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What do these combinatorial libraries look like? These 10,000 different compounds?

Yes, we have published papers on the 10,000 member libraries, as you know. What inspired us there was, in looking in the literature at natural products for medicinal chemistry, we recognized that there were a great number of naturally occurring compounds and medicinal compounds [with common structures]. And they were endowed with a variety of biological effects, including anti-cancer, antibiotic, antiviral, enzyme inhibitory and so on.

So immediately, we felt that instead of waiting for people to go and collect these compounds from nature, one at a time, we could design a strategy in which we could produce them in the laboratory in large numbers, and make relatives of these compounds, analogues of these compounds. We call these libraries.

The universe of molecular diversity, as we call it, is huge—essentially unlimited. The wise thing to do is to design sub-libraries. From this huge universe of molecular diversity, we design a sub-library, say, looking like vancomycin, or the epothilones, or like nothing you’ve seen before—something that you’ve just imagined—but within the domain of structural variation that you can make through the same synthetic technology. Yet you can have a variation of 10,000 compounds. Then once you’ve done this library, you can start over from scratch. Totally different structures, again, but within a framework, a scaffold.

In the last decade, you and your lab have synthesized rapamycin, vancomycin, taxol, brevetoxin, epothilones...

And calicheamicin. Don’t forget calicheamicin. That’s an important one. 1992.

This compound came out of a rock. It was collected at Waco, Texas, in 1987 by a touring scientist. He picked up this rock thinking, "Maybe there’s some bacteria or fungi living inside." So he brought this rock to the laboratory and grew a culture. Inside this culture they discovered a compound called calicheamicin. A phenomenally active compound, extremely active against tumor cells—it binds to DNA, chops it into pieces, and kills the tumor cells.

It was too toxic to be used as a medicine, but the structure was so beautiful, so unusual, and unprecedented—it looked impossible to synthesize. We had the courage to try to make this compound, and we synthesized it in 1992. Then, after several years, people in industry attached this compound to antibodies so they were able to deliver it to certain cancer types selectively without the side effects of the very toxic compound. And it’s now in the clinic. It’s been approved by the FDA. Certain types of lymphomas, I believe, can be attacked by conjugates of the calicheamicin with the antibodies. The story of this compound is fascinating, and I’m very proud of it.

So what’s next?

That’s a good question. Everybody’s been asking me the same question for the last 10 years. "What’s next?" It’s like the stock market: what should we buy next? [LAUGHS]. If I knew, I’d be a much more famous chemist than I am today.

Let me ask you a more general question then. In looking to the 21st century, what are the big synthetic targets for you and for others in the field?

Well, I think the best targets in the field are going to reveal themselves to us in the future. We have only just touched the tip of the iceberg in terms of molecular diversity from nature. A lot of the structures that we have synthesized were not known to us 10 years ago. I strongly believe that we are going to see a lot of new structures creeping into the literature with exciting biological activities that will keep us busy.

I consider myself very fortunate to be in such an exciting field. It’s not necessarily that we will discover the miracle drugs of tomorrow, but the basic science that we develop is the kind that is used in the pharmaceutical and biotechnology industries to invent and discover the new generation of medicines. The training that we provide to the students is very instrumental for that. It’s basically the collection of the accomplishments of my students that I am most proud of. And instilling in these students the habit of rational and deep thinking required by such projects, an invaluable companion for their future careers.

Is there anything else?

It’s very important to give credit to all my team—my students, my staff, Vicky Nielsen, Janise Petrey, my colleagues in the chemistry department, and our administration here, especially Richard Lerner [president of TSRI] for his visionary moves and his generosity and support over the years. We couldn’t have done what we have done in the chemistry department without his support.

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A rock, above, collected by a touring scientist in Waco, Texas, yielded calicheamicin, below, a compound extremely active against tumor cells. "We have only just touched the tip of the iceberg in terms of molecular diversity from nature," says Nicolaou.







See also:

The Nicolaou lab web page

The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century