5-Iodo-2′-Deoxyuridine-Protein Conjugates: Synthesis and Enzymatic Degradation

Janina Baranowska-Kortylewicz, S. James Adelstein, Amin I. Kassis

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Several halogenated analogs of thymidine and cytidine possess antineoplastic and antiviral activity. They are also powerful sensitizers of bacterial and mammalian cells to lethal effects of x-irradiation. An important factor limiting the effectiveness of these agents in therapy is their extremely short half-life in circulation due to rapid hepatic dehalogenation. An approach to this problem is to deliver the drug directly to its target using monoclonal antibodies. This study evaluates the lysosomotropic delivery systems of halogenated pyrimidines using 5-iodo-2′-deoxyuridine [IUdR] as a model. IUdR, derivatized and activated at either the 3′- or the 5′-position forms covalent adducts with the ε-amino groups of the lysine residues in proteins (bovine serum albumin [BSA], and immunoglobulins [IgG]). Two methods suitable for conjugation of IUdR to proteins involving either the formation of acyl-imidazoles in the reaction of IUdR succinates with N,N′-carbonyldiimidazole or the preparation of N-succinimidyl esters of IUdR succinates were established. Both derivatives express comparable reactivity toward proteins. The degree of IUdR incorporation is easily controlled by the ratio of reagents. The succinate “arm“ linking IUdR to protein is susceptible to lysosomal hydrolysis in vitro releasing intact IUdR. The half-life of the IUdR-IgG conjugate in the presence of the lysosomal enzymes was shown to be approximately twice that of the IUdR-BSA conjugate.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalSelective Cancer Therapeutics
Volume6
Issue number1
DOIs
StatePublished - Jan 1 1990

Fingerprint

Idoxuridine
Deoxyuridine
Proteins
Succinates
Bovine Serum Albumin
Half-Life
Immunoglobulin G
Imidazoles
Cytidine
Pyrimidines
Succinic Acid
Antineoplastic Agents
Thymidine
Lysine
Antiviral Agents
Immunoglobulins
Esters
Hydrolysis
Monoclonal Antibodies

ASJC Scopus subject areas

  • Pharmacology
  • Cancer Research

Cite this

5-Iodo-2′-Deoxyuridine-Protein Conjugates : Synthesis and Enzymatic Degradation. / Baranowska-Kortylewicz, Janina; Adelstein, S. James; Kassis, Amin I.

In: Selective Cancer Therapeutics, Vol. 6, No. 1, 01.01.1990, p. 1-13.

Research output: Contribution to journalArticle

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