• Reflections of graduating students

• Discoveries from Heathcock alumni

Sitting in his office on a gloriously clear Northern California day, Clayton Heathcock was explaining the evolution of organic synthesis and the challenge of his new project.

“In the 1960s, we were pushing the envelope in synthesizing compounds, seeing what could be made. By the 1980s it was clear that, given enough time, we could make pretty much anything we wanted, but sometimes in only very tiny amounts, which was not useful to anyone,” said Heathcock. “Now the challenge is to synthesize compounds in significant enough amounts to be useful, say a jarful of material that can be used to treat cancer patients.

“Natural products are important targets for organic chemists because many of these compounds can be used as drugs against nasty diseases like cancer,” he continued.

Starting with the paper sludge
Almost from the start of his career, Heathcock was intrigued by organic compounds. “After I received my B.Sc. from Abilene Christian College in Texas, I worked for a paper company. When paper is made, the first step is to cut up trees into wood chips, which are then digested in a big pressure cooker with caustic soda. The resulting thick stew is filtered to obtain the paper fibers,” he explained.

“A byproduct of the caustic digestion is a thick sludge composed of terpenoids and steroids. Because it was a complex mixture, it was simply burned to create heat that was used to power the digestion process.

“From my undergraduate class work, I knew that the steroids in this byproduct, called ‘tall oil,’ were potentially valuable. So when I went to graduate school [at the University of Colorado, Boulder, where he studied with Alfred Hassner], I studied steroid synthesis so I could turn material like that discarded byproduct into a valuable commodity.” He became a master at synthesizing intricate, complicated compounds and followed his studies at Colorado with a postdoctoral stint at Columbia under the illustrious Gilbert Stork.

Natural products at Berkeley

Heathcock arrived at Berkeley in 1964 and immediately focused on natural products, continuing his goal of creating valuable steroids. “The very essence of natural product synthesis is that it is a problem with multiple solutions. It’s the challenge of the synthesis, the logic and the planning, that is sometimes more appealing than the actual product.”

Heathcock’s career has been characterized by creative approaches to creating natural products. He has planned and directed the synthesis of almost fifty natural products. “One of my most enjoyable projects—achieving acyclic stereocontrol through the aldol condensation—started out as a very classic steroid synthesis approach, going from step A to step B lockstep. As we progressed, we learned more about a group of related compounds and figured out a method that we suspected the plants themselves were using. We made all five rings in one simple process—a synthetic shortcut that was very rewarding,” he explained. This was a novel approach: chemistry based on biology. “It turned out to be a useless compound, and we still don’t know whether the plants actually use this method,” he said with a laugh, “but our approach served as an inspiration to other scientists.”

His current target is spongistatin 2, which depolymerizes tubulin and inhibits cancer cell growth. Spongiostatin compounds (originally isolated from an Eastern Indian sponge) have been synthesized before, but only in tiny amounts. “To achieve a multi-gram synthesis of spongiostatin 2, we have to pursue over 100 separate reaction steps to make it as cheaply and efficiently as possible. We want to make enough of the product so that it can be evaluated for safety and efficacy against various cancers. If we are successful, this can spur companies and investors to either farm sponges or to isolate the genes responsible for the protein machinery that manufactures spongiostatins in sponges, insert the genes into bacteria, and set up a bacterial production ‘factory,’ ” he explained.

Chemistry Infrastructure
In addition to supervising laboratory research, Heathcock has made major contributions to the infrastructure of chemical study. He is the coauthor with fellow chemistry professor Andrew Streitweiser of Introduction to Organic Chemistry, an impressive work that has been through four editions and translated into five languages. Furthermore, he served as chair of the ACS Division of Organic Chemistry in 1985, editor-in-chief of Organic Synthesis in 1986, and editor-in-chief of the Journal of Organic Chemistry from 1988 through 1999.

He has also advised almost 150 graduate students and postdocs, some of whom have discovered important drugs (see below) both in industry and academia. “Clayton has this remarkable ability to get young scientists to open their eyes and see the bigger picture,” notes a former student.

Gone to the dogs
And then there are his dogs: he is an award-winning breeder of champion Rhodesian Ridgebacks—one of his top dogs, Bruiser (aka Ch. Camelot’s Technical Knockout), was ranked among the top three Ridgebacks for three years in the early 1990s. Heathcock spends much of his free time, along with his wife, Cheri, taking care of and showing his nine dogs. Everyone on his holiday-card list can appreciate the affection that Heathcock has for these dogs, as they are usually the stars of these cards. (Visit http://camelotrr.com/xmas to see examples.)

Not content to just show dogs, Heathcock is also very active in the Rhodesian Ridgeback Club of the United States, serving as its president from 1999 to 2000 and is currently the organizer for the 2004 Rhodesian Ridgeback World Congress, which will be held in Forth Worth, Texas, in September of this year.

Just the latest project in a career filled with academic adventure and success.

Discoveries from Heathcock Alumni. . . . . . . . . . . . .

A number of students from Heathcock’s lab have made waves in the drug discovery field, synthesizing numerous potentially-lifesaving therapies. To name a few:

• Roger Ruggeri (Ph.D. ’90), a scientist at Pfizer, discovered “torcetrapib,” an inhibitor of cholesteryl ester transfer protein (CETP) that raises high density lipoprotein cholesterol (HDL — the good cholesterol) “My training in Clayton’s group allowed me to look at the original lead molecule and invent new ways of synthesizing it that enabled more-active analogs to be created,” he said recently.
  
• Thomas VonGeldern (Ph.D. ’84) led the chemistry team at Abbott that discovered Xinlay (atrasentan), which is in late Phase III trials for the treatment of prostate cancer. Bruce Szczepankiewicz (Ph.D. ’95), another graduate
  student of Heathcock’s, played a significant role in developing backup compounds. Additionally, Clayton himself played a role, serving on the Abbott Scientific Advisory Committee (SAC) at the time the drug was discovered.
  “Clayton was a firm proponent of ‘keeping things simple’ whenever possible and of finding ways to take advantage of what the system gives you,” said VonGeldern, noting how his education in the Heathcock lab has helped him succeed as a chemist.
  
• Steven Young (Ph. D. ’82), an executive director at Merck Research Labs, discovered Efavirenz, a non-nucleoside reverse transcriptase inhibitor that has become a first line therapy for the treatment of AIDS. “My synthesis training taught me how to design efficient, versatile routes to target compounds,” he said.
  
• Robin Clark (Ph.D. ’75) invented Aloxi, an FDA-approved drug to treat the nausea and emesis induced by cancer chemotherapy, while he was at Syntex. Roche, which bought Syntex out, has licensed the drug to MGI Pharma.

UC Berkeley