1106759-75-4Relevant academic research and scientific papers
Total synthesis and evaluation of iso-duocarmycin SA and iso-yatakemycin
MacMillan, Karen S.,Nguyen, Trihn,Hwang, Inkyu,Boger, Dale L.
supporting information; experimental part, p. 1187 - 1194 (2009/06/28)
The total synthesis and evaluation of iso-duocarmycin SA (5) and iso-yatakemycin (6), representing key analogues of the corresponding natural products incorporating an isomeric alkylation subunit, are detailed. This pyrrole isomer of the natural alkylation subunit displayed an enhanced reaction regioselectivity and a 2-fold diminished stability. Although still exceptionally potent, the /so-duocarmycin SA derivatives and natural product analogues exhibited a corresponding approximate 3-5-fold reduction in cytotoxic activity [L1210 IC50 for (+)-iso-duocarmycin SA = 50 pM and for (+)-/so-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 ortho-spirocyclization with such derivatives was explored via the preparation, characterization, and evaluation of 34 that is incapable of themore conventional para-spirocyclization. Although 34 proved sufficientl y stable for isolation and characterization, it displayed little stability in protic solvents (f1/2 = 0.19hatpH3, t 1/2 = 0.20 h at pH 7), a pH-independent (H+ independent) solvolysisrate profile at pH 3/4-7, and a much reduced cytotoxic potency, but a D NA alkylation selectivity and efficiency comparable to those of duocarmycin SA and iso-duocarmycin SA. The implications of these observations onthe source of the DNA alkylation selectivity and catalysis for this cla ss of natural products are discussed.
