Version 2 2021-03-03, 14:03Version 2 2021-03-03, 14:03
Version 1 2021-01-23, 01:06Version 1 2021-01-23, 01:06
journal contribution
posted on 2021-03-03, 14:03authored byXiao Liang, Qi-Yin Chen, Gustavo M. Seabra, Susan Matthew, Jason C. Kwan, Chenglong Li, Valerie J. Paul, Hendrik Luesch
New cyanobacteria-derived bifunctional
analogues of doscadenamide
A, a LasR-dependent quorum sensing (QS) activator in Pseudomonas aeruginosa, characterized by dual acylation
of the pyrrolinone core structure and the pendant side chain primary
amine to form an imide/amide hybrid are reported. The identities of
doscadenamides B–J were confirmed through total synthesis and
a strategic focused library with different acylation and unsaturation
patterns was created. Key molecular interactions for binding with
LasR and a functional response through mutation studies coupled with
molecular docking were identified. The structure–activity relationships
(SARs) were probed in various Gram-negative bacteria, including P. aeruginosa and Vibrio harveyi, indicating that the pyrrolinone-N acyl chain is critical for full
agonist activity, while the other acyl chain is dispensable or can
result in antagonist activity, depending on the bacterial system.
Since homoserine lactone (HSL) quorum sensing activators have been
shown to act in synergy with TRAIL to induce apoptosis in cancer cells,
selected doscadenamides were tested in orthogonal eukaryotic screening
systems. The most potent QS agonists, doscadenamides S10–S12,
along with doscadenamides F and S4 with partial or complete saturation
of the acyl side chains, exhibited the most pronounced synergistic
effects with TRAIL in triple negative MDA-MB-231 breast cancer cells.
The overall correlation of the SAR with respect to prokaryotic and
eukaryotic targets may hint at coevolutionary processes and intriguing
host–bacteria relationships. The doscadenamide scaffold represents
a non-HSL template for combination therapy with TRAIL pathway stimulators.