title: Stereochemical Studies of the Karlotoxin Class Using NMR Spectroscopy and DP4 Chemical-Shift Analysis: Insights into their Mechanism of Action.
abstract: 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.
authors.affiliation: Department of Pharmacognosy, Pharmacology, School of Pharmacy, and Department of Chemistry and Biochemistry, University of Mississippi, University, MS 38677 (USA).
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Waters
authors.affiliation: Department of Pharmacognosy, Pharmacology, School of Pharmacy, and Department of Chemistry and Biochemistry, University of Mississippi, University, MS 38677 (USA).
authors.forename: Joonseok
authors.initials: J
authors.lastname: Oh
authors.affiliation: Institute of Marine and Environmental Technology, University of Maryland Center for Environmental Sciences, Suite 236 Columbus Center, Baltimore, MD 21202 (USA).
authors.forename: Allen R
authors.initials: AR
authors.lastname: Place
authors.affiliation: Department of Pharmacognosy, Pharmacology, School of Pharmacy, and Department of Chemistry and Biochemistry, University of Mississippi, University, MS 38677 (USA). mthamann@olemiss.edu, hamannm@musc.edu.|Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425 (USA). mthamann@olemiss.edu, hamannm@musc.edu.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Hamann
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D061065:Polyketides; D011714:Pyrans / Q000737:chemistry* / Q000633:toxicity; D013237:Stereoisomerism
chemical_list: D061065:Polyketides; D011714:Pyrans; C550130:karlotoxin 2
keywords: cancer; computational chemistry; membranes; natural products; polyketides