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Synthesis

Combinatorial Chemistry: Extending Nature’s Structure Inventory

Using additive synthesis techniques, chemists have learned how to create vast collections of natural-product-like compounds for drug discovery

by Stu Borman
December 23, 2013 | A version of this story appeared in Volume 91, Issue 51

Ten years ago, Stuart L. Schreiber of Harvard University and coworkers reported a technique for making natural-product-like compound collections that featured an unprecedented diversity of structures. These so-called libraries were designed to serve as a pool of promising bioactive molecules for drug discovery and biomedical research (Science 2003, DOI: 10.1126/science.1089946). Fast-forward a decade, and a number of drug leads have emerged from such libraries.

The 2003 technique was not the first to synthesize diverse collections of compounds—researchers had already been generating libraries for drug discovery for about a decade. The approach was instead a versatile variation on a set of techniques Schreiber had previously labeled “diversity-oriented synthesis.”

The early versions created many different compounds “combinatorially” by adding sets of building blocks to common molecular skeletons. But the common skeletons displayed the building blocks in limited numbers of spatial orientations, restricting the diversity that could be attained.

In their 2003 variation, Schreiber and coworkers replaced some of the building blocks with “skeletal information elements,” which are molecular components that react and combine with common skeletons to transform them into varied core structures. This approach boosted the achievable molecular diversity considerably, producing compounds even more like the complex compounds found in nature.

ADDING UP DIVERSITY
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A decade ago, Schreiber and coworkers used a combinatorial synthetic approach, like the one above, to make a library of 1,260 natural-product-like compounds based on the six skeletons shown below. In the reactions, skeletal information elements (σ) react and combine with core structures (squares). BB = building block, Ac = acetyl, Ar = aryl group, and M = macrobead solid support.
A set of structures illustrating a combinatorial synthetic chemistry approach to make natural-product-like compounds.
A decade ago, Schreiber and coworkers used a combinatorial synthetic approach, like the one above, to make a library of 1,260 natural-product-like compounds based on the six skeletons shown below. In the reactions, skeletal information elements (σ) react and combine with core structures (squares). BB = building block, Ac = acetyl, Ar = aryl group, and M = macrobead solid support.

Schreiber says compounds made by diversity-oriented synthesis now make up almost one-fifth of the nearly half-million compounds in the compound library at the Broad Institute of Harvard and Massachusetts Institute of Technology, where he directs the Center for the Science of Therapeutics. A number of drug leads have been found by screening the Broad library, including a candidate for treating malaria, an agent that could help diabetics by preventing premature death of insulin-producing cells, and a molecule that interferes with lipid uptake and could be used to probe cholesterol metabolism.

Other combinatorial techniques for creating natural-product-like libraries include biology-oriented synthesis developed by Herbert Waldmann of the Max Planck Institute of Molecular Physiology, in Dortmund, Germany, and coworkers. In this approach, structural modifications relevant to a specific disease or biological function are used to construct bioinspired compounds.

In another example, Thomas Kodadek of Scripps Research Institute Florida and Glenn C. Micalizio, now at Dartmouth College, developed a way to synthesize chirally and conformationally constrained compounds resembling natural products made by bacterial polyketide synthase enzymes—a class of compounds that displays antibiotic and anticancer properties. And Paul J. Hergenrother and coworkers at the University of Illinois, Urbana-Champaign, developed a way to start with actual natural products and chemically modify their rings and functional groups to create new molecules.

In a further extension of combinatorial chemistry, Waldmann, his colleague Kamal Kumar, and coworkers developed a reaction cascade method in which a sequence of transformations in a single pot efficiently leads to a family of compounds called centrocountins. These natural-product-like compounds affect the stability and formation of centrosomes and mitotic spindles inside cells and have anticancer effects.

Waldmann points out that big pharma companies understand the relevance of natural-product-inspired libraries from academic labs and are incorporating them into their corporate libraries. “I could have distributed my in-house library of about 10,000 natural-product-inspired compounds several times over in the past decade or so,” Waldmann says. “Interest is always high.”

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