ACS NEWS
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THE DISCOVERY OF CAMPTOTHECIN ANDTAXQL
ANTICANCER RESEARCH HONORED AT RTI ACS designates the lab a National Historic Chemical Landmark L I N D A R. R A B E R , C & E N
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WASHINGTON
ESEARCH TRIANGLE INSTITUTE'S
(RTI) Natural Products Laboratory in Research triangle Park, N . C . , was honored late last month as a National Historic Chemical Landmark. Ceremonies held under sunny Carolina blue skies hailed the discovery of the revolutionary anticancer drugs camptothecin andTaxol (paclitaxel) by Mansukh C. Wani and the late Monroe E. Wall at RTI. Being at the institute brought back a lot of good memories for Eli M. Pearce, immediate past president ofACS, who was on hand to unveil the landmark's plaque. Wall, who died last year at the age of 85, had hired Pearce to be director of the Dreyfus Laboratory at RTI, a job which Pearce held from 1973 to 1974. Pearce presented the bronze plaque to Victoria F. Haynes, president and chief executive officer of the institute. Haynes thanked Wani, a 40-year employee of RTI, "for saving hundreds of thousands of people by following [his] curiosity to turn science into practice." Wani, who is still actively researching natural products at RTI, also spoke at the dedication ceremony ACS has designated more than 40 National Historic Chemical Landmarks since the program's inception in 1992. The program has commemorated discoveries, products, achievements, and places that 58
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born in Mumbai whom Wall recruited to RTI in 1962, the institute was "nothing but four 'walls.' It was not until the fifth 'Wall' arrived that the chemistry programs, in the form of the Natural Products Laboratory, started moving." First, the researchers had to isolate the active component in the plant. In 1963, the team started working on a 20-kg sample of the wood and bark of C. acuminata using a process called "bioactivity-directed fractionation." In this process, the crude plant extract is purified in an iterative manner. Fractions showing potent activity are carried on to the next stages, and the process is repeated until the compound or compounds responsible for the bioactivity observed in the crude extract are isolated. Once isolated, the structure of the pure compound was determined by X-ray crystallography This research was published in the Journal of the American Chemical Society [88,3888 (1966)]. Taxus brevifolia is a slow-growing evergreen tree with reddish bark and flat, inchlong needles. It has few natural pests because most of it is poisonous. An extract of its bark showed cytotoxicity against one strain of cancer cells. In 1964, during the same period they were working on C. acuminata, Wall and Wani initiated a bioactivity-directed fractionation to isolate the antitumor compound in T. brevifolia. In 1966, they came up with a crystalline substance that Wall named "taxol," a name since trademarked by Bristol-Myers Squibb. After analysis by mass spectrometry, X-ray crystallography, and nuclear magnetic resonance spectroscopy, they published the structure in
have expanded the frontiers of knowledge and advanced medicine and industry The RTI Landmark was sponsored by the ACS North Carolina Section along with RTI. Much of the work that made the event possible was done by RTFs Nicholas Oberlies and University of North Carolina, Chapel Hill, chemistry professor emeritus and former ACS president Ernest L. Eliel. "Research is a tough business," Haynes said, "and most experiments fail at first. JACS {93,2325 (1971)}. A breakthrough in understanding how We drive forward on small victories, which paclitaxel works came in the late 1970s in the over decades lead to great breakthroughs." laboratory of Susan B. Horwitz, a molecuA look at the development of camplar pharmacologist at Albert Einstein Coltothecin andTaxol illustrates the stepwise lege of Medicine at New York's Yeshiva nature of the research. University Unlike previous antitumor agents After World War II, Wall, a research that inhibited cell division by preventing chemist at the Agriculture Department's the production of micro tubules, Taxol stimEastern Regional Research Center in ulates microtubule formation. Cells treated Philadelphia, became involved in screenwith Taxol make so many microtubules that ing plants for phytosteroids that could be they can't coordinate cell division. used as precursors to cortisone. Wall sent 1,000 or so of these plant extracts to the Today, Taxol and analogs of campNational Cancer Institute to test their antothecin, descended from the work of ticancer potential. One of the plant extracts Wall and Wani on natural products, comtested, that of the Chinese tree Camptothe- prise one-third of the worldwide $10 bilca acuminata, demonstrated potent antitu- lion-per-year market in chemotherapeutic mor activity Wall was determined to find drugs. the active component, but USDA was not "Words cannot describe the intense satinvolved in anticancer drug research. So, isfaction I personally feel," Wani tells Wall waited, and in I960, RTI recruited C&EN. "Few if any scientists see their work him specifically to study C. acuminata. recognized by a landmark in their lifetimes. I am fortunate to be one of them." • According to Wani, an organic chemist HTTP://WWW.CEN-ONLINE.ORG
