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Science: Piecing together the Easter Island molecule

点击量:   时间:2019-03-02 10:10:01

By DAVID BRADLEY (see Graphic) An efficient method for making a natural drug which is a potential antitumour, antibiotic and immunosuppressive compound has been discovered by American chemists. Kyriacos Nicolaou and his team at the University of California at San Diego and the Scripps Research Institute in La Jolla have devised a ‘total synthesis’ of rapamycin. The molecule is one of a host of compounds with interesting biological properties that have been isolated from bacteria and microscopic fungi. Rapamycin is produced by the microbe Streptomyces hygroscopicus, which is grown from a strain found originally in soil samples on Easter Island. The bacterium produces rapamycin as a chemical weapon against invading bacteria, much as moulds which produce penicillins. Rapamycin and related compounds, such as cyclosporin A and FK506, are currently being investigated as potential candidates for treating bacterial infection and cancer, and for suppressing the immune system to stop transplanted organs being rejected. Such compounds have an advantage over drugs called ‘antiproliferative agents’, which destroy dividing cells, because they generally do not have severe side effects. Cyclosporin is already finding a large market in immunosuppression for the drug company Sandoz. Wyeth-Ayerst, a company in Princeton, New Jersey, is carrying out clinical trials on rapamycin. ‘The first use of these drugs is transplantation,’ says Norman Jensen of Wyeth-Ayerst. ‘The next phase of world research will be into their effects in autoimmune diseases, such as psoriasis, and on solid tumours.’ Making rapamycin from scratch seems like a synthetic chemist’s nightmare (see Diagram). The molecule is a 31-membered ring of carbon and oxygen atoms with various chemical groups attached. However, almost every one of the carbon atoms in the main ring is a ‘chiral’ centre – that is, it can exist in two mirror-image forms. If just one of the centres is inverted in the ring, the properties of the molecule could change. One chiral form of the compound, limonene, tastes of lemons while another tastes of oranges. Nicolaou and his colleagues used a daring approach to make rapamycin. They worked out a ‘retrosynthetic’ method, a technique pioneered by the Nobel prizewinning chemist Elias Corey in the 1960s. With this approach, they built up a picture of the molecular jigsaw and then imagined breaking pieces apart until they reached a point where it was easy to see how the constituent pieces might fit together again. In chemical terms, the pieces are either simple laboratory reagents or simpler puzzles that chemists have already solved. The researchers realised that if they imagined splitting rapamycin at certain points, they would have a simple puzzle; this could then be further broken down into two main pieces, each of which they already knew how to make (Journal of the Chemical Society, Chemical Communications, 1993, p 617 and 619). They used a coupling reaction to join these two precursors and then a ‘stitching’ cyclisation to form the rapamycin molecule itself. In stitching, an organotin compound is used to complete the ring by introducing a double bond between the ends. The researchers’ method, which could easily have led to many inverted chiral carbons and so loss of function, sidesteps many of the reactions that would cause inversion and so faithfully recreates the molecule made by S. hygroscopicus (Journal of the American Chemical Society, vol 115,