Total Synthesis and Biological Evaluation of Apratoxin E and Its C30 Epimer: Configurational Reassignment of the Natural Product

Wu, Ping; Cai, Weiping; Chen, Qi-Yin; Xu, Senhan; Yin, Ruwen; Li, Yingxia; Zhang, Wei; Luesch, Hendrik

doi:10.1021/acs.orglett.6b02780

Cited by 26 publications

(14 citation statements)

References 28 publications

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“…Providing perspective of our findings, doscadenamides were isolated from a natural product “superproducer” with tremendous biosynthetic capability, Moorena bouillonii from Apra Harbor, Guam, which previously yielded several apratoxins, − lyngbyabellins, − lyngbyalosides, , laingolide B, apramides, , lyngbyastatin 2, lyngbyapeptins, , and apratyramide . The lipopeptides apramides possess partial structural similarity to doscadenamides.…”

Section: Discussionmentioning

confidence: 80%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 80%

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

et al. 2021

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“…Another chiral electrophile, such as aldehyde 8 prepared in five steps from (−)-citronellal, was submitted by Luesch and Zhang to diastereoselective zinc-mediated Reformatsky reaction with tert- butyl bromoacetate ( 9a ) in THF at reflux [ 20 ]. The process afforded in almost quantitative yield (97%) the corresponding β-hydroxy ester 10 as a single diastereomer, as illustrated in Scheme 4 .…”

Section: Reviewmentioning

confidence: 99%

“… Synthesis of apratoxin E and its C30 epimer through a Zn-mediated Reformatsky reaction. Fmoc = 9-fluorenylmethoxylcarbonyl [ 20 ]. …”

Section: Reviewmentioning

confidence: 99%

Recent developments in the asymmetric Reformatsky-type reaction

Pellissier¹

2018

Beilstein J. Org. Chem.

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“…Here we profiled the broad-spectrum activity of preclinical candidate apratoxin S4 ( Chen et al., 2011 ), a synthetic analogue inspired by the natural products apratoxins A and E ( Fig. 1 ) ( Luesch et al., 2001 ; Matthew et al., 2008 ; Wu et al., 2016 ), across cell types with respect to antiproliferative activity, relevant RTK substrates for cotranslational translocation, and deciphered cell type dependent differences in breast cancer panels. We also provided deeper insight into the fate and potential mechanism of degradation of secretory proteins induced by apratoxin S4.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of cotranslational translocation by apratoxin S4: Effects on oncogenic receptor tyrosine kinases and the fate of transmembrane proteins produced in the cytoplasm

Cai

Ratnayake

Wang

et al. 2021

Current Research in Pharmacology and Drug Discovery

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Receptor tyrosine kinases (RTKs) have become major targets for anticancer therapy. However, resistance and signaling pathway redundancy has been problematic. The marine-derived apratoxins act complementary to direct kinase inhibitors by downregulating the levels of multiple of these receptors and additionally prevent the secretion of growth factors that act on these receptors by targeting Sec61α, therefore interfering with cotranslational translocation. We have profiled the synthetic, natural product-inspired apratoxin S4 against panels of cancer cells characterized by differential sensitivity to RTK inhibitors due to receptor mutations, oncogenic KRAS mutations, or activation of compensatory pathways. Apratoxin S4 was active at low-nanomolar to sub-nanomolar concentrations against panels of lung, head and neck, bladder, and pancreatic cancer cells, concomitant with the downregulation of levels of several RTKs, including EGFR, MET and others. However, the requisite concentration to inhibit certain receptors varied, suggesting some differential substrate selectivity in cellular settings. This selectivity was most pronounced in breast cancer cells, where apratoxin S4 selectively targeted HER3 over HER2 and showed greater activity against ER+ and triple negative breast cancer cells than HER2+ cancer cells. Depending on the breast cancer subtype, apratoxin S4 differentially downregulated transmembrane protein CDCP1, which is linked to metastasis and invasion in breast cancer and modulates EGFR activity. We followed the fate of CDCP1 through proteomics and found that nonglycosylated CDCP1 associates with chaperone HSP70 and HUWE1 that functions as an E3 ubiquitin ligase and presumably targets CDCP1, as well as potentially other substrates inhibited by apratoxins, for proteasomal degradation. By preventing cotranslational translocation of VEGF and other proangiogenic factors as well as VEGFR2 and other receptors, apratoxins also possess antiangiogenic activity, which was validated in endothelial cells where downregulation of VEGFR2 was observed, extending the therapeutic scope to angiogenic diseases.

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Total Synthesis and Biological Evaluation of Apratoxin E and Its C30 Epimer: Configurational Reassignment of the Natural Product

Cited by 26 publications

References 28 publications

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

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

Recent developments in the asymmetric Reformatsky-type reaction

Inhibition of cotranslational translocation by apratoxin S4: Effects on oncogenic receptor tyrosine kinases and the fate of transmembrane proteins produced in the cytoplasm

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