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

Abstract

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.

Keywords: anticancer agents; drug discovery; limonin; natural products; scaffold diversity.

Figure 1.

Scaffold collection derived from limonin (1).

Figure 2.

Biological evaluation of key compounds against cancer cells in culture. Bioactivity is expressed as a 72-hour IC₅₀ value (in μM) against a panel of cell lines, as measured by Alamar Blue assay. Data represent mean ± SEM, Raptinal (50 μM) was used as dead control, n = 3 biological replicates; ^[a] number of steps from limonin, ^[b] not soluble at 100 μM.

Scheme 1.

Overview of the scaffolds generated from the triterpenoid limonin.

Scheme 2.

Limonin B-ring expansion, E-ring opening, and further manipulations of the A and B rings.

Scheme 3.

Synthesis and functionalization of the ring-opened derivatives 10 and 11.

Scheme 4.

Rearrangement of the B and C rings of limonol (3).

Scheme 5.

Manipulation of the ring-rearranged derivative 4.

Scheme 6.

Manipulation of the D-ring cleaved derivative 5.