A detailed study of the duocarmycins, exceptionally potent antitumor antibiotics, are described. We have demonstrated that the duocarmycins derive their biological properties through a sequence selective alkylation of duplex DNA which proceeds by reversible, stereoelectronically- controlled adenine N3 addition to the least substituted carbon of the activated cyclopropane within minor groove 3.5 base pair AT-rich sites. Further studies to define the characteristics of this alkylation reaction, to determine the origin of the DNA alkylation selectivity, and define fundamental principles underlying the relationships between structure, chemical or functional reactivity, DNA alkylation properties, and biological activity are detailed. The development of an asymmetric total synthesis of duocarmycin A and its extension to duocarmycin SA are described. The successful completion of this work would constitute the first asymmetric synthesis of a natural agent in this series amenable to the preparation of structural analogs. The extension of these studies to the preparation and evaluation of a series of analogs of the natural products possessing deep-seated structural changes are detailed in efforts to define fundamental relationships between structure, functional reactivity, and biological activity.
| Eis, P S; Smith, J A; Rydzewski, J M et al. (1997) High resolution solution structure of a DNA duplex alkylated by the antitumor agent duocarmycin SA. J Mol Biol 272:237-52 |
| Boger, D L; Johnson, D S; Palanki, M S et al. (1993) Evaluation of functional analogs of CC-1065 and the duocarmycins incorporating the cross-linking 9a-chloromethyl-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-on e (C2BI) alkylation subunit. Bioorg Med Chem 1:27-38 |
