New Design And Synthesis To Develop Drugs That Mimic Natural Products

Almost a third of available pharmaceuticals are based on natural products. The discovery of new natural products-inspired drugs, however, is slow due to their limited chemical diversity, their high chemical complexity, and the resulting low yields. The group of Herbert Waldmann has found a way to bypass these limitations by developing substances with new molecular frameworks that don’t look like natural substances but hold the same biological properties.

Through Biology Oriented Synthesis (BIOS) natural product scaffolds are structurally reduced to less complex scaffolds that do not lose their properties but provide a better platform for synthetic modifications. However, the same natural selection process that created the natural products also limited their number and diversity.

The group of Herbert Waldmann developed a new design and synthesis principles to go beyond the chemical space explored by nature by combining the principles of BIOS and fragment-based compound design. In simple terms, scaffolds from different natural products were fragmented and reconnected into to new alternative molecular frameworks. To achieve a higher potential bioactivity the group applied basic guidelines based on known structural characteristics of natural products. In general, employed fragments should derive from natural products with diverse bioactivities. They should be biosynthetically unrelated to combine different structural parameters for binding to proteins. To ensure structural diversity the fragments should contain complementary heteroatoms. Since stereogenic content correlates with bioactivity, the fragments should also be combined into a three-dimensional scaffold.

Following these principles, a new class of pseudo-natural products was designed, termed chromopynones as they consist of a chromane and a tetrahydropyrimidinone fragment. Biological investigations of the chromopynones revealed a restriction in the increased uptake of glucose in cancer cells. This effect results from inhibition of the glucose transporters GLUT-1 and -3 and leads to the suppression of cancer cell growth.

This pioneering strategy gives access to larger areas of the biologically relevant chemical space not covered by nature and opens the door to a new class of nature-inspired products with new biological activity. This concept and the underlying design principles need to be further validated by developing different classes of pseudo natural products. The example of chromopynones as a novel inhibitor of glucose uptake in cancer cells shown here, promises to serve as an inspiration for new drug discovery programmes aimed at tumour metabolism.