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Stereochemical Studies of the Karlotoxin Class Using NMR Spectroscopy and DP4 Chemical‐Shift Analysis: Insights into their Mechanism of Action
Author(s) -
Waters Amanda L.,
Oh Joonseok,
Place Allen R.,
Hamann Mark T.
Publication year - 2015
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201507418
Subject(s) - nuclear magnetic resonance spectroscopy , heteronuclear single quantum coherence spectroscopy , chemical shift , chemistry , mode of action , two dimensional nuclear magnetic resonance spectroscopy , chemical structure , mechanism of action , computational chemistry , stereochemistry , combinatorial chemistry , biochemistry , organic chemistry , in vitro
After publication of karlotoxin 2 (KmTx2; 1 ), the harmful algal bloom dinoflagellate Karlodinium sp. was collected and scrutinized to identify additional biologically active complex polyketides. The structure of 1 was validated and revised at C49 using computational NMR tools including J ‐based configurational analysis and chemical‐shift calculations. The characterization of two new compounds [KmTx8 ( 2 ) and KmTx9 ( 3 )] was achieved through overlaid 2D HSQC NMR techniques, while the relative configurations were determined by comparison to 1 and computational chemical‐shift calculations. The detailed evaluation of 2 using the NCI‐60 cell lines, NMR binding studies, and an assessment of the literature supports a mode of action (MoA) for targeting cancer‐cell membranes, especially of cytostatic tumors. This MoA is uniquely different from that of current agents employed in the control of cancers for which 2 shows sensitivity.