recent studies of marine organisms have focused on their potential applications , particularly in the treatment of human diseases .
several marine natural products are currently in pre - clinical and clinical evaluation , others show promising biological activities .
one of them , sarcophytol a ( 1 ) , an oxygenated cembrane - type diterpenoid isolated from the soft coral sarcophyton glaucum has been shown to inhibit the development of large bowel cancer in female rats , as well as to suppress carcinogenesis in liver , breast , thymus and skin in mice .
this marine natural product has shown significant inhibitory activity against various classes of tumor promoters .
sarcophytol a inhibits tumor promotion induced by both known tumor promoters okadaic acid and 12-o - tetradecanoylphorbol- 13-acetate ( tpa ) .
it was also found that sarcophytol a inhibits hydrogen peroxide formation by tpa activated human polymorphonuclear leukocytes .
treatment with sarcophytol a during both inititation and tumor promotion was more effective than treatment in the tumor promotion stage only .
because of these activities , sarcophytol a and its analogs , have become very promising cancer chemopreventive agents . due to its cancer preventive activity
a major obstacle in clinical studies of sarcophytol a , however , is supply of the material .
our research focuses on sarcophine ( 2 ) as a source of potential pharmaceutical agents .
in contrast with sarcophytol a ( 1 ) , sarcophine ( 2 ) is one of the most abundant cembranolides ever known .
it is the major metabolite of soft coral sarcophyton glaucum , and may be isolated in 13 % yield ( of dry weight ) from the crude extracts .
sarcophine is a stable crystalline compound and can be easily modified to derivatives with high chemopreventive activity . in our recent work , we described the semisynthesis of several sarcophine derivatives with and without an unsaturated -lactone ring .
we observed that derivatives with 1,2-propanediol moiety have much better chemopreventive activity than those with an intact lactone ring .
based on this observation we have built a hypothesis that the 1,2-propanediol moiety in cembranoid skeleton is responsible for enhancing the chemopreventive activity to an extent superior to sarcophytol a , the standard used in our assays .
a comparison of biological activities for analogous compounds ( 36 ) with and without lactone ring proved this hypothesis ( table 1 ) .
the yields of the products obtained varied from 1223% , and it became obvious that there is a need to prepare a lead compound that can be produced in a good yield and retain good chemopreventive activity to be used to further modify the structure of this class of compounds for sar studies .
this compound is a simple representative of this class of cembranoids with a 1,2-propanediol moiety instead of the lactone ring , and without any other substitutions . in our recent publication ,
compound 7 was obtained in a small yield ( 13% ) during the reaction of the reduced sarcophine ( 8) with selenium dioxide at room temperature , together with the main reaction products which were the 7,8-epoxy-1,3,11-cembratriene-13r()-15r()-triol ( 5 ) and its  isomer .
thus in this investigation , two main goals were targeted , the first was to prove that compound 7 with its simple structure possess as potent activity as the other members reported in our previous work .
the second goal was to develop a procedure to improve the synthesis of this compound to be produced as a sole reaction product and in a highest possible yield .
we now report the in vitro chemopreventive activity , and an improved synthesis of the 7,8- epoxy-1,3,11-cembratriene-15r(),16-diol ( 7 ) .
the inhibition of ebv - ea activation was assayed using raji cells ( virus non - producer type ) using a previously described method .
results of this assay ( table 2 ) show that 7,8-epoxy-1,3,11-cembratriene-15r(),16-diol exhibits a strong inhibitory effect ( about 95% inhibition at a concentration of 32 nmol / ml compared to 91.5% inhibition with sarcophytol - a at the same concentration ) .
the results of the in vitro chemopreventive assay proved our hypothesis that the 1,2- propanediol moiety is responsible for enhancing the chemopreventive activity of the sarcophine molecule to an extent superior to sarcophytol - a .
the second goal was accomplished through a detailed study of the different factors affecting the oxidation of the reduced sarcophine ( time , temperature , grade and molar amount of selenium dioxide ) .
it was found that when using 98.0 % selenium dioxide , the reaction proceeded much slower and in a more controllable way than when using 99.9 % grade .
when the reaction of the reduced sarcophine with equimolar amounts of 98.0 % selenium dioxide was allowed to run at room temperature for just 15 minutes , it gave the 7,8-epoxy-1,3,11-cembratriene-15r(),16-diol ( 7 ) as an exclusive product with 90% yield .
when the reaction was allowed to run for a longer time , additional formation of both 7,8-epoxy-1,3,11-cembratriene-13r(),15r(),16-triol ( 5 ) and its enantiomeric 7,8-epoxy-1,3,11-cembratriene-13r(),15r(),16-triol was observed .
