The apratoxin marine natural products: isolation, structure determination, and asymmetric total synthesis

Tarsis, Emily M.; Rastelli, Ettore J.; Wengryniuk, Sarah E.; Coltart, Don M.

doi:10.1016/j.tet.2015.05.047

Cited by 18 publications

(4 citation statements)

References 58 publications

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“…The synthetic route of 1 is depicted in Scheme . We applied a similar synthetic strategy that we previously developed for the synthesis of apratoxins S4–S9, , which is a modification of other published methods. − Recently, some other papers were published on total syntheses of apratoxins. − The known compounds 2 , 3 , and 7 were synthesized as we established previously . The N -Boc group in 3 was selectively removed with TMSOTf in the presence of 2,6-lutidine, which was subsequently followed by a coupling reaction of deprotected 3 with 2 to afford compound 4 in 92% yield.…”

mentioning

confidence: 99%

Apratoxin S10, a Dual Inhibitor of Angiogenesis and Cancer Cell Growth To Treat Highly Vascularized Tumors

Cai

Chen

Dang

et al. 2017

ACS Med. Chem. Lett.

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Renal, hepatocellular, and neuroendocrine carcinomas are known as highly vascularized tumors. Although vascular endothelial growth factor A (VEGF-A)-targeted therapies have shown efficacy in the treatment of these cancers, drug resistance is a major concern and might be mediated by interleukin 6 (IL-6). Furthermore, upon antiangiogenic drug exposure, tumor cells may adapt to survive in a vascular-independent manner. Apratoxins are potent marine-derived cytotoxic in vivo-active agents, preventing cotranslational translocation in the secretory pathway, and show promise to overcome resistance by targeting angiogenesis and tumor growth simultaneously. We designed and synthesized a novel apratoxin analogue, apratoxin S10, with a balanced potency and stability as well as synthetic accessibility and scalability. We showed that apratoxin S10 potently inhibits both angiogenesis in vitro and growth of cancer cells from vascularized tumors. Apratoxin S10 down-regulated vascular endothelial growth factor receptor 2 (VEGFR2) on endothelial cells and blocked the secretion of VEGF-A and IL-6 from cancer cells. It inhibited cancer cell growth through down-regulation of multiple receptor tyrosine kinases (RTKs) and compares favorably to currently approved RTK inhibitors in both angiogenesis and cancer cell growth.

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confidence: 99%

Apratoxin S10, a Dual Inhibitor of Angiogenesis and Cancer Cell Growth To Treat Highly Vascularized Tumors

Cai

Chen

Dang

et al. 2017

ACS Med. Chem. Lett.

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“…For NPs, there are an essentially unlimited number of categories for different compound families, with many being unknown at the present time. Additionally, it is quite common for each category to contain fewer than 50 different members; in the work of our laboratory with marine cyanobacterial NPs, this is the case for all of the molecular families we have encountered over the past 40 years, including the curacins 18 – 20 , apratoxins 21 , lyngbyabellins 22 and majusculamides 23 – 25 .…”

Section: Introductionmentioning

confidence: 96%

Small Molecule Accurate Recognition Technology (SMART) to Enhance Natural Products Research

Zhang

Idelbayev

Roberts

et al. 2017

Sci Rep

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Various algorithms comparing 2D NMR spectra have been explored for their ability to dereplicate natural products as well as determine molecular structures. However, spectroscopic artefacts, solvent effects, and the interactive effect of functional group(s) on chemical shifts combine to hinder their effectiveness. Here, we leveraged Non-Uniform Sampling (NUS) 2D NMR techniques and deep Convolutional Neural Networks (CNNs) to create a tool, SMART, that can assist in natural products discovery efforts. First, an NUS heteronuclear single quantum coherence (HSQC) NMR pulse sequence was adapted to a state-of-the-art nuclear magnetic resonance (NMR) instrument, and data reconstruction methods were optimized, and second, a deep CNN with contrastive loss was trained on a database containing over 2,054 HSQC spectra as the training set. To demonstrate the utility of SMART, several newly isolated compounds were automatically located with their known analogues in the embedded clustering space, thereby streamlining the discovery pipeline for new natural products.

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“…6,7 This small group of unique macrolides, as depicted in Figure 1, consists of laingolide (1), 8 laingolide A (2), 9,10 laingolide B (3), [11][12][13] palmyrolide A (4), [14][15][16] and madangolide (5). 9 Moreover, the tert-butyl carbinol-containing polyhydroxylated macrolides, such as amantelides A/B, 17 bastimolide A, 18 and nuiapolide, 19 and cyclic depsipeptides, such as apratoxins A/B/E-H 20,21 and janadolide, 22 have been isolated from marine cyanobacteria. Palmyrolide A was isolated in 2010 from a marine cyanobacterial assemblage composed of Leptolyngbya cf.…”

Section: Introductionmentioning

confidence: 99%

Multimodule Assembly Strategy for Diverted Total Synthesis and Stereochemical Determination of Laingolide A and Laingolide

Cui¹,

Lai²,

Dai³

2021

Preprint

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Diverted total synthesis of diastereomers of laingolide A and laingolide has been accomplished and the stereochemistry of both (E)-enamide-containing 15-membered macrolides has been assigned. Laingolide A and laingolide have 3 and 4 stereogenic centers, respectively, and only their planar structures were reported. The former has 4 possible diastereomers while the latter has up to 8 diastereomers. A multimodule assembly (MMA) strategy was utilized to disconnect both target molecules into 5 small structural modules among which only one stereochemically varied module (stereo-module) needed to be prepared with other 4 modules available commercially. A sequence of ring-closing metathesis (RCM) and alkene isomerization was used for construction of the macrocyclic skeleton and installation of the (E)-enamide moiety. Four each diastereomers of laingolide A and laingolide have been synthesized, leading to assignment of (2R*,7R*,9S*) and (2R*,4R*,7R*,9S*) relative stereochemistry for laingolide A and laingolide, respectively. Moreover, according to the (2S,9R) absolute configuration of the congener, laingolide B, the (2S,7S,9R) and (2S,4S,7S,9R) absolute configurations are suggested for laingolide A and laingolide, respectively. The current synthetic efforts reveal, for the first time, that both laingolide A and laingolide possess the 7,9-syn-Me/t-Bu subunit.

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The apratoxin marine natural products: isolation, structure determination, and asymmetric total synthesis

Cited by 18 publications

References 58 publications

Apratoxin S10, a Dual Inhibitor of Angiogenesis and Cancer Cell Growth To Treat Highly Vascularized Tumors

Apratoxin S10, a Dual Inhibitor of Angiogenesis and Cancer Cell Growth To Treat Highly Vascularized Tumors

Small Molecule Accurate Recognition Technology (SMART) to Enhance Natural Products Research

Multimodule Assembly Strategy for Diverted Total Synthesis and Stereochemical Determination of Laingolide A and Laingolide

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