Structure-Based Design of a New Bisintercalating Anthracycline Antibiotic

• Published in: Journal of medicinal chemistry Vol. 40; no. 3; pp. 261 - 266
• Main Authors: Chaires, Jonathan B, Leng, Fenfei, Przewloka, Teresa, Fokt, Izabela, Ling, Yi-He, Perez-Soler, Roman, Priebe, Waldemar
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 31.01.1997
• Subjects: Antibiotics, Antineoplastic - chemical synthesis; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - metabolism; Antibiotics, Antineoplastic - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Calorimetry, Differential Scanning; Daunorubicin - analogs & derivatives; Daunorubicin - chemical synthesis; Daunorubicin - chemistry; Daunorubicin - metabolism; Daunorubicin - pharmacology; DNA - metabolism; Drug Design; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Intercalating Agents - chemical synthesis; Intercalating Agents - chemistry; Intercalating Agents - metabolism; Intercalating Agents - pharmacology; Magnetic Resonance Spectroscopy; Medical sciences; Miscellaneous. Antibiotics with multiple activities; Molecular Structure; Nucleic Acid Denaturation; Pharmacology. Drug treatments; Temperature; Thermodynamics; Tumor Cells, Cultured; Viscosity; Antineoplastic agent; Human; Viscosity; Intercalating agent; Ammonium Compounds; Carcinoma; Malignant tumor; In vitro; Biological activity; Mammary gland diseases; Antibiotic; Biological fixation; Daunorubicin; DNA; Multiple resistance; Anthracyclins; Thermodynamic properties; Chemical synthesis; Tumor cell; Organic dication; Rheological properties
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9607414

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 × 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.