Recent developments in the chemistry of deoxyribonucleic acid (DNA) intercalators: principles, design, synthesis, applications and trends

Abstract

In the present overview, we describe the bases of intercalation of small molecules (cationic and polar neutral compounds) in DNA. We briefly describe the importance of DNA structure and principles of intercalation. Selected syntheses, possibilities and applications are shown to exemplify the importance, drawbacks and challenges in this pertinent, new, and exciting research area. Additionally, some clinical applications (molecular processes, cancer therapy and others) and trends are described.

Figure 1

DNA basic 3D structure and bases interactions: (A) DNA and its representative form. Note major and minor grooves indication in the DNA structure; (B) Purine (A and G) and pyrimidine (T and C) bases; (C) Complementary base-pairs interactions (hydrogen bonding).

Figure 2

Stereochemistry of the phosphate groups in the DNA biomolecule. Note two possible configurations (pro-R and pro-S) in the P=O bound and the negatively charged oxygen atoms. DNA is a negatively charged biomolecule.

Figure 3

(a) Generic intercalation representation (figure based on a previous report [48]); (b) dsDNA and a schematic representation of a general intercalating agent (figure based on a previous report [49]). Note the intercalation in the major groove of the dsDNA structure; (c) Generic groove binding representation (based on a previous report [48]).

Scheme 1

Synthesis of N-arylamino-acridizinium derivatives.

Scheme 2

Synthesis of fluorescent BTD derivatives.

Scheme 3

Intercalation model proposed for 2,1,3-BTDs derivatives. The intercalation requires the presence of a C≡C spacer at least on one side of the molecule.

Scheme 4

Synthesis of fluorescent benzothienoindole and a benzofuroindole tested as intercalating agents.

Scheme 5

Synthesis of cationic fluorescent derivatives 17 and 18.

Scheme 6

Synthesis of a novel family of planar triazinium fluorescent salts.

Scheme 7

Synthesis of a novel family of planar triazinium fluorescent derivatives.

Scheme 8

Synthesis of a novel family of quinoxalines derivatives.

Scheme 9

Quercetin zinc(II) complex derivative.

Scheme 10

Proposed intermediate of DNA binding with quercetin zinc(II) complex 33 and proposed DNA cleavage mechanism. The fluorescent complex helps in the hydrolysis process on the phosphate group.