Nucleophilic Anticancer

Anticancer drugs that target DNA have been used in the clinic for more than 60 years.1 Despite the recent major advances in cancer research, the mechanism by which most clinically relevant anticancer drugs kill cells consists of interference with replication, which can be achieved most simply by DNA alkylation. Alkylat-ing agents can be defined as compounds capable of covalently binding an alkyl group to a biomolecule under physiological conditions (aqueous solution, 37 °C, pH 7.4). DNA alkylating agents interact with resting and proliferating cells in any phase of the cell cycle, but they are more cytotoxic during the late G1 and S phases

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

DOI: 10.1016/B978-0-444-52824-7.00005-6 All rights reserved.

because not enough time is available to repair the damage before DNA synthesis takes place.

In principle, covalent bonds can arise from attack of either nucleophilic or electrophilic species to DNA, and indeed some nucleophiles (e.g., hydrazine, hydroxylamine, bisulfite) are known to attack DNA bases under physiological conditions. On the contrary, with the exception of the nitrogen atoms involved in the nucleoside bond (N9 and N1 in purines or pyrimidines), all nitrogen and oxygen atoms of purine and pyrimidine bases are nucleophiles and, consequently, therapeutically useful drugs always behave as carbon electrophiles.2 Attraction between nucleophiles and electrophiles is governed by two related but independent interactions: electrostatic attraction between positive and negative charges (electrostatic control) and orbital overlap between the highest occupied molecular orbital (HOMO) of the nucleophile and the lowest unoccupied molecular orbital (LUMO) of the electrophile (orbital control). These two types of reactivities have been termed as ''hard'' and ''soft,'' respectively. Thus, the highly electronegative oxygen atoms tend to react under electrostatic control and are considered as ''hard'' nucleophiles, and accordingly they react with ''hard'' electrophiles, that is, those with a more pronounced cationic character. Because nitrogen atoms of DNA bases are softer nucleophiles than oxygen atoms and that many therapeuti-cally useful alkylating agents are relatively ''soft'' electrophiles, they react mainly at nitrogen sites, in the following order: N7 of guanine > N1 of adenine > N3 of cytosine > N3 of thymine. Diazonium salts, generated from nitrosoureas and other antitumor agents, are examples of therapeutically relevant ''hard'' electrophiles, which tend to preferentially alkylate oxygen atoms at phosphate residues and carbonyl oxygen atoms in DNA bases, specially O-6 of guanine. DNA alkylation is governed to a great extent by steric effects, and nucleophilic sites placed inside the double helix are less exposed to alkylation, while those in the major and minor groove are more easily attacked.3

Structure and dynamics of DNA are greatly affected by base alkylation, which leads to several types of effects. In the first place, alkylation prevents DNA replication and RNA transcription from the affected DNA. It also leads to the fragmentation of DNA by hydrolytic reactions and also by the action of repair enzymes when attempting to remove the alkylated bases. Alkylation also induces the mispairing of the nucleotides by alteration of the normal hydrogen bonding between bases. Finally, compounds capable of bisalkylation can form bridges within a single DNA strand (intrastrand cross-linkage). It can also lead to cross-linking between DNA and associated proteins or between two complementary DNA strands (interstrand cross-linkage), preventing their separation during DNA replication or transcription (Fig. 5.1). It has been proved that bifunctional alkylat-ing compounds are considerably more cytotoxic than their monofunctional counterparts, and also that there is a direct correlation between the degree of interstrand cross-linking and cytotoxicity.

The main types of DNA alkylating drugs that will be covered in this chapter have been classified as follows:

• Nitrogen mustards

• Aziridines (ethyleneimines)

Interstrand cross-linking FIGURE 5.1 Different modes of DNA cross-linking.

• Methanesulfonates

• Nitrosoureas

• Methylhydrazines

• Platinum complexes

• Miscellaneous alkylating and acylating antitumor agents

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