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Pierre Potier (1934–2006)

2006; Wiley; Volume: 45; Issue: 16 Linguagem: Inglês

10.1002/anie.200600811

1521-3773

Samir Z. Zard,

Plant-based Medicinal Research

Pierre Potier, one of France's pre-eminent scientists and benefactors, passed away on February 3, 2006. He spearheaded the discovery of two important anticancer drugs, Navelbine and Taxotere. Pierre Potier was born in Bois-Colombes, near Paris, on August 22, 1934. He decided upon a career in pharmacy and graduated from the Faculty of Pharmacy of the University of Paris in 1957. His fascination with natural products and their relationship to pharmacy and medicine guided him towards completing a PhD under the joint supervision of Maurice-Marie Janot and Jean Le Men at the Institut de Chimie des Substances Naturelles (ICSN) in Gif-sur-Yvette. These two eminent natural product chemists were at the forefront of the isolation and structural determination of alkaloids. Potier's early interests were in the lunaria alkaloids, numismine, lunarine, and lunaridine, as well as steroidal alkaloids and ellipticines. His studies on plant alkaloids led to reflections concerning their biogenesis and the possibility that N-oxides could be biosynthetic precursors of iminium species, in parallel to their known chemical behavior.1 Iminium, imine, and enamine intermediates are key players in the biosynthesis and total syntheses of alkaloids hinging on the Mannich, Pictet–Spengler, and other related reactions. The conversion of tertiary amine N-oxides into iminium-derived products by the action of acetic anhydride—the so-called Polonovski reaction—suffered in general from complications due to the modest electrophilicity of acetic anhydride and the corresponding nucleophilicity of the ensuing acetate. Potier and his collaborators found that replacement of acetic anhydride with the more reactive trifluoroacetic anhydride transformed this rather obscure reaction into a synthetic tool of tremendous power.2 The lack of nucleophilicity of the trifluoroacetate anion essentially froze the reaction at the iminium intermediate, at which point typical transformations of iminium salts could be achieved cleanly. Even the simplest and highly reactive iminium trifluoroacetate derived from trimethylamine N-oxide could be prepared. The Polonovski–Potier reaction has since played an important role in the biomimetic syntheses of alkaloids,3 and its role in the next major topic of Potier's research was decisive. His first wife, Marie-France, died from cancer at a very young age, an event that lead Potier to focus his research on the discovery of drugs to combat this dreadful disease by using substances found in what he called the “good Lord's shop”. He was 34 years old with three children to care for. The Madagascar periwinkle, Catharanthus roseus, was locally used as an antidiabetic, and thus the plant extracts were initially examined for possible antidiabetic activity. However, instead of lowering blood sugar levels, the extracts depleted the concentration of white blood cells and thus appeared as potentially useful in treating leukemia. Indeed, two anticancer bis(indole) alkaloids isolated from the periwinkle, namely vinblastine and vincristine, were later marketed. However, the drugs were extremely expensive as a result of the difficulties encountered in obtaining large quantities of the active ingredients. For instance, only 2 g of vincristine could be obtained from 1000 kg of catharanthus (0.0002 % yield). To remedy this problem, Potier and his team set out to assemble biomimetically, through an iminium intermediate, the two subunits of anhydrovinblastine, namely catharantine and vindoline, which were much more abundant than the more complex bis(indole) alkaloids themselves. Access to the reactive iminium species would rely on the modified Polonovski reaction. This approach was ultimately successful, but serendipity intervened in the attempted conversion of anhydrovinblastine into vinblastine, which called for a second application of the Polonovski–Potier reaction.4 An unexpected extrusion of one carbon atom occurred to give noranhydrovinblastine, which exhibited strong activity in the tubulin test (vinblastine and vincristine act by binding to tubulin in the mitotic spindle, preventing its polymerization into microtubules). Further studies indicated that the new semisynthetic analogue, now called vinorelbine, was orally active and less neurotoxic than the natural alkaloids. The compound was developed and marketed as Navelbine. Taxol was another promising anticancer natural product that suffered from a severe supply problem. It is present in minute quantities in the bark of the slow-growing pacific yew tree (Taxus brevifolia), and a huge number had to be felled in order to allow extraction of sufficient quantities for complete pharmacological testing. The dilemma of a looming ecological disaster on one hand and dying cancer patients on the other was solved unexpectedly when local authorities decided to build a road through a park in Gif-sur-Yvette. Several century-old European yew trees (Taxus baccata) were to be felled, and Potier obtained permission to recover these trees and carried out a systematic study. From the leaves, a substance was isolated whose structure resembled that of taxol but lacked an acetate group and the aliphatic side chain. This compound, 10-deacetylbaccatin III, could solve the supply problem: it was extracted from leave clippings without harm to the tree and could essentially be converted into taxol in a few steps. During the partial synthesis of taxol from 10-deacetylbaccatin III, serendipity struck yet again. All taxoid derivatives were systematically subjected to the improved tubulin test, and one of the intermediates in the projected synthesis turned out to be more soluble and twice as active as taxol itself.5 This compound was developed into the drug Taxotere. Potier's later interests ranged from exploring the biochemistry and therapeutic potential of the ubiquitous nitric oxide to the role of pyruvaldehyde, a glucose metabolite, in type II diabetes. The latter topic was one of his main concerns as he suffered from diabetes. He even tested an ointment based on metformine on himself to heal a recalcitrant wound. A patent was filed following the success of the test, but unfortunately he did not live to see its outcome. Pierre Potier rapidly rose through the ranks at the ICSN, becoming a co-director in 1974 and Director in 1990. In the same year, he was also appointed to the prestigious Chair of Chemistry at the Muséum National d'Histoire Naturelle in Paris. He was elected a member of the French Academy of Sciences and was the recipient of numerous prizes, including the Gold Medal of the CNRS, the highest scientific distinction in France. He was appointed Director General of Science and Technology (1994–1996) and later became President of the Fondation de la Maison de la Chimie. He was a man of many exceptional talents, humanity, and generosity, and had a sharp wit. He once gave me the “French” definition of serendipity, which was “to look for a needle in a haystack and to find the farmer's daughter”. Sharing a meal with him was another delightful experience. He was a true bon vivant and would regale you with culinary anecdotes and tales of the French terroir. Pierre Potier accomplished much more than any of us could ever dream of doing. Millions of cancer patients are grateful to him for his unwavering search for the “magic bullet”. He will be greatly missed by all of us who knew him and remembered by many more.