Systematic exploration of the structural features of yatakemycin impacting DNA alkylation and biological activity.
A systematic examination of the impact of the yatakemycin left and right subunits and their substituents is detailed along with a study of its unique three subunit arrangement (sandwiched vs extended and reversed analogues). The examination of the ca. 50 analogues prepared illustrate that within the yatakemycin three subunit structure, the subunit substituents are relatively unimportant and that it is the unique sandwiched arrangement that substantially increases the rate and optimizes the efficiency of its DNA alkylation reaction. This potentiates the cytotoxic activity of yatakemycin and its analogues overcoming limitations typically observed with more traditional compounds in the series (CC-1065, duocarmycins). Moreover, a study of the placement of the alkylation subunit within the three subunit arrangement (sandwiched vs extended and reversed analogues) indicates that it not only has a profound impact on the rate and efficiency of DNA alkylation but also controls and establishes the DNA alkylation selectivity as well, where both enantiomers of such sandwiched agents alkylate the same adenine sites exhibiting the same DNA alkylation selectivity independent of their absolute configuration.
Tichenor
Mark S
MS
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
MacMillan
Karen S
KS
Trzupek
John D
JD
Rayl
Thomas J
TJ
Hwang
Inkyu
I
Boger
Dale L
DL
D000478:Alkylation / Q000187:drug effects; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000494:pharmacology; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D000080890:Duocarmycins; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D011758:Pyrroles; C474180:yatakemycin; D004247:DNA
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