Total Synthesis and Evaluation of iso-Duocarmycin SA and iso-Yatakemycin

摘要

The total synthesis and evaluation of iso-duocarmycin SA (>5) and iso-yatakemycin (>6) are detailed representing key analogues of the corresponding natural products incorporating an isomeric alkylation subunit. This pyrrole isomer of the natural alkylation subunit displayed an enhanced reaction regioselectivity and a 2-fold diminished stability. Although still exceptionally potent, the iso-DSA derivatives and natural product analogues exhibited a corresponding approximate 3- to 5-fold reduction in cytotoxic activity (L1210 IC50 for (+)-iso-duocarmycin SA = 50 pM and (+)-iso-yatakemycin = 15 pM) consistent with their placement on a parabolic relationship correlating activity with reactivity. The DNA alkylation selectivity of the resulting key natural product analogues was unaltered by the structure modification in spite of the minor groove presentation of a potential H-bond donor. Additionally, a unique o-spirocyclization with such derivatives was explored with the preparation, characterization, and evaluation of >34 that is incapable of the more conventional p-spirocyclization. Although >34 proved sufficiently stable for isolation and characterization, it displayed little stability in protic solvents (t1/2 = 0.19 h at pH 3, t1/2 = 0.20 h at pH 7), a pH independent (H⁺ independent) solvolysis rate profile at pH 3/4–7, and a much reduced cytotoxic potency, but a DNA alkylation selectivity and efficiency comparable to duocarmycin SA and iso-duocarmycin SA. The implications of these observations on the source of the DNA alkylation selectivity and catalysis for this class of natural products are discussed.