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The non-covalent interaction of pyrrolo[2, 1-c] [1, 4]benzodiazepine-5, 11-diones with DNA.

Publication ,  Journal Article
Jones, GB; Davey, CL; Jenkins, TC; Kamal, A; Kneale, GG; Neidle, S; Webster, GD; Thurston, DE
Published in: Anticancer Drug Des
August 1990

A series of 15 pyrrolo[2, 1-c] [1, 4]benzodiazepine-5, 11-diones has been synthesized and evaluated for in vitro DNA binding by thermal denaturation and fluorescence quenching studies with calf thymus (CT) DNA. The results indicate that two compounds of the series, 7 and 8, elevate the melting point of DNA by 2.9 +/- 0.6 and 3.3 +/- 0.8 K, respectively. Similarly, a significant quenching of the fluorescence of the dihydroxy analogue 8 was observed upon interaction with CT-DNA. As controls, the dihydroxy isomer 9 with the reverse stereochemistry at C2 and the non-substituted parent dilactam 12, failed to increase the DNA melting point or exhibit significant quenching upon interaction with DNA. In addition, preliminary experiments with GC- and AT-rich polymers suggest some sequence-dependent properties for dilactams 7 and 8. Overall, these results indicate a highly specific structural requirement for DNA binding. Molecular modelling with d(GTAGATC), d(GCAGATC) and d(GCGTAGC) duplex sequences has provided a model based on hydrogen bonding between the dihydroxy dilactam 8 and DNA, that rationalizes some of the results obtained. It is possible that the observed interactions represent the non-covalent (binding) component of the interaction of covalently-bonding anthramycin-type anti-tumour antibiotics with DNA.

Duke Scholars

Published In

Anticancer Drug Des

ISSN

0266-9536

Publication Date

August 1990

Volume

5

Issue

3

Start / End Page

249 / 264

Location

United States

Related Subject Headings

  • Structure-Activity Relationship
  • Stereoisomerism
  • Pyrroles
  • Oncology & Carcinogenesis
  • Medicinal & Biomolecular Chemistry
  • Drug Interactions
  • DNA
  • Computer Simulation
  • Chemistry
  • Chemical Phenomena
 

Citation

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Jones, G. B., Davey, C. L., Jenkins, T. C., Kamal, A., Kneale, G. G., Neidle, S., … Thurston, D. E. (1990). The non-covalent interaction of pyrrolo[2, 1-c] [1, 4]benzodiazepine-5, 11-diones with DNA. Anticancer Drug Des, 5(3), 249–264.
Jones, G. B., C. L. Davey, T. C. Jenkins, A. Kamal, G. G. Kneale, S. Neidle, G. D. Webster, and D. E. Thurston. “The non-covalent interaction of pyrrolo[2, 1-c] [1, 4]benzodiazepine-5, 11-diones with DNA.Anticancer Drug Des 5, no. 3 (August 1990): 249–64.
Jones GB, Davey CL, Jenkins TC, Kamal A, Kneale GG, Neidle S, et al. The non-covalent interaction of pyrrolo[2, 1-c] [1, 4]benzodiazepine-5, 11-diones with DNA. Anticancer Drug Des. 1990 Aug;5(3):249–64.
Jones, G. B., et al. “The non-covalent interaction of pyrrolo[2, 1-c] [1, 4]benzodiazepine-5, 11-diones with DNA.Anticancer Drug Des, vol. 5, no. 3, Aug. 1990, pp. 249–64.
Jones GB, Davey CL, Jenkins TC, Kamal A, Kneale GG, Neidle S, Webster GD, Thurston DE. The non-covalent interaction of pyrrolo[2, 1-c] [1, 4]benzodiazepine-5, 11-diones with DNA. Anticancer Drug Des. 1990 Aug;5(3):249–264.

Published In

Anticancer Drug Des

ISSN

0266-9536

Publication Date

August 1990

Volume

5

Issue

3

Start / End Page

249 / 264

Location

United States

Related Subject Headings

  • Structure-Activity Relationship
  • Stereoisomerism
  • Pyrroles
  • Oncology & Carcinogenesis
  • Medicinal & Biomolecular Chemistry
  • Drug Interactions
  • DNA
  • Computer Simulation
  • Chemistry
  • Chemical Phenomena