Charting Biological and Chemical Space: PSSC and SCONP as Guiding Principles for the Development of Compound Collections Based on Natural Product Scaffolds

Abstract

Finding small molecules that selectively modulate protein function remains one of the major challenges in the fields of chemogenomics and drug development. Natural products interact with proteins in their biosynthesis and when displaying biological activity, and can therefore be considered as "privileged structures". Thus, natural products may serve as biologically validated starting points for the design of focused compound collections. In recent years, effective synthesis methods for natural-product-based focused compound collections have been developed, including multi-component reactions. This review discusses recent advances in the synthesis of natural-product-inspired compound collections as well as the application of Protein Structure Similarity Clustering (PSSC) and a Structural Classification Of Natural Products (SCONP) as guiding principles for the design of focused compound collections based on natural products.

Structural Simplification of Bioactive Natural Products with Multicomponent Synthesis. 2. Antiproliferative and Antitubulin Activities of Pyrano[3,2-c]pyridones and Pyrano[3,2-c]quinolones

“…[1][2][3][4][5][6] Such efforts, however, are often complicated by the structural complexity of natural products, which often contain a large number of stereogenic centers and intricate ring systems. 7 We have recently initiated a research program aimed at structural simplification of natural products, specifically by utilizing multicomponent synthetic processes.…”

Generation of molecular diversity using a complexity-generating MCR-platform towards triazinane diones

“…The crude product was purified by column chromatography yielding 9 (203 mg, 62%) as a white foam as a 1 : 1 mixture of diastereomers. Diastereomer a: 1 …”

“…The crude product was purified by column chromatography (cyclohexaneEtOAc = 2 : 1) affording 11 (63 mg, 64%) as a grey solid. 1 128.7 (2C), 128.7 (2C), 128.3, 128.2, 127.8, 125.6 (2C), 84.7 …”

“…1 were added to the white suspension and this was stirred for 2.5 h. Then, acetonitrile (400 ll) was added and the mixture was stirred overnight. An additional batch of sodium ascorbate and CuSO 4 ·5H 2 O were added to the clear yellow solution and the mixture was stirred for another 2 h. The reaction was worked up by adding H 2 O (10 mL) and extraction with CH 2 Cl 2 (2 × 20 mL).…”

“…1 Combinatorial synthesis is undisputed as an enabling tool to access the required smallmolecule based compound collections. Although the benefit for drug discovery seems obvious, the actual hit rates for new drug candidates have decreased steadily over the past decade.…”