in conclusion , the improved synthesis of the 7,8-epoxy-1,3,11-cembratriene-15r(),16-diol ( 7 ) , accomplished our goal in preparing a parent compound in a simple two steps reaction from sarcophine in an excellent yield , suitable for further derivatization for future sar studies of a new class of chemopreventive compounds .
anhydrous 1,4-dioxane was purchased from aldrich chemical co. in sure seal bottles and used under nitrogen . selenium dioxide ( 98.0 % )
was also purchased from aldrich chemical co. melting point ( uncorrected ) was determined in open capillary tube on a thomas hoover capillary melting point apparatus .
the nmr spectra were obtained on bruker drx-400 operating at 400 mhz for h- and 100 mhz for c - nmr and chemical shifts were reported in ppm relative to internal chcl3 ( 7.26 ppm for h , 77 ppm for c ) .
high - resolution fast atom bombardment mass ( hrfabms ) spectra were conducted at the university of kansas .
high - resolution electron spray mass ( hresms ) spectra were obtained on bruker - magnex bioapex 30es spectrometer .
analytical thin - layer chromatography ( tlc ) was performed on precoated silica gel g-25 uv254 plates ( 0.25 mm ) , visualized with short- and long wave uv light and/or iodine .
the soft coral sarcophyton glaucum was collected on red sea in sharm - el - sheikh , egypt , at the depth of 16 ft ( 5 m ) .
sarcophine was isolated from the extract by column chromatography on silica gel eluting with etoac - hexane ( 2:1 ) , and crystallized from ethyl acetate .
inhibition of epstien barr virus early antigen activation for primary screening on anti - tumor promoters was carried out at kyoto pharmaceutical university , japan .
assays were performed as described previously . selenium dioxide ( 98.0 % , 1 mmol )
was added a solution of the reduced sarcophine ( 8)   ( 1 mmol ) in dry 1,4-dioxane ( 30 ml ) , and the reaction mixture was stirred at room temperature for 15 minutes and followed by tlc for completion of reaction .
the solvent was evaporated and the residue was chromatographed on silica gel using hexane : ethyl acetate ( 1:2 ) as an eluent to obtain the product ( 8590% ) .
the product was identified by comparing its physical data and spectra with those an authentic sample as we previously reported .
anhydrous 1,4-dioxane was purchased from aldrich chemical co. in sure seal bottles and used under nitrogen . selenium dioxide ( 98.0 % )
was also purchased from aldrich chemical co. melting point ( uncorrected ) was determined in open capillary tube on a thomas hoover capillary melting point apparatus .
the nmr spectra were obtained on bruker drx-400 operating at 400 mhz for h- and 100 mhz for c - nmr and chemical shifts were reported in ppm relative to internal chcl3 ( 7.26 ppm for h , 77 ppm for c ) .
high - resolution fast atom bombardment mass ( hrfabms ) spectra were conducted at the university of kansas .
high - resolution electron spray mass ( hresms ) spectra were obtained on bruker - magnex bioapex 30es spectrometer .
analytical thin - layer chromatography ( tlc ) was performed on precoated silica gel g-25 uv254 plates ( 0.25 mm ) , visualized with short- and long wave uv light and/or iodine .
the soft coral sarcophyton glaucum was collected on red sea in sharm - el - sheikh , egypt , at the depth of 16 ft ( 5 m ) .
sarcophine was isolated from the extract by column chromatography on silica gel eluting with etoac - hexane ( 2:1 ) , and crystallized from ethyl acetate .
inhibition of epstien barr virus early antigen activation for primary screening on anti - tumor promoters was carried out at kyoto pharmaceutical university , japan .
selenium dioxide ( 98.0 % , 1 mmol ) was added a solution of the reduced sarcophine ( 8)   ( 1 mmol ) in dry 1,4-dioxane ( 30 ml ) , and the reaction mixture was stirred at room temperature for 15 minutes and followed by tlc for completion of reaction .
the solvent was evaporated and the residue was chromatographed on silica gel using hexane : ethyl acetate ( 1:2 ) as an eluent to obtain the product ( 8590% ) .
the product was identified by comparing its physical data and spectra with those an authentic sample as we previously reported .
 an effective method for the synthesis of 7,8-epoxy-1,3,11-cembratriene- 15r(),16-diol and its in vitro epstein - barr virus early antigen ( ebv - ea ) activation chemopreventive assay are reported . 
 this semisynthetic product is a new cembranoid with a potent tumor inhibitory activity that is expected to be a lead compound for a new class of chemopreventive agents of marine origin . 
Introduction
Results and Discussion
Conclusions
Experimental
General
Materials
Chemopreventive activity
Synthesis of 7, 8-epoxy-1,3,11-cembratriene-15R()-16-diol (7)