DNA cross-linking

FIGURE 6.15 Bioreductive activation of bioxalomycin ß2.

cross-links with 5'-CpG-3' selectivity, involving alkylation at C-7 following the usual mechanism and also at C-13b, as shown in Fig. 6.15.

The ecteinascidins are broad-spectrum antitumor agents, several orders of magnitude more potent than other tetrahydroisoquinoline alkaloids. Ecteinasci-din 743 (ET-743, trabectedin), originally isolated from the marine tunicate Ecteinascidia turbinata,56 has undergone extensive clinical studies57-59 and is currently being tested in Phase III for several types of cancer. This drug was granted the status of orphan drug for treatment of soft tissue sarcoma and ovarian cancer,60 and, more recently, it has been approved by the European Medicines Agency (EMEA) for the former indication.

Recognition of ET-743 by the DNA minor groove is specific for certain sequences like 5'-AGC61 and involves hydrogen bonding with three different base pairs, as shown in Fig. 6.16 (the arrows are oriented from hydrogen donor to hydrogen acceptor groups).62,63 DNA alkylation involves attack of the guanine amino group onto an iminium species generated at C-21 by loss of the hydroxyl group. NMR studies have shown that the covalent adduct is protonated at N-12, and this has led to the proposal that iminium generation is assisted by proton transfer from N-12 to the hydroxyl acting as a leaving group.64

On the basis of gel electrophoresis and 1H NMR experiments, the site selectivity of ET-743 has been shown to depend on the rate of reversibility of the covalent adducts and not on the covalent reaction rate. Minor groove alkylation by ET-743 is reversible, and it has been proposed that the differences in rate of the reverse reaction are responsible for the observed sequence specificity, since non-favoured sequences (e.g. 5'-AGT) are dealkylated at an enhanced rate, allowing migration of ET-743 to the favoured ones (e.g. 5'-AGC). Due to hydrogen bonding, ET-743 forms a stable and tight complex at the 5'-AGC target sequence, where the covalent linkage is less accessible to attack by a water molecule. In the case of ET-743-AGT adducts, the complex is less stable and has more dynamic motion, leading h3co h3co

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