title: Total synthesis and evaluation of iso-duocarmycin SA and iso-yatakemycin.
abstract: 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 iso-duocarmycin SA derivatives and natural product analogues exhibited a corresponding approximate 3-5-fold reduction in cytotoxic activity [L1210 IC(50) for (+)-iso-duocarmycin SA = 50 pM and for (+)-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 ortho-spirocyclization with such derivatives was explored via the preparation, characterization, and evaluation of 34 that is incapable of the more conventional para-spirocyclization. Although 34 proved sufficiently stable for isolation and characterization, it displayed little stability in protic solvents (t(1/2) = 0.19 h at pH 3, t(1/2) = 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 those of 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.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: MacMillan
authors.forename: Trinh
authors.initials: T
authors.lastname: Nguyen
authors.forename: Trihn
authors.initials: T
authors.lastname: Nguyen
authors.forename: Inkyu
authors.initials: I
authors.lastname: Hwang
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000478:Alkylation; D000818:Animals; D001688:Biological Products / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry; D000080890:Duocarmycins; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D007536:Isomerism; D051379:Mice; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D001688:Biological Products; D000080890:Duocarmycins; D007211:Indoles; D011758:Pyrroles; C474180:yatakemycin; C066098:duocarmycin SA; D004247:DNA