Limonin as a Starting Point for the Construction of Compounds with High Scaffold Diversity

Structurally complex natural products have been a fruitful source for the discovery and development of new drugs. In an effort to construct a compound collection populated by architecturally complex members with unique scaffolds, we have used the natural product limonin as a starting point. Limonin is an abundant triterpenoid natural product and, through alteration of its heptacyclic core ring system using short synthetic sequences, a collection of 98 compounds was created, including multiple members with novel ring systems. The reactions leveraged in the construction of these compounds include novel ring cleavage, rearrangements, and cyclizations, and this work is highlighted by the discovery of a novel B-ring cleavage reaction, a unique B/C-ring rearrangement, an atypical D-ring cyclization, among others. Computational analysis shows that 52 different scaffolds/ring systems were produced during the course of this work, of which 36 are unprecedented. Phenotypic screening and structure-activity relationships identified compounds with activity against a panel of cancer cell lines.

Automated summary

Alteration of the abundant triterpenoid natural product limonin using short synthetic sequences led to the creation of a collection of 98 compounds, including multiple members with novel ring systems. The reactions involved in constructing these compounds include novel ring cleavage, rearrangements, and cyclizations, resulting in the discovery of new reactions such as B-ring cleavage and B/C-ring rearrangement. Computational analysis revealed the production of 52 different scaffolds/ring systems, with 36 being unprecedented. Phenotypic screening identified compounds with activity against a panel of cancer cell lines.