Structure-activity relationship of anthracyclines in vitro

• Published in: Journal of medicinal chemistry Vol. 33; no. 1; pp. 166 - 171
• Main Authors: Hoffmann, D, Berscheid, H. G, Boettger, D, Hermentin, P, Sedlacek, H. H, Kraemer, H. P
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.01.1990
• Subjects: Animals; Antibiotics, Antineoplastic - metabolism; Antibiotics, Antineoplastic - therapeutic use; Antineoplastic agents; Biological and medical sciences; Chemical Phenomena; Chemistry, Physical; Colonic Neoplasms - drug therapy; DNA - metabolism; General aspects; Humans; Leukemia L1210 - drug therapy; Medical sciences; Molecular Structure; Neoplasms - drug therapy; Pharmacology. Drug treatments; Regression Analysis; Structure-Activity Relationship; Tumor Cells, Cultured; Antineoplastic agent; Leukemia; Cytotoxicity; Lipophily; Partition coefficient; Physicochemical properties activity relationship; In vitro; Biological fixation; Structure activity relation; DNA; Anthracyclins; Tumor cell; Physicochemical properties
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00163a028

The cytotoxic activities of several natural and semisynthetic anthracyclines against L1210 leukemia and two human colon tumor cells (Colon 4, HT 29) in vitro were examined after short (1 h) and long (7 days) incubation times and correlated with the water/octanol partition coefficients and the DNA-binding affinity of the compounds. Analysis of equation in which cytotoxicity against L1210 (1-h incubation) was parabolically related to the partition coefficient revealed an almost exclusive correlation (r = 0.80) between the cytotoxicity and the parameters, and this correlation was only slightly improved by addition of DNA-binding affinity (r = 0.85). On the other hand, cytotoxic activities displayed after continuous incubation were partially related to both partition coefficients (parabolic dependence) and DNA-binding affinities (linear dependence). In this case the correlation between the activity and partition coefficient (r = 0.67) was significantly improved by addition of DNA-binding affinity (r = 0.90). Similar results were also obtained for human colon tumor cells although the corresponding correlation coefficients were generally of lower value, indicating that cytotoxic activity of anthracyclines against these primary resistant cells may be influenced by additional factors not yet determined.