title: Asymmetric total synthesis of (+)- and ent-(-)-yatakemycin and duocarmycin SA: evaluation of yatakemycin key partial structures and its unnatural enantiomer.
abstract: Complementary to studies that provided the first yatakemycin total synthesis resulting in its structure revision and absolute stereochemistry assignment, a second-generation asymmetric total synthesis is disclosed herein. Since the individual yatakemycin subunits are identical to those of duocarmycin SA (alkylation subunit) or CC-1065 (central and right-hand subunits), the studies also provide an improvement in our earlier total synthesis of CC-1065 and, as detailed herein, have been extended to an asymmetric total synthesis of (+)-duocarmycin SA. Further extensions of the studies provided key yatakemycin partial structures and analogues for comparative assessments. This included the definition of the DNA selectivity (adenine central to a five-base-pair AT sequence, e.g., 5'-AAAAA), efficiency, relative rate, and reversibility of ent-(-)-yatakemycin and its comparison with the natural enantiomer (identical selectivity and efficiency), structural characterization of the adenine N3 adduct confirming the nature of the DNA reaction, and comparisons of the cytotoxic activity of the natural product (L1210, IC50 = 5 pM) with those of its unnatural enantiomer (IC50 = 5 pM) and a series of key partial structures including those that probe the role of the C-terminus thiomethyl ester. The only distinguishing features between the enantiomers is that ent-(-)-yatakemycin alkylates DNA at a slower rate (krel = 0.13) and is reversible, whereas (+)-yatakemycin is not. Nonetheless, even ent-(-)-yatakemycin alkylates DNA at a faster rate and with a greater thermodynamic stability than (+)-duocarmycin SA, illustrating the unique characteristics of such "sandwiched" agents.
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Tichenor
authors.forename: John D
authors.initials: JD
authors.lastname: Trzupek
authors.forename: David B
authors.initials: DB
authors.lastname: Kastrinsky
authors.forename: Futoshi
authors.initials: F
authors.lastname: Shiga
authors.forename: Inkyu
authors.initials: I
authors.lastname: Hwang
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000225:Adenine / Q000737:chemistry; D000477:Alkylating Agents / Q000138:chemical synthesis*; D000478:Alkylation; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis*; D020029:Base Pairing; D001483:Base Sequence; D004247:DNA / Q000737:chemistry*; D000080890:Duocarmycins; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000138:chemical synthesis*; D007700:Kinetics; D008956:Models, Chemical; D011758:Pyrroles / Q000138:chemical synthesis*; D013237:Stereoisomerism; D013302:Streptomyces / Q000737:chemistry*; D013696:Temperature
chemical_list: D000477:Alkylating Agents; D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D011758:Pyrroles; C474180:yatakemycin; C066098:duocarmycin SA; D004247:DNA; D000225:Adenine