Design and Synthesis of Natural Product Inspired Libraries Based on the Three-Dimensional (3D) Cedrane Scaffold: Toward the Exploration of 3D Biological Space

A chemoinformatic
method was developed to extract nonflat scaffolds
embedded in natural products within the Dictionary of Natural Products
(DNP). The cedrane scaffold was then chosen as an example of a nonflat
scaffold that directs substituents in three-dimensional (3D) space.
A cedrane scaffold that has three orthogonal handles to allow generation
of 1D, 2D, and 3D libraries was synthesized on a large scale. These
libraries would cover more than 50% of the natural diversity of natural
products with an embedded cedrane scaffold. Synthesis of three focused
natural product-like libraries based on the 3D cedrane scaffold was
achieved. A phenotypic assay was used to test the biological profile
of synthesized compounds against normal and Parkinson’s patient-derived
cells. The cytological profiles of the synthesized analogues based
on the cedrane scaffold revealed that this 3D scaffold, prevalidated
by nature, can interact with biological systems as it displayed various
effects against normal and Parkinson’s patient-derived cell
lines.