processes such as the intramolecular cyclization to form the corresponding diketopiperazines (3, DKPs, Scheme 1). 7,8 The major drawback of using dipeptides as carrier candidates for prodrugs is their susceptibility to non-specific peptidases. However, enzymatically stable dipeptides (e.g., containing 2-aminoisobutyric acid or N-methylglycine as carriers) have been used successfully to improve physico-chemical properties of cytarabine 9 and cyclosporine.…”