ORGANIC LETTERS
Lodopyridone, a Structurally Unprecedented Alkaloid from a Marine Actinomycete
2009 Vol. 11, No. 23 5422-5424
Katherine N. Maloney,† John B. MacMillan,† Christopher A. Kauffman,† Paul R. Jensen,† Antonio G. DiPasquale,‡ Arnold L. Rheingold,‡ and William Fenical*,† Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, and Department of Chemistry and Biochemistry Small Molecule Crystallography Facility, UniVersity of California, San Diego, La Jolla, California 92093-0204
[email protected] Received August 27, 2009
ABSTRACT
Chemical examination of the secondary metabolites of a marine Saccharomonospora sp., isolated from marine sediments collected at the mouth of the La Jolla Submarine Canyon, yielded the unprecedented alkaloid lodopyridone (1). The low proton-to-carbon ratio of 1 precluded structure elucidation by NMR spectroscopic methods, thus the structure was defined by X-ray crystallography. Lodopyridone is cytotoxic to HCT-116 human colon cancer cells with IC50 ) 3.6 µM.
As a group, the actinomycete bacteria are a prolific source of structurally interesting and biologically active compounds, responsible for over 45% of all microbial natural products,1 including the clinicially important antibiotics tetracycline, erythromycin, and vancomycin.2 Over the past 15 years, we have focused our efforts on an underexplored subgroup of these bacteriasthe actinomycetes dwelling in marine
sedimentssand this effort has yielded a cornucopia of novel bioactive molecules,3 including salinisporamide A,4 which recently completed phase I clinical trials for the expected treatment of multiple myeloma. The usually calm waters off the coast of La Jolla belie a dramatic underwater topography. The La Jolla Submarine Canyon is a major subsurface canyon with a depth in excess of 3000 ft that nearly reaches the pier at Scripps Institution
†
Scripps Institution of Oceanography. Department of Chemistry and Biochemistry Small Molecule Crystallography Facility. (1) Be´rdy, J. J. Antibiot. 2005, 58, 1–26. (2) Walsh, C. Antibiotics: Actions, origins, resistance; ASM Press: Washington, D.C., 2003; Chapter 11, pp 160-161. ‡
10.1021/ol901997k CCC: $40.75 Published on Web 11/02/2009
2009 American Chemical Society
(3) Reviewed in: Fenical, W.; Jensen, P. R. Nat. Chem. Biol. 2006, 2, 666–673. (4) Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. Angew. Chem., Int. Ed. Engl. 2003, 42, 355– 357.
of Oceanography. This canyon, and the millions of years of fault activity that created it, led to a very unusual pattern of sediment deposition on the ocean floor.5 As part of our ongoing efforts to discover novel secondary metabolites from marine sediment actinomycetes, we decided to explore the sediments of this geologically unique area.6 We report here the isolation of a unique actinomycete, strain CNQ490, and the production by this strain of lodopyridone (1), a modified alkaloid with an unprecedented carbon skeleton. The new strain was collected near the mouth of the La Jolla Canyon. Marine bacterial strain CNQ490 was isolated from a sediment sample collected approximately 2 km west of the
Scripps pier at a depth of 45 m. Sequence analysis of its 16S rRNA gene showed only modest identity with Saccharomonospora caesia, while subsequent phylogenetic analysis indicated this strain was a new operational taxonomic unit (OTU) within the genus Saccharomonospora.6 Strain CNQ490 requires saltwater for growth, indicating a high level of adaptation to the marine environment.7 LCMS analysis of a crude extract of a CNQ490 shake flask culture revealed trace amounts of several high molecular weight, chlorinated molecules with an unusual UV chromophore. A large-scale fermentation was undertaken to obtain enough material for structure elucidation. Two rounds of flash chromatography followed by HPLC gave pure 1 (4.0 mg), along with other lodopyridone isomers too minor (
