The movie I was involved in a couple of years ago, the Cure, is finally out. It isn’t getting a general release in New Zealand but I think you can down-load it or buy the DVD from the website www.thecuremovie.com and Wellingtonians can buy or rent from Aro Video here. And of course I recommend that you do so that I get, and I hope I use the right term, my residuals.
At the time I was quoted in the press release saying “I’m mostly looking forward to helping build a convincing set and showing actors how to look like they are really doing interesting chemistry in it,” says Slim. “You wouldn’t get away with using a saucepan upside down in a cooking show so why is the equivalent in a lab ok on film?” Brave words indeed.
Of course, as the press release points out, even braver is the fact that the film was entirely self funded by the producer, David Gould. What this means in the case of David is that he mortgaged the house his baby had been born in only a few weeks before to work about 24 hours a day on a project that might or might not get its money back two years down the line. That should give you some idea of just how brave David is. And a clue to the intensity of the film.
The plot involves workers in a San Diego (Lower Hutt) pharmaceutical company laboratory synthesising the Cure for Cancer, which they stumble upon in rather fraught circumstances (like I said go and buy the DVD to learn the rest). The synthesis had to be done quickly – over a few hours – and the final step needed to be carried out later in a disused laboratory, after a machine-gun fight, and immediately before being put in syringes and injected into people dying before our eyes. Oh, yes, and preferably involve a colour change.
So looking real without the facts getting too much in the way was my brief. We didn’t discuss chromatography between steps or the sterile filling of vials under good laboratory practice (GMP) before the impromptu Phase I/IIB trial. When you see the film you will see why. The bad guys were getting very close. No time to wait for FDA approval.
It was a lot of fun. The highlight was riding around in the van with the head of props setting up one set while they were finishing on the last and trying not to take off with anything that was going to be in shot. Not to mention showing Antonia Prebble how to set up for a reflux under argon and having it played back to me in her best Playschool manner. She is a better demonstrator than I ever was. The red carpet was cool too. In the end I don’t think I saw any really unsettling Avatar style misuse of the equipment in the final film so I was pretty happy (but feel free to buy a copy and check).
But what about the molecule? RLS1713 spent quite a bit of time on screen quietly rotating. I was disappointed that the energy minimisation to make it quite so long and thin (obviously I should have expected that) but David liked it because it was easier to fit on the screen. And next time the cancer is breaking out all over and the bad guys are kicking down the door, here is how you make it. I don’t think my website is keen to publish the structures so if you want them, ask for a full copy in the comments.
SYNTHESIS of RLS 1713
3-0-Triflylestradiol (2)
To a solution of estradiol 1 (5g, 18mmol) in acetonitrile (150mL) was added a solution of trifluroacetic anhydride (7.56g, 5.2mL, 36mmol) dropwise with stirring. The resulting solution was heated to 50oC and stirred for a further 15min.
The reaction mixture was cooled, diluted with ethyl acetate (500mL), washed with saturated sodium bicarbonate solution (500mL) and water. The organic phase was dried over sodium sulphate and evaporated to give 3-O-triflylestradiol 2 as a white foam (6.98g, 96%).
3-O-Triflyl-17-O-?-pentylamidoestradiol (3)
To as solution of 3-O-triflylestradiol 2 (6.5g, 0.016mmol) in acetonitile (180mL) was added piperidine-2,6-dione (1.6g, 36mmol) and the resulting solution reluxed over strongly basic anion exchange resin (DOMEX 12900AC, 5g) for 30min. The resin was filtered off, the solution diluted with ethylacetate (600mL) and washed successively with 0.1M hydrochloric acid, saturated sodium bicarbonate solution, brine and water. The organic phase was dried over sodium sulphate and evaporated to give 3-O-triflyl-17-O-?-pentylamidoestradiol (3) as apale yellow oil (7.78g, 94%)
3-O-Triflyl-17-O-?-6-N’-benzoyladenosyl pentylphophoramidainoestradiol (4)
3-O-Triflyl-17-O-?-pentylamidoestradiol (3) (7.5g, 14mmol) was dissolved in dichlomethane (100mL) with triethylamine (4.3g, 5.8mL, 43mmol) and dimethylaminopyridine (0.17g, 1.4mmol) and the resulting solution cooled to 0oC. A solution of 7-N-benzoyl cyclic adenosine monophosphate (9.5g, 21mmol) in dichloromethane (50ml) was added dropwise with stirring over 30min and stirring continued for 15min. The solution became a deep purple colour. The cold solution was poured into 0.1N HCl (500mL) and the organic phase washed with brine and water. The organic phase was dried over sodium sulphate and evaporated to give 3-O-triflyl-17-O-?-6-N’-benzoyladenosyl pentylphophoramidinoestradiol (4) as purple oil (12.16g, 92%)
17-O-?-Adenosyl pentyl-phophoramidinoestradiol (RLS 1713)
The final deprotection of the biologically active molecule was accomplished by dissolving 3-O-triflyl-17-O-?-6-N’-benzoyladenosyl pentylphophoramidinoestradiol (4) (12.0g, 12.8mmol) in methanol (200ml) and the solution brought to reflux under an inert atmosphere. 0.1N Potassium carbonate solution (50mL) was added dropwise to the refluxing over 5min solution and the solution cooled. The solution was diluted with water (400ml) and extracted wit ethylacetate (200mL). Residual methanol was removed on a rotary evaporator and the volume reduced to 50ml to leave a milky white solution of 17-O-?-adenosyl pentylphophoramidinoestradiol (RLS 1713) as the potassium salt ready for injection.
