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Bifunctional Doscadenamides Activate Quorum Sensing in Gram-Negative Bacteria and Synergize with TRAIL to Induce Apoptosis in Cancer Cells
Journal of Natural Products ( IF 5.1 ) Pub Date : 2021-01-22 , DOI: 10.1021/acs.jnatprod.0c01003
Xiao Liang 1, 2 , Qi-Yin Chen 1, 2 , Gustavo M Seabra 1, 2 , Susan Matthew 1 , Jason C Kwan 1 , Chenglong Li 1, 2 , Valerie J Paul 3 , Hendrik Luesch 1, 2
Affiliation  

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.

中文翻译:

双功能多卡登胺激活革兰氏阴性菌的群体感应并与 TRAIL 协同诱导癌细胞凋亡

报道了源自蓝藻的新型双功能多卡登酰胺 A 类似物,多卡登酰胺 A 是铜绿假单胞菌中一种 LasR 依赖性群体感应 (QS) 激活剂,其特征是吡咯啉酮核心结构和侧链伯胺双酰化,形成酰亚胺/酰胺杂化物。通过全合成确认了多斯卡登酰胺 B–J 的特性,并创建了具有不同酰化和不饱和模式的战略重点库。通过突变研究和分子对接确定了与 LasR 结合的关键分子相互作用和功能反应。在包括铜绿假单胞菌哈维氏弧菌在内的各种革兰氏阴性细菌中探讨了结构-活性关系(SAR),表明吡咯啉酮-N酰基链对于完全激动剂活性至关重要,而其他酰基链是可有可无的或可能导致拮抗剂活性,取决于细菌系统。由于高丝氨酸内酯 (HSL) 群体感应激活剂已被证明与 TRAIL 协同作用以诱导癌细胞凋亡,因此在正交真核筛选系统中测试了选定的多卡登酰胺。最有效的 QS 激动剂多卡登酰胺 S10-S12,以及酰基侧链部分或完全饱和的多卡登酰胺 F 和 S4,在三阴性 MDA-MB-231 乳腺癌细胞中与 TRAIL 表现出最显着的协同作用。SAR 与原核和真核目标的总体相关性可能暗示着共同进化过程和有趣的宿主-细菌关系。多斯卡登胺支架代表了与 TRAIL 通路刺激剂联合治疗的非 HSL 模板。
更新日期:2021-03-26
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