Structure-based design of a new bisintercalating anthracycline antibiotic

Jonathan B. Chaires, Fenfei Leng, Teresa Przewloka, Izabela Fokt, Yi He Ling, Roman Perez-Soler, Waldemar Priebe

Research output: Contribution to journalArticle

137 Citations (Scopus)

Abstract

A new bisintercalating anthracycline antibiotic, WP631, has been designed and synthesized. The rational design of the new compound was based upon the geometry of monomeric anthracyclines bound to DNA oligonucleotides observed in high-resolution crystal structures. Monomeric units of daunorubicin have been linked through their reactive 3' NH2 substituents on the daunosamine moieties to form the new bisanthracycline WP631. Viscosity studies confirmed that WP631 binds to DNA by bisintercalation. Differential scanning calorimetry and UV melting experiments were used to measure the ultratight binding of WP631 to DNA. The binding constant for the interaction of WP631 with herring sperm DNA was determined to be 2.7 x 1011 M-1 at 20 °C. The large, favorable binding free energy of -15.3 kcal mol-1 was found to result from a large, negative enthalpic contribution of -30.2 kcal mol- 1. A molecular model was generated that shows the favorable stereochemical fit of the linker in the DNA minor groove. The cytotoxicity of WP631 was compared to that of doxorubicin using MCF-7-sensitive and MCF-7/VP-16 MRP- mediated multidrug-resistant cell lines. These initial studies showed that while WP631 is slightly less cytotoxic than doxorubicin in the sensitive cell line, it appears to overcome MRP-mediated multidrug resistance and was much more cytotoxic against the MCF-7/VP-16 cell line than was doxorubicin. The design of new potential anticancer agents based on known structural principles was found to produce a compound with significantly increased DNA binding affinity and with interesting biological activity.

Original languageEnglish (US)
Pages (from-to)261-266
Number of pages6
JournalJournal of Medicinal Chemistry
Volume40
Issue number3
DOIs
StatePublished - Jan 31 1997
Externally publishedYes

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Anthracyclines
Anti-Bacterial Agents
DNA
Doxorubicin
Cells
Etoposide
Cell Line
Daunorubicin
Molecular Models
Differential Scanning Calorimetry
Multiple Drug Resistance
Cytotoxicity
Bioactivity
WP 631
Viscosity
Oligonucleotides
Antineoplastic Agents
Freezing
Free energy
Spermatozoa

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Chaires, J. B., Leng, F., Przewloka, T., Fokt, I., Ling, Y. H., Perez-Soler, R., & Priebe, W. (1997). Structure-based design of a new bisintercalating anthracycline antibiotic. Journal of Medicinal Chemistry, 40(3), 261-266. https://doi.org/10.1021/jm9607414

Structure-based design of a new bisintercalating anthracycline antibiotic. / Chaires, Jonathan B.; Leng, Fenfei; Przewloka, Teresa; Fokt, Izabela; Ling, Yi He; Perez-Soler, Roman; Priebe, Waldemar.

In: Journal of Medicinal Chemistry, Vol. 40, No. 3, 31.01.1997, p. 261-266.

Research output: Contribution to journalArticle

Chaires, JB, Leng, F, Przewloka, T, Fokt, I, Ling, YH, Perez-Soler, R & Priebe, W 1997, 'Structure-based design of a new bisintercalating anthracycline antibiotic', Journal of Medicinal Chemistry, vol. 40, no. 3, pp. 261-266. https://doi.org/10.1021/jm9607414
Chaires, Jonathan B. ; Leng, Fenfei ; Przewloka, Teresa ; Fokt, Izabela ; Ling, Yi He ; Perez-Soler, Roman ; Priebe, Waldemar. / Structure-based design of a new bisintercalating anthracycline antibiotic. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 3. pp. 261-266.
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