Introduction

Besides non-specific electrostatic interaction with phosphate groups, there are two main ways in which a molecule can bind to DNA in a reversible way: (a) groove-binding interactions, which do not require conformational changes in DNA and usually shows high sequence specificity; and (b) intercalation of planar or quasi-planar aromatic ring systems between adjacent base pairs, which requires separation of the latter and normally takes place with low sequence specificity (Fig. 6.1).

Because of the differences in electrostatic potential, hydration, hydrogen bonding ability, and steric hindrance, the major and minor grooves differ in their molecular recognition properties. Thus, the major groove normally binds to large molecules, like proteins and oligonucleotides, and the minor groove has a tendency to bind to small molecules. Because of the curved shape of the minor groove, molecules with torsional freedom interact with it more easily (Fig. 6.1A),

Medicinal Chemistry of Anticancer Drugs © 2008 Elsevier B. V.

DOI: 10.1016/B978-0-444-52824-7.00006-8 All rights reserved.

FIGURE 6.1 Main types of reversible interactions with DNA.

and for this reason many of the compounds studied in this chapter contain several simple aromatic or heteromatic rings linked by torsionally free bonds. The interaction with the minor groove of some antitumor agents has been mentioned in previous chapters (anthracyclines in Section 3, bleomycins in Section 7, and enediynes in Section 8 of Chapter 4).

2. NETROPSIN, DISTAMYCIN, AND RELATED COMPOUNDS

Minor groove interaction was first discovered in the natural products netropsin and distamycin A. Although these compounds do not have relevant antitumor activity, they are the prototype minor groove binders (MGBs) and for this reason they will be briefly discussed below. They bind non-covalently to the minor groove of DNA, thereby preventing DNA and RNA synthesis by inhibition of the corresponding polymerase reaction and display a pronounced sequence specificity, leading to much current interest in them.1

Distamycin A

Studies on this specificity have been carried out mainly on distamycin and related compounds, which have shown a pronounced specificity for AT sequences.2 Ligand recognition by the minor groove is governed, in the first place, by hydrogen bonding interactions, involving hydrogen acceptor groups in DNA bases, particularly N3 and C2=O of the adenine-thymine or guanine-citosine pairs. As shown in Fig. 6.2, these interactions are hampered in the latter pair, mainly due to steric reasons. Additionally, the minor groove is strongly solvated, and liberation of water molecules into the bulk solvent upon complex formation leads to a favourable binding entropy (hydrophobic effect), since

Major groove

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