Chemical Diversification of Natural Product Extracts

RAMALLO, IA; SALAZAR, MO; GARCIA, P; FURLAN, RLE

Studies in Natural Products Chemistry

Elsevier Science Publishers BV

Lugar: Amsterdam; Año: 2019; p. 371 - 398

Natural products (NPs) contain bioactive substructures that have been validated by nature?s long evolution. The correlation between biosynthetic enzyme and target enzyme of natural products has been studied, observing that an imprint of recognition of protein surfaces during biosynthesis is transferred to recognition of therapeutically useful enzyme targets. This biosynthetic enzyme/target correlation provides the underlying reason why natural products are validated starting points for drug design and explains the success of compound libraries based on natural product substructures.Natural products scaffolds have been invaluable platforms for developing drugs. Given the sustained success of NPs as source of bioactive compounds, several research groups have analyzed the differences between natural products, synthetic compounds, combinatorial compounds and bioactive compounds using cheminformatics tools.In a pioneering work Henkel et al. compared NPs and synthetic molecules and found clear differences in their molecular properties and structural features. Later, Feher and Schmidt compared the distribution of a variety of molecular properties among NPs, drugs and combinatorial molecules, finding that the number of chiral centers, the presence of aromatic rings, the degree of saturation and the number of various heteroatoms are the most important differences. Ertl and Schuffenhauer performed a cheminformatics analysis of a large collection of natural product structures and compared their physicochemical properties and their typical structural features with those of bioactive molecules and average organic molecules. They found that natural product molecules are less flexible and contain more oxygen atoms and less nitrogen atoms than the compounds from the other two sets. Taking advantage of the biomolecular recognition properties of NPs, different strategies have been developed to explore the bioactivity of nature-inspired molecular scaffolds.A biology oriented synthesis has been introduced by Waldmann et al., which builds on the diversity created by nature and aims at its local extension in areas of proven biological relevance using simplified core structures of NPs as a starting points.Another strategy is the chemical diversification of natural product mixtures to produce chemically diversified extracts or chemically engineered extracts (CEEs). These CEEs are mixtures produced through chemical reactions that introduce bioactivity relevant fragments or elements into most of the natural molecules present in natural product mixtures such as crude herbal extracts. This approach is somehow related to the libraries from libraries approach wherein synthetic combinatorial libraries are transformed in other libraries which have very different biological properties compared to the libraries from which they are derived . The main difference between both strategies is the previous knowledge about the chemical composition of the starting libraries. In one case, the exact composition of the starting synthetic library is known whereas in CEEs, the approach involves chemical transformation of partially characterized mixtures.Depending on the complexity of the starting natural mixture, a potentially high number of natural product-derived molecules can be produced in one pot. In order to increase the impact of the applied reaction protocol on the chemical composition of the starting extract, it is important to achieve the chemical transformation of reactive fragments that are present in a big proportion of the natural components of the starting material. The successful transformation of these fragments would mean that a big proportion of the molecules present in the extract has been chemically modified. Carbonyl groups, double bonds, aromatic rings and amines have been used as reactive fragments to introduce significant changes in the chemical composition of extracts. In order to increase the impact of the applied reaction protocol on the bioactivity of the extract, it is desirable to introduce fragments that are more commonly found in drugs than in natural products. As is it described in the following sections, to date, several CEEs enriched in sulfur, halogens, nitrogen, etc. have been prepared and used as the source of a series of new bioactive compounds.