Analogues of the Potent Antitumor Compound Leiodermatolide from a Deep-Water Sponge of the Genus <i>Leiodermatium</i>

Wright, Amy E.; Roberts, Jill C.; Guzmán, Esther A.; Pitts, Tara P.; Pomponi, Shirley A.; Reed, John K.

doi:10.1021/acs.jnatprod.6b01140

Cited by 10 publications

(9 citation statements)

References 15 publications

(22 reference statements)

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“…415 Equally surprising as the lack of new peptides, only one report of new macrolides 1013, 1014 was published in 2017. 416 Four new amino acid compounds 1015-1018 were reported from the sponge genera Hymeniacidon, Lendenfeldia and Oscarella; the synthesis of the last compound was also achieved. [417][418][419] Pyrazole NPs 1019-1021 were reported from Cinachyrella sp., 403 while a Haliclona yielded three new 3-alkylpyridinium alkaloids 1022-1024.…”

Section: Spongesmentioning

confidence: 99%

Marine natural products

et al. 2019

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Section: Spongesmentioning

confidence: 99%

Marine natural products

et al. 2019

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“…However, 10 nM leiodermatolide was sufficient to induce G2/M arrest in PANC‐1 cells at 24 hrs of treatment. Leiodermatolide also induces G2/M cell cycle arrest in other cell lines such as the lung carcinoma A549 1 and the lymphoma line U937 (data not shown).…”

Section: Resultsmentioning

confidence: 87%

Leiodermatolide, a novel marine natural product, has potent cytotoxic and antimitotic activity against cancer cells, appears to affect microtubule dynamics, and exhibits antitumor activity

Guzmán

Pitts

et al. 2016

Intl Journal of Cancer

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Pancreatic cancer, the fourth leading cause of cancer death in the United States, has a negative prognosis because metastasis occurs before symptoms manifest. Leiodermatolide, a polyketide macrolide with antimitotic activity isolated from a deep water sponge of the genus Leiodermatium, exhibits potent and selective cytotoxicity towards the pancreatic cancer cell lines AsPC-1, PANC-1, BxPC-3, and MIA PaCa-2, and potent cytotoxicity against skin, breast and colon cancer cell lines. Induction of apoptosis by leiodermatolide was confirmed in the AsPC-1, BxPC-3 and MIA PaCa-2 cells. Leiodermatolide induces cell cycle arrest but has no effects on in vitro polymerization or depolymerization of tubulin alone, while it enhances polymerization of tubulin containing microtubule associated proteins (MAPs). Observations through confocal microscopy show that leiodermatolide, at low concentrations, causes minimal effects on polymerization or depolymerization of the microtubule network in interphase cells, but disruption of spindle formation in mitotic cells. At higher concentrations, depolymerization of the microtubule network is observed. Visualization of the growing microtubule in HeLa cells expressing GFP-tagged plus end binding protein EB-1 showed that leiodermatolide stopped the polymerization of tubulin. These results suggest that leiodermatolide may affect tubulin dynamics without directly interacting with tubulin and hint at a unique mechanism of action. In a mouse model of metastatic pancreatic cancer, leiodermatolide exhibited significant tumor reduction when compared to gemcitabine and controls. The anti-tumor activities of leiodermatolide, as well as the proven utility of anti-mitotic compounds against cancer, make leiodermatolide an interesting compound with potential chemotherapeutic effects that may merit further research.

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“…The order Tetractinellida is known for its rich diversity of bioactive compounds. To date, the natural product chemistry of few deep-water tetractinellids has been investigated, but those few have yielded a variety of natural products including bisindole alkaloids [11], cytotoxic peptide lactones [12], macrolides [13,14] and other polyketides [15], steroidal saponins [16], and cytotoxic linear acetylenes [17], suggesting this group has potential for yielding new bioactive metabolites.…”

Section: Introductionmentioning

confidence: 99%

Unveiling the Chemical Diversity of the Deep-Sea Sponge Characella pachastrelloides

et al. 2022

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Sponges are at the forefront of marine natural product research. In the deep sea, extreme conditions have driven secondary metabolite pathway evolution such that we might expect deep-sea sponges to yield a broad range of unique natural products. Here, we investigate the chemodiversity of a deep-sea tetractinellid sponge, Characella pachastrelloides, collected from ~800 m depth in Irish waters. First, we analyzed the MS/MS data obtained from fractions of this sponge on the GNPS public online platform to guide our exploration of its chemodiversity. Novel glycolipopeptides named characellides were previously isolated from the sponge and herein cyanocobalamin, a manufactured form of vitamin B12, not previously found in nature, was isolated in a large amount. We also identified several poecillastrins from the molecular network, a class of polyketide known to exhibit cytotoxicity. Light sensitivity prevented the isolation and characterization of these polyketides, but their presence was confirmed by characteristic NMR and MS signals. Finally, we isolated the new betaine 6-methylhercynine, which contains a unique methylation at C-2 of the imidazole ring. This compound showed potent cytotoxicity towards against HeLa (cervical cancer) cells.

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Analogues of the Potent Antitumor Compound Leiodermatolide from a Deep-Water Sponge of the Genus Leiodermatium

Cited by 10 publications

References 15 publications

Marine natural products

Marine natural products

Leiodermatolide, a novel marine natural product, has potent cytotoxic and antimitotic activity against cancer cells, appears to affect microtubule dynamics, and exhibits antitumor activity

Unveiling the Chemical Diversity of the Deep-Sea Sponge Characella pachastrelloides

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