Cylindrocyclophanes with proteasome inhibitory activity from the Cyanobacterium Nostoc sp

Abstract

Material collected from a parkway in the city of Chicago afforded the isolation of a Nostoc species (UIC 10022A). The extract of this strain displayed significant inhibition of the 20S proteasome as well as antiproliferative activity against HT29, MCF7, NCI-H460, and SF268 cancer cell lines. A standardized dereplication protocol allowed for the rapid identification of three known (11-13) and nine new (1-9) chlorinated cylindrocyclophanes from less than 100 mg of organic extract. Scale-up isolation of 1-9 and 11-13 from a larger extract was guided by LC-UV-MS data. In addition, KBr enrichment of the culture media afforded the isolation of a brominated cylindrocyclophane (10). Biological evaluation of 1-5, 9, and 10-13 revealed a large range of activity against the 20S proteasome and allowed the determination of preliminary structure-activity relationships of the cylindrocyclophane pharmacophore.

Figure 1

Key COSY, TOCSY, and HMBC correlations used for assignment of side-chain moieties.

Figure 2

Chemical structures of 3, 5, and 7 with corresponding IC₅₀ values for the 20S proteasome bioassay. The key “adjacent” relationship is shown with a solid double arrow.

Figure 3

Phylogenetic relationships of 16S rDNA from cyanobacteria. The tree was constructed using maximum evolution (ME) method with a bootstrap consensus of 1000 replicates. Strains denoted with an asterisk (*) are “Bergey's” reference strains. Cyanobacterial strains previously reported to produce cylindrocyclophanes are denoted by a triangle (▲). Only bootstrap values greater than or equal to 75% are displayed.