Bioactive natural, biocatalytic, and semisynthetic tobacco cembranoids.
The two major Nicotiana tabacum tobacco cembranoids, (1 S,2 E,4 R,6 R,7 E,11 E)-2,7,11-cembratriene-4,6-diol (1) and its C-4 epimer, exhibit a wide range of interesting biological activities. Although the tumorigenesis inhibition activity of tobacco cembranoids have been known since the mid 1980's, only a limited number of investigations have targeted their optimization and structure-activity relationship. This study reports the isolation of the new (1 S,2 E,4 S,6 E,8 S,11 E)-2,6,11-cembratriene-8- O-methyl-4,8-diol (3) and the known (1 S,2 E,4 R,6 R,7 E,11 E)-2,7,11-cembratriene-4- O-methyl-4,6-diol (2) from fresh N. tabacum leaves. Cembranoid 2 showed good anti-migratory activity against prostate cancer cell lines, and was therefore subjected to microbial transformation and semisynthetic optimization studies. Biotransformation of 2 using the fungal strains Cunninghamella NRRL 5695 and Mucor ramannianus ATCC 9628 afforded new ( 4 and 5) and known ( 6 and 7) metabolites. Semisynthetic esterification, oxidation, epoxidation, and reaction with Lawesson's reagent afforded the new products 8- 14. Cembranoid 2 and its epoxidation product 9 showed potent anti-migratory activities against the highly metastatic human prostate cancer cell lines PC-3M-CT+ (spheroid disaggregation assay) and PC-3 (wound-healing assay).
Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana, USA.
Hany N
HN
Baraka
Mohammad A
MA
Khanfar
John C
JC
Williams
Emad M
EM
El-Giar
Khalid A
KA
El Sayed
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D020093:Cunninghamella / Q000378:metabolism; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009089:Mucor / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D018515:Plant Leaves / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000473:pathology; D018874:Spheroids, Cellular; D013329:Structure-Activity Relationship; D014026:Nicotiana / Q000737:chemistry*
D004224:Diterpenes; D010936:Plant Extracts