U80224

The structure of CC-1065 and their analogues fits the DNA minor groove curvature, where they bind specifically to AT-rich sequences, followed by irreversible alkylation of adenine N-3 (Fig. 6.18A). The halomethyl compounds are activated by cyclization to a cyclopropane derivative after hydrolysis of any protection on the phenolic hydroxyl (Fig. 6.18B).

As shown in Fig. 6.18A, cyclopropane ring opening needs to be assisted by the electron-withdrawing effect of the carbonyl group. Prior to interaction with DNA, this assistance is prevented by the conjugation between the carbonyl and the indole nitrogen atom, which form a vinylogous amide. However, the twist that the drug molecule needs to undergo in order to be accommodated into the deep and narrow minor groove AT regions forces the nitrogen atom out of the plane of the unsaturated carbonyl system and therefore out of conjugation (Fig. 6.19).

FIGURE 6.18 A. DNA alkylation by cyclopropylindoles. B. In vivo generation of the cyclopropane ring from halomethyl precursors.

FIGURE 6.18 A. DNA alkylation by cyclopropylindoles. B. In vivo generation of the cyclopropane ring from halomethyl precursors.

Free molecule

Free molecule

iAiW

DNA-associated molecule x o

Loss of conjugation FIGURE 6.19 Conjugative effects in cyclopropylindoles.

DNA-associated molecule

6. PYRROLO[1,4]BENZODIAZEPINES

Anthramycin, tomaymycin, and sibiromycin are natural pyrrolo[1,4]benzodi-azepine antitumor antibiotics that react with the minor groove of DNA to form covalently bound complexes. They show activity towards several tumors, but their clinical use is limited by their cardiotoxicity and tissue necrosis induction.

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