N-(2-chloroethyl)-N-nitrosoureas covalently bound to nonionic and monocationic lexitropsin dipeptides. Synthesis, DNA affinity binding characteristics, and reactions with sup 32 P-end-labeled DNA
- Univ. of Nebraska Medical Center, Omaha (USA)
The synthesis and characterization of a series of compounds that contain an N-alkyl-N-nitrosourea functionality linked to DNA minor groove binding bi- and tripeptides (lexitropsins or information-reading peptides) based on methylpyrrole-2-carboxamide subunits are described. The lexitropsins (lex) synthesized have either a 3-(dimethylamino)propyl or propyl substituent on the carboxyl terminus. The preferred DNA affinity binding sequences of these compounds were footprinted in {sup 32}P-end-labeled restriction fragments with methidiumpropyl-EDTA{center dot}Fe(II), and in common with other structural analogues, e.g., distamycin and netropsin, these nitrosoureas recognize A-T-rich runs. The affinity binding of the compound with the dimethylamino terminus, which is ionized at near-neutral pH, appeared stronger than that observed for the neutral dipeptide. The sequence specificity for DNA alkylation by (2-chloroethyl)nitrosourea-lex dipeptides (Cl-ENU-lex), with neutral and charged carboxyl termini, using {sup 32}P-end-labeled restriction fragments, was determined by the conversion of the adducted sites into single-strand breaks by sequential heating at neutral pH and exposure to base. The DNA cleavage sites were visualized by polyacrylamide gel electrophoresis and autoradiography. Linking the Cl-ENU moiety to minor groove binders is a viable strategy to qualitatively and quantitatively control the delivery and release of the ultimate DNA alkylating agent in a sequence-dependent fashion.
- OSTI ID:
- 5982606
- Journal Information:
- Biochemistry; (USA), Vol. 29:29; ISSN 0006-2960
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
59 BASIC BIOLOGICAL SCIENCES
ANTINEOPLASTIC DRUGS
BIOCHEMISTRY
DNA
AUTORADIOGRAPHY
NITROSOUREAS
BIOLOGICAL EFFECTS
ALKYLATING AGENTS
ALKYLATION
ELECTROPHORESIS
PHOSPHORUS 32
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
CHEMICAL REACTIONS
CHEMISTRY
DAYS LIVING RADIOISOTOPES
DRUGS
ISOTOPES
LIGHT NUCLEI
NITROSO COMPOUNDS
NUCLEI
NUCLEIC ACIDS
ODD-ODD NUCLEI
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PHOSPHORUS ISOTOPES
RADIOISOTOPES
560300* - Chemicals Metabolism & Toxicology
550201 - Biochemistry- Tracer Techniques