Interactions of molecules with nucleic acids. VI. Computer design of chromophoric intercalating agents

✍ Scribed by Kenneth J. Miller; Donald D. Newlin

• Publisher: Wiley (John Wiley & Sons)
• Year: 1982
• Tongue: English
• Weight: 898 KB
• Volume: 21
• Category: Article
• ISSN: 0006-3525
• DOI: 10.1002/bip.360210311

✦ Synopsis

Abstract

The mode of action of many antitumor agents entails the inhibition of nucleic acid synthesis. Because many of the drugs can intercalate, it is assumed that intercalation is an important step in the mechanism of biological activity. As intercalants contain a planar chromophore as an ingredient essential for intercalation, chromophores that should fit into DNA are desired. This is the main theme of this investigation. Binding to DNA of fundamental moieties, protonated pyridine, aniline, phenol, quinone, and 4H‐thiopyran‐4‐one, is studied to determine their optimum placement in DNA. The optimum orientations for each moiety are superimposed to form polyaromatic systems that can intercalate in a manner in which functional groups on these chromophores are oriented as in the moieties themselves. Ideal intercalants proposed contain three and four fused ring system, have protonated ring nitrogen atoms located to maximize the electrostatic interactions with DNA, hydroxy and amino groups that can hydrogen bond to the O~II~ and O~5′~ phosphate backbone atoms, and carbonyl and sulfur groups in the central position of the ring system to provide variations in the chromophore and to interact with the relatively positive region in the intercalation site. The optimum orientation occurs when the chromophore and the base pairs overlap to the maximum extent. The ideal intercalants are fundamentally of the type: magnified image