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to higher conformational flexibility that renders it more accessible to solvation, with the consequent increase in the rate of the reverse reaction, as shown in Fig. 6.17.

The mechanism of action of ET-743 and related compounds has been the matter of intense investigation in several laboratories.65 X-ray crystallography and NMR studies show that ET-743 alkylates guanine amino groups in a sequence-specific manner, binding tightly into the minor groove of DNA. This induces widening of the minor groove and bending of the helix towards the major groove,66'67 a distortion of the helix that would normally trigger nucleotide excision repair (NER) in which the damaged part of sequence is cut out by endonuclease and repaired by DNA polymerase (see Section 4.4.3 of Chapter 10). However, ET-743, in a unique mechanism of action, reverses NER, causing the endonuclease components to create lethal single-strand breaks in the DNA rather than repairing it.68,69 At biological concentrations, the ET-743-DNA adduct also interacts with some DNA transcription factors, specially the NF-Y factor.70 A molecular modelling study has shown that the DNA-ET-743 complex is superimposable with the minor groove of DNA bound to the zinc finger of the transcription regulator EGR-1, suggesting that ET-743 may target chromosome sites where zinc fingers of transcription factors interact with DNA.71 Other studies have revealed that, like taxol, ET-743 disrupts the microtubule network of tumor cells,72 and, at doses higher than therapeutic, it forms a cross-link between DNA and topoisomerase I by interaction of its spirotetrahydroisoquinoline subunit with the protein.73

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