Synergistic Contribution of Tiglate and Cinnamate to Cytotoxicity of Ipomoeassin F

Zong, Guanghui; Whisenhunt, Lucas; Hu, Zhijian; Shi, Wei

doi:10.1021/acs.joc.7b00409

Cited by 26 publications

(43 citation statements)

References 22 publications

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“…Attracted by single-digit nanomolar IC 50 values against several cancer cell lines (Table 1), four total syntheses of ipomoeassin F have been accomplished by three independent research teams including ourselves. [5–9] In recent NCI-60 cell line screens, we further confirmed both high potency (the average GI 50 of ~30 nM) and potential novel functional mechanism (the correlation index < 0.5 in the compare analyses) of ipomoeassin F,[6] which suggests that the ipomoeassins are unique chemical space for studying biology. To accelerate future ipomoeassin research in chemical biology and even drug discovery, however, analogues that can be synthesized more easily but have biological activity similar or superior to ipomoeassin F are still highly desirable.…”

Section: Introductionsupporting

confidence: 69%

New insights into structure–activity relationship of ipomoeassin F from its bioisosteric 5-oxa/aza analogues

Zong

Sun

Bhakta

et al. 2018

European Journal of Medicinal Chemistry

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Ipomoeassin F, a plant-derived macrolide, exhibited single-digit nanomolar growth inhibition activity against many cancer cell lines. In this report, a series of 5-oxa/aza analogues was prepared and screened for cytotoxicity. Replacement of 5-CH with O/NH simplified the synthesis and led to only a small activity loss. N-methylation almost completely restored the potency. Further studies with additional 5-oxa analogues suggested, for the first time, that size and flexibility of the ring also significantly influence the bioactivity of ipomoeassin F.

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Section: Introductionsupporting

confidence: 69%

New insights into structure–activity relationship of ipomoeassin F from its bioisosteric 5-oxa/aza analogues

Zong

Sun

Bhakta

et al. 2018

European Journal of Medicinal Chemistry

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“…To investigate this, we examined the published comparative growth inhibitory phenotypes across the cell lines assayed in the USA National Cancer Institute panel of 60 cancer cell lines (NCI-60) 38 against CbA, 3 AprA, 11 and IpoF. 39 This correlative analysis revealed that each of the three compounds was designated as “COMPARE-negative,” suggestive of having distinct cytotoxic mechanisms. While not all data from the two testing events for each compound were available, there were activity data from one test event for at least 55 cell lines in each case, out of a total of 61 different cell lines tested across the three compounds.…”

Section: Discussionmentioning

confidence: 99%

Coibamide A Targets Sec61 to Prevent Biogenesis of Secretory and Membrane Proteins

et al. 2020

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Coibamide A (CbA) is a marine natural product with potent antiproliferative activity against human cancer cells and a unique selectivity profile. Despite promising antitumor activity, the mechanism of cytotoxicity and specific cellular target of CbA remain unknown. Here, we develop an optimized synthetic CbA photoaffinity probe (photo-CbA) and use it to demonstrate that CbA directly targets the Sec61α subunit of the Sec61 protein translocon. CbA binding to Sec61 results in broad substrate-nonselective inhibition of ER protein import and potent cytotoxicity against specific cancer cell lines. CbA targets a lumenal cavity of Sec61 that is partially shared with known Sec61 inhibitors, yet profiling against resistance conferring Sec61α mutations identified from human HCT116 cells suggests a distinct binding mode for CbA. Specifically, despite conferring strong resistance to all previously known Sec61 inhibitors, the Sec61α mutant R66I remains sensitive to CbA. A further unbiased screen for Sec61α resistance mutations identified the CbA-resistant mutation S71P, which confirms nonidentical binding sites for CbA and apratoxin A and supports the susceptibility of the Sec61 plug region for channel inhibition. Remarkably, CbA, apratoxin A, and ipomoeassin F do not display comparable patterns of potency and selectivity in the NCI60 panel of human cancer cell lines. Our work connecting CbA activity with selective prevention of secretory and membrane protein biogenesis by inhibition of Sec61 opens up possibilities for developing new Sec61 inhibitors with improved drug-like properties that are based on the coibamide pharmacophore.

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“…13 Intriguingly, ipomoeassins A and F (see Figure 1) have distinct cytotoxicity profiles, as revealed in the NCI 60-cell-line screen, suggesting that the ipomoeassins may possess an unusual mode of action. 16,17 On this basis, ipomoeassin F is a very promising candidate for molecular probe and even chemotherapeutic development; however, the absence of knowledge about the cellular targets of ipomoeassin F has significantly impeded such efforts. To overcome this challenge, after improving our understanding of the structure–activity relationship (SAR) of ipomoeassin F through medicinal chemistry studies, 18−20 we employed a chemical proteomics approach to identify its binding partner(s) in human cells.…”

Section: Introductionmentioning

confidence: 99%

Ipomoeassin F Binds Sec61α to Inhibit Protein Translocation

et al. 2019

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Ipomoeassin F is a potent natural cytotoxin that inhibits growth of many tumor cell lines with single-digit nanomolar potency. However, its biological and pharmacological properties have remained largely unexplored. Building upon our earlier achievements in total synthesis and medicinal chemistry, we used chemical proteomics to identify Sec61α (protein transport protein Sec61 subunit alpha isoform 1), the pore-forming subunit of the Sec61 protein translocon, as a direct binding partner of ipomoeassin F in living cells. The interaction is specific and strong enough to survive lysis conditions, enabling a biotin analogue of ipomoeassin F to pull down Sec61α from live cells, yet it is also reversible, as judged by several experiments including fluorescent streptavidin staining, delayed competition in affinity pulldown, and inhibition of TNF biogenesis after washout. Sec61α forms the central subunit of the ER protein translocation complex, and the binding of ipomoeassin F results in a substantial, yet selective, inhibition of protein translocation in vitro and a broad ranging inhibition of protein secretion in live cells. Lastly, the unique resistance profile demonstrated by specific amino acid single-point mutations in Sec61α provides compelling evidence that Sec61α is the primary molecular target of ipomoeassin F and strongly suggests that the binding of this natural product to Sec61α is distinctive. Therefore, ipomoeassin F represents the first plant-derived, carbohydrate-based member of a novel structural class that offers new opportunities to explore Sec61α function and to further investigate its potential as a therapeutic target for drug discovery.

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Synergistic Contribution of Tiglate and Cinnamate to Cytotoxicity of Ipomoeassin F

Cited by 26 publications

References 22 publications

New insights into structure–activity relationship of ipomoeassin F from its bioisosteric 5-oxa/aza analogues

New insights into structure–activity relationship of ipomoeassin F from its bioisosteric 5-oxa/aza analogues

Coibamide A Targets Sec61 to Prevent Biogenesis of Secretory and Membrane Proteins

Ipomoeassin F Binds Sec61α to Inhibit Protein Translocation

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