A divergent intermediate strategy yields biologically diverse pseudo-natural products

Abstract

The efficient exploration of biologically relevant chemical space is essential for the discovery of bioactive compounds. A molecular design principle that possesses both biological relevance and structural diversity may more efficiently lead to compound collections that are enriched in diverse bioactivities. Here the diverse pseudo-natural product (PNP) strategy, which combines the biological relevance of the PNP concept with synthetic diversification strategies from diversity-oriented synthesis, is reported. A diverse PNP collection was synthesized from a common divergent intermediate through developed indole dearomatization methodologies to afford three-dimensional molecular frameworks that could be further diversified via intramolecular coupling and/or carbon monoxide insertion. In total, 154 PNPs were synthesized representing eight different classes. Cheminformatic analyses showed that the PNPs are structurally diverse between classes. Biological investigations revealed the extent of diverse bioactivity enrichment of the collection in which four inhibitors of Hedgehog signalling, DNA synthesis, de novo pyrimidine biosynthesis and tubulin polymerization were identified from four different PNP classes.

Discovery of a Novel Pseudo‐Natural Product Aurora Kinase Inhibitor Chemotype through Morphological Profiling

“…The pseudo-NP has a median similarity of 0.15 and a maximum similarity of 0.25 to the CAKis. These values align with 100 subsets containing 100 random compounds from the Enamine Advanced Screening Collection (median = 0.14, 95th percentile median = 0.23) [37] and confirm the pseudo-NP has significantly different connectivities than any of the CAKis. Similar conclusions were obtained when a fingerprint of a different design (ecfp6) was employed (Figure 9B).…”

“…The dashed line at 0.23 represents an upper threshold of randomness. [ 37 ] B) Violin plot of the Tanimoto similarities of the Morgan fingerprints (ECFP6, bit fingerprint of length 1024, radius 3) of ChEMBL Aurora kinase inhibitors to B12 (range = 0.04–0.16; median = 0.09). The median and quartiles are indicated on the violin by dashed lines.…”

“…In this site immediately adjacent to the B12 binding location, a glutamate side chain would sterically clash with the majority of the binding poses modeled although more subtle effects relating to protein dynamics and conformation cannot be discounted as a contributing factor for the isoform selectivity observed. [37] B) Violin plot of the Tanimoto similarities of the Morgan fingerprints (ECFP6, bit fingerprint of length 1024, radius 3) of ChEMBL Aurora kinase inhibitors to B12 (range = 0.04-0.16; median = 0.09). The median and quartiles are indicated on the violin by dashed lines.…”

“…A) Violin plot of the Tanimoto similarities of the Morgan fingerprints (ECFC4, count fingerprint, radius 2) of ChEMBL Aurora kinase inhibitors to B12 (range = 0.04-0.25; median = 0.15). The median and quartiles are indicated on the violin by dashed lines.The dashed line at 0.23 represents an upper threshold of randomness [37]. B) Violin plot of the Tanimoto similarities of the Morgan fingerprints (ECFP6, bit fingerprint of length 1024, radius 3) of ChEMBL Aurora kinase inhibitors to B12 (range = 0.04-0.16; median = 0.09).…”

“…The median and quartiles are indicated on the violin by dashed lines. The dashed line at 0.17 represents an upper threshold of randomness [37]. (C) Principle moments of inertia plot of the pseudo-NP B12 (blue triangle) and ChEMBL Aurora kinase inhibitors (CAKis, red circles).…”