Prolidase as a prodrug converting enzyme I. Synthesis of proline analogue of chlorambucil and its susceptibility to the action of prolidase

Rocz Akad Med Bialymst. 1997;42(1):148-55.

Abstract

The feasibility to targeting prolidase as an antineoplastic prodrug-converting enzyme has been examined. The synthesis of proline analogue of chlorambucil (well known antineoplastic agent) conjugated through imido-bond (potential target for prolidase action) has been performed. It was found that the product of synthesis, N-[4-[4-(N,N-bis(2-chloroethyl)amino) phenyl]butyryl]-L-proline is insoluble in aqueous solutions but it may be solubilized in methanol. The methanol in 30% concentration reduces catalytic activity of prolidase to 40% of values found in aqueous solution, although it allows in such conditions the measurement of substrate susceptibility to the action of this enzyme. It has been presented that product of synthesis is weakly susceptible to the action of purified prolidase, comparable to the susceptibility of glycyl-L-hydroxyproline. Although insolubility of the proline analogue of chlorambucil in aqueous solutions limit its potential therapeutic value, the presented data suggest that prolidase may have a broader substrate specificity. It suggests that targeting of prolidase as a prodrug-converting enzyme may serve as a novel strategy in therapy of various diseases.

Publication types

  • Comparative Study

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents, Alkylating / chemical synthesis*
  • Antineoplastic Agents, Alkylating / chemistry
  • Chlorambucil / analogs & derivatives*
  • Chlorambucil / chemical synthesis
  • Chlorambucil / chemistry
  • Dipeptidases / chemistry*
  • Dipeptides / chemistry
  • Hydrogenation
  • Imides / chemistry
  • Magnetic Resonance Spectroscopy
  • Methanol / chemistry
  • Molecular Structure
  • Prodrugs / chemistry*
  • Proline / analogs & derivatives*
  • Proline / chemical synthesis
  • Proline / chemistry
  • Solubility
  • Substrate Specificity

Substances

  • Antineoplastic Agents
  • Antineoplastic Agents, Alkylating
  • Dipeptides
  • Imides
  • Prodrugs
  • Chlorambucil
  • glycyl-4-hydroxyproline
  • chlorambucyl-proline
  • Proline
  • Dipeptidases
  • proline dipeptidase
  • Methanol