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

Abstract

The synthesis and examination of two unique classes of duocarmycin SA analogs are described which we refer to as reversed and sandwiched analogs. Their examination established both the origin of the DNA alkylation selectivity and that both enantiomers of this class of natural products are subject to the same polynucleotide recognition features. The most beautiful demonstration of this is the complete switch in the enantiomeric alkylation selectivity of the reversed analogs which is only 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 were observed among the agents and correlate with the presence or absence of an extended, rigid N2 amide substituent. This has led to the proposal of a previously unrecognized source of catalysis for the DNA alkylation reaction which was introduced in the preceding paper of this issue (J. Am. Chem. Soc. 1997, 119, 4977−4986).

Are the Duocarmycin and CC-1065 DNA Alkylation Reactions Acid-Catalyzed? Solvolysis pH−Rate Profiles Suggest They Are Not

“…The establishment of the solvolysis pH-rate profiles for 5 and 6 and the determination that the uncatalyzed S N 2 reaction dominates at pH g6 has important ramifications on the source of catalysis for the DNA alkylation reactions of 1-3. First, it established that the assumed requirement for acid catalysis is not necessary 2 consistent with recent experimental observations 7,8 and indicates that reaction models 3 or alkylation selectivity models 2,6 based on pH 2-3 studies 4,5 and a requirement for acid catalysis are unlikely to be accurate. More importantly, it illustrates that the structural and corresponding reactivity features embodied in 5 and 6, which we suggest are analogous to those accompanying the DNA binding-induced conformational change in 1-3, are sufficient to provide activation for an uncatalyzed S N 2 nucleophilic attack independent of pH.…”

CC-1065 and the duocarmycins: recent developments

“…In particular, the alkylating subunit of duocarmycin SA, which contains a C6 methyl ester, provides the opportunity to introduce DNA binding subunits on either side of this portion. Thus, coupling of a DNA binding subunit through the C6 carboxylate provides a novel class of agents referred to as reversed analogues [46,82]. The reversed compounds exhibit an AT-rich alkylation selectivity that extends in the atypical reverse direction from an alkylation site.…”

Structural Features of the (+)‐Yatakemycin/d(GACTAATTGAC)‐(GTCAATTAGTC) Complex – Quantum Mechanical Calculation of NMR Parameters as a Tool for the Characterization of Ligand/DNA Interactions

“…[31] For instance, DSA, presenting a larger χ1 value in the bound conformation than the other two analogues, shows a higher reaction efficiency than (+)-DA and (+)-DSI (Scheme 1). [24] Subsequent studies on sandwiched analogues such as (+)-and (-)-CDPI-DSA-CDPI [1][2][3][4][32][33] have made great contributions to understanding of the shape-dependent catalysis, because these compounds show faster alkylation rates. The steric bulk of the sandwiched analogues in fact forces such a compound into greater perturbation from the free planar conformation to allow penetration into the minor groove.…”

“…(+)-Yatakemycin, like the preceding sandwiched derivatives, [4,32,33] shows improved alkylating properties, [1] displaying faster alkylation rate and higher alkylation selectivity, and consequently more potent cytotoxic activity than preceding analogues (Table 1).…”