Bifunctional Doscadenamides Activate Quorum Sensing in Gram-Negative Bacteria and Synergize with TRAIL to Induce Apoptosis in Cancer Cells

Abstract

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.

Metabolomic Characterization of a cf. Neolyngbya Cyanobacterium from the South China Sea Reveals Wenchangamide A, a Lipopeptide with In Vitro Apoptotic Potential in Colon Cancer Cells

“…This molecule was not able to be isolated in pure form in sufficient quantity for empirical structural characterization in this study, and is suggested for targeted isolation, structure elucidation, and more accurate pharmacological characterization in future research. This strategy of structure proposal based on MS/MS fragmentation analysis and molecular networking for compounds beyond isolation in the initial study, later followed by targeted isolation or synthesis for confirmation and structure-activity relationship (SAR) study, has been recently exemplified by Gerwick, Luesch, and coworkers in the expansion of the cyanobacterial natural product family of doscadenamides [ 47 , 48 , 49 ].…”

Targeting regulated cell death (RCD) with small-molecule compounds in triple-negative breast cancer: a revisited perspective from molecular mechanisms to targeted therapies

“…For example, pterostilbene (PTER), a natural analogue of resveratrol, was proved to enhance TRAIL-induced apoptosis via reactive oxygen species (ROS)-mediated C/EBP homologous protein (CHOP) activation, leading to the expression of DR4 and DR5 [ 34 ]. Like PTER, doscadenamide A could also synergistically interact with TRAIL that induced exogenous apoptosis, and bound to death receptors to induce apoptosis of TNBC cells [ 35 ].…”