Chemically engineered extracts: source of bioactive compounds

Biological research and drug discovery critically depend on access to libraries of small molecules that have an affinity for biomacromolecules. By virtue of their sustained success as sources of lead compounds, natural products are recognized as "privileged" starting points in structural space for library development. Compared with synthetic compounds, natural products have distinguishing structural properties; indeed, researchers have begun to quantify and catalog the differences between the two classes of molecules. Measurable differences in the number of chiral centers, the degree of saturation, the presence of aromatic rings, and the number of the various heteroatoms are among the chief distinctions between natural and synthetic compounds. Natural products also include a significant proportion of recurring molecular scaffolds that are not present in currently marketed drugs: the bioactivity of these natural substructures has been refined over the long process of evolution. In this Account, we present our research aimed at preparing libraries of semisynthetic compounds, or chemically engineered extracts (CEEs), through chemical diversification of natural products mixtures. The approach relies on the power of numbers, that is, in the chemical alteration of a sizable fraction of the starting complex mixture. Major changes in composition can be achieved through the chemical transformation of reactive molecular fragments that are found in most natural products. If such fragments are common enough, their transformation represents an entry point for chemically altering a high proportion of the components of crude natural extracts. We have searched for common reactive fragments in the Dictionary of Natural Products (CRC Press) and identified several functional groups that are expected to be present in a large fraction of the components of an average natural crude extract. To date, we have used reactions that incorporate (i) nitrogen atoms through carbonyl groups, (ii) sulfur by transformation of -OH and amines, and (iii) bromine through double bonds and aromatic rings. The resulting CEEs had different composition and biomolecular properties than their natural progenitors. We isolated a semisynthetic β-glucosidase inhibitor from a CEE prepared by reaction with benzenesulfonyl chloride, an antifungal pyrazole from a CEE prepared by reaction with hydrazine, and an acetylcholinesterase inhibitor from a CEE prepared through bromination. Our results illustrate how biological activity can be generated through chemical diversification of natural product mixtures. Moreover, the level of control that can be asserted in the process by judicious design and experimental choices underscores the potential for further development of CEEs in both basic research and drug discovery.