REVERSED AND SANDWICHED ANALOGS OF DUOCARMYCIN SA - ESTABLISHMENT OF THE ORIGIN OF THE SEQUENCE-SELECTIVE ALKYLATION OF DNA AND NEW INSIGHTS INTO THE SOURCE OF CATALYSIS

The synthesis and examination of two unique classes of duocarmycin SA analogs are described which we refer to as reversed and sandwiched ana logs. Their examination established both the origin of the DNA alkylat ion selectivity and that both enantiomers of this class of natural pro ducts are subject to the same polynucleotide recognition features. The most beautiful demonstration of this is the complete switch in the en antiomeric alkylation selectivity of the reversed analogs which is onl y consistent with the noncovalent binding model and incompatible with alkylation site models of the origin of the DNA alkylation selectivity . In addition, dramatic alterations in the rates of DNA alkylation wer e observed among the agents and correlate with the presence or absence of an extended, rigid N-2 amide substituent. This has led to the prop osal of a previously unrecognized source of catalysis for the DNA alky lation reaction which was introduced in the preceding paper of this is sue.