Alkylating and Non Alkylating Compounds Interacting with the DNA Minor Groove

Contents 1. Introduction 177

2. Netropsin, Distamycin, and Related Compounds 178

3. Mitomycins 182

4. Tetrahydroisoquinoline Alkaloids 189

5. Cyclopropylindole Alkylating Agents 193

6. Pyrrolo[1,4]Benzodiazepines 195 References 196

1. 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.

Classes Anticancer Drug
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
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

>TNi

Hydrogen bonding is hampered by the NH2 group

Sterically inhibits penetration of molecules in GC-rich regions

Minor groove

FIGURE 6.2 Adenine-thymine and guanine-cytosine pairs.

AT-rich regions are more hydrated than GC-rich regions and hence they provide a bigger entropic contribution. Finally, the negative electrostatic potential is greater in AT-rich than in GC-rich regions, thus favouring an initial electrostatic interaction with positively charged groups in the ligand. Hydration of the ligand molecules is also an important factor in the understanding of differences in binding affinity.3

Hydrogen bonds involve the amido or amidino groups of the drugs as hydrogen donors and the N3 of adenine and C2=O groups of thymine as hydrogen acceptors, as shown in Fig. 6.3 for the case of distamycin A.

Theoretical and X-ray diffraction studies suggest the formation of bifurcated (three-centred) hydrogen bonds,4 where each carboxamide is bound to two acceptor groups belonging to bases in complementary DNA strands (Fig. 6.4). Contrary to

3 CH3

Distamycin A

FIGURE 6.3 Hydrogen bonds between distamycin A and the DNA minor groove. 5'

FIGURE 6.3 Hydrogen bonds between distamycin A and the DNA minor groove. 5'

Distamycin

Distamycin A

Distamycin A

FIGURE 6.4 Three-centred hydrogen bonds in the distamycin A-DNA interaction.

initial expectations, the protonated guanidine or amidine groups do not bind directly to DNA phosphate groups, but line the floor of the minor groove.

The synthesis of analogues of distamycin A by increasing the number of N-methylpyrrole-2-carboxamide units or replacement of some pyrrole nucleus by an imidazole, and also by preparation of hybrid structures with intercalating or alkylating portions, has led, in some instances, to much enhanced cyto-toxicity.5 Two of the most promising compounds in this area are tallimustine and brostallicin (PNU-166196).

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