Now picture a modern organic chemistry lab. The chemist appears to be carrying out a standard reaction: A + B yields C. But now A is actually a mixture of five components while B may be a composite of 10. Instead of a single product C, the chemist deliberately produces a mixture of 50 different compounds! In the not-too-distant past, the second scenario might have been the trademark of a somewhat sloppy chemist or the consequences of a set of very impure reagents. But today, such mixtures of products--combinatorial chemistry--are being heralded as the future of pharmaceutical research. Others see in this the genesis of a new revolution in the search for superconductors or other space-age materials. Whether heresy or panacea, combinatorial chemistry is here to stay. Once the similarities between natural product extraction and deliberate mixture production were recognized, the dogma that chemical entities should be synthesized, purified and analyzed one at a time began to erode. The result is a somewhat tumultuous, totally controversial, but infinitely exciting and challenging new future for the chemical sciences. Some laboratories are deliberately preparing (and successfully decoding) mixtures as large as 200 billion separate compounds in each product vial. Meanwhile, analytical chemists are busy improving both the sensitivity and the resolution capabilities of their diverse groups of hyphenated instruments (GC-MS, LC-MS, MS-MS, CZE-MS, etc.) in order to keep up with the demands of mixture analysis.
And it is with amino acids that modern combinatorial chemistry began. Mario Geysen, in the mid 1980s, began synthesizing peptides by the hundreds, first in parallel fashion and later as mixtures. The classic technique of solid phase synthesis, developed in the 1960s by R. Bruce Merrifield of Rockefeller University, quickly became the key to the production of entire proteins and enzymes during the past three decades. And it has also become the basis for the explosion of solid phase organic synthesis, whereby molecular diversity can be introduced by producing a nearly infinite variety of heterocycles, steroids, carbohydrates, and soon, organometallics, all while tethered by one reversible link to a suitable polymeric support. This dramatic detour from traditional methods of chemical research leads to all sorts of interesting questions. Will all possible compounds be prepared before today's graduate students complete their Ph.D.s? If Chemical Abstracts recorded only several million pure compounds in the past 50 years, but a lone undergraduate student can beat that total in a single afternoon of peptide synthesis, what will be left to make? And can there be any room for rationality in drug design in the future?
Copyright 2000 Arno F. Spatola |
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Imagine a biologist collecting leaves
from exotic rain forest species. The samples are carefully ground,
extracted, and the resulting leaf components are analyzed for
potentially vital biological properties. Perhaps one leaf contains
a heretofore undiscovered antibiotic, while another tree yields
an antitumor agent. Never mind that each extract may contain
hundreds of different leaf components. If the assay proves positive,
the chemists will be able to discern the formulae of the critical
components.
Combinatorial
chemistry has many parallels in nature. Our immune system is
able to produce hundreds of millions of different antibodies
by recombining segments of a variable region of primary structure.
Even deadly South Pacific cone snails appear to have been making
mixtures for the past 50 million years or so. Baldomero Olivera
of Utah has found that these creatures have the ability to harpoon
and paralyze their prey using highly effective peptide toxins.
The active ingredients are actually mixtures of 100 or more deadly
venoms, essentially produced by the combinatorial scrambling
of amino acids.
Never fear. Even if one considers only
a single class of compounds-- peptides --the number of possible
combinations of common D- and L-amino acids soon exceeds the
number of atoms in the universe, even before one reaches 100
units (the size of a relatively small protein). So whether preparing
one compound or one million, the chemist is soon forced to the
realization that there must be introduced some rationale in this
apparently irrational act. Having a clue to where you wish to
go and what you wish to find is essential. A compelling analogy
has been suggested: even with a very large net, one is much more
likely to catch a tuna if the net is dropped into the Pacific
rather than over the Rockies.
Combinatorial chemistry and
molecular diversity--how can one achieve both? Can amino acids
and carbohydrates be mixed as easily in the laboratory as in
glycoproteins? What about using steroids (those ubiquitous four-ring
structures that can either be cholesterol or one of the sex hormones)
as scaffolds for attachment of new heterocycles, some at ring
A with others at D? And can all the elements of the periodic
table be mixed in various proportions to yield new alloys or
new high temperature superconductors? These will be the fascinating
questions that those involved in combinatorials will be wrestling
with in the years to come. The possibilities are literally quite
endless.