Research 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 and Taxol (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 of ACS, 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 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 RTI’s 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. We drive forward on small victories, which over decades lead to great breakthroughs.” A look at the development of camptothecin and Taxol illustrates the stepwise nature of the research.

After World War II, Wall, a research chemist at the Agriculture Department’s Eastern Regional Research Center in Philadelphia, became involved in screening plants for phytosteroids that could be used as precursors to cortisone. Wall sent 1,000 or so of these plant extracts to the National Cancer Institute to test their anticancer potential. One of the plant extracts tested, that of the Chinese tree Camptotheca acuminata, demonstrated potent antitumor activity. Wall was determined to find the active component, but USDA was not involved in anticancer drug research. So, Wall waited, and in 1960, RTI recruited him specifically to study C. acuminata.

According to Wani, an organic chemist 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, inch-long 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 JACS [93, 2325 (1971)].

A breakthrough in understanding how paclitaxel works came in the late 1970s in the laboratory of Susan B. Horwitz, a molecular pharmacologist at Albert Einstein College of Medicine at New York’s Yeshiva University. Unlike previous antitumor agents that inhibited cell division by preventing the production of microtubules, Taxol stimulates microtubule formation. Cells treated with Taxol make so many microtubules that they can’t coordinate cell division.

Today, Taxol and analogs of camptothecin, descended from the work of Wall and Wani on natural products, comprise one-third of the worldwide $10 billion-per-year market in chemotherapeutic drugs.

“Words cannot describe the intense satisfaction I personally feel,” Wani tells C&EN. “Few if any scientists see their work recognized by a landmark in their lifetimes. I am fortunate to be one of them.”

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