Total synthesis of yatakemycin: Structure revision, analogue studies, and biological properties.

摘要

The duocarmycins are potent antitumor natural products that exert their biological properties through a sequence-selective alkylation of duplex DNA. Disclosed in 2003, yatakemycin attracted our attention as the newest and most potent member of this class, having a unique structural arrangement that was anticipated to have important consequences for its interaction with DNA. During the course of our total synthesis of yatakemycin, we prepared the published structure which failed to match the reported spectra of the natural product. Two alternative structures were synthesized, and the second served to revise the natural product structure and absolute stereochemistry by correlation with an authentic sample of yatakemycin. Our second generation asymmetric synthesis featured a late stage intramolecular copper-mediated opening of an epoxide derived from (R)- or (S)-glycidol which efficiently provided both enantiomers of the natural product in high enantiomeric purity.;A new DNA alkylation subunit MeCTI consisting of a single atom change in the alkylation subunit of CC-1065 (S vs. NH) was designed based on the fundamental relationship between reactivity and biological potency observed for this class of DNA alkylating agents. The alkylation subunit MeCTI and its isomer iso-MeCTI were more stable than the alkylation subunit found in CC-1065 and consequently more potent, placing it at an optimal balance between chemical reactivity and stability based on the parabolic relationship established for this class of agents.;Biological studies on (+)- and ent-(-)-yatakemycin documented extraordinarily rapid rates of DNA alkylation, remarkably potent biological activities, and uniquely altered DNA alkylation selectivities for both enantiomers. Both (+)- and ent-(-)- yatakemycin alkylated DNA at adenine-N3 central to a five base-pair A/T tract (e.g. 5'- AAAAA), in a manner distinct from the related natural products which alkylate the 3' terminal adenine of a five base-pair A/T tract (CC-1065) or a three to four base-pair A/T tract (duocarmycin SA). A systematic examination of the yatakemycin left and right-hand subunits and their substituents established their impact on the cytotoxic potency and DNA alkylation properties of such sandwiched compounds. Within the context of yatakemycin's three subunit "sandwiched" arrangement, the subunit substituents are relatively unimportant and the left-hand subunit can compensate for suboptimal right-hand subunits or structural features (i.e. unnatural enantiomer configuration) that limit the effectiveness of previous compounds in the series.