Exploration of the influence of spiro-dienone moiety on biological activity of the cytotoxic marine alkaloid discorhabdin P

Lam, Cary F.C.; Cadelis, Melissa M.; Copp, Brent R.

doi:10.1016/j.tet.2017.06.057

Cited by 9 publications

(12 citation statements)

References 24 publications

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“…We have studied this mode of reactivity for discorhabdin B ( 1 ), finding that reactions with thiols including N -acetyl- l -cysteine affords C-1 thiol substituted C-2/N-18 ring closed analogues (e.g., 3 , Figure 2 ) [ 16 ] and that semi-synthetic derivatives that lack electrophilic reactivity exhibit less potent cytotoxicity. A similar conclusion was drawn from a study of N -13 methyl discorhabdin C (discorhabdin P) [ 17 ].…”

Section: Introductionsupporting

confidence: 81%

“…Collectively these studies characterise the electrophilic reactivity of the spiro-dienone moiety of discorhabdin C, a structural feature that is known to be a factor, but not the sole determinant, for the cytotoxicity reported for this class of alkaloid [ 15 , 16 , 17 ]. To further explore the degree of essentiality of the dienone ring towards cytotoxicity, discorhabdin C was subjected to hydrogenation using Pd/C under an H 2 atmosphere for 15 min to afford, after workup, a blue-coloured product in 71% yield.…”

Section: Resultsmentioning

confidence: 99%

“…In an effort to understand the potential role played by the spiro-(di)enone moiety in the cytotoxicity of discorhabdin alkaloids, we have previously investigated the electrophilic reactivity of discorhabdin B towards biomimetic nucleophiles [ 16 ] and prepared semi-synthetic analogues of discorhabdin P [ 17 ]. Collectively these studies concluded that electrophilic reactivity was a major, though not exclusive, source of alkaloid cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

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Exploration of the Electrophilic Reactivity of the Cytotoxic Marine Alkaloid Discorhabdin C and Subsequent Discovery of a New Dimeric C-1/N-13-Linked Discorhabdin Natural Product

2020

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The cytotoxic marine natural product discorhabdin C contains a 2,6-dibromo-cyclohexa-2,5-diene moiety, previously proposed to be a critical feature required for biological activity. We have determined that the dienone-ring of discorhabdin C is indeed electrophilic, reacting with thiol and amine nucleophiles, affording debrominated adducts. In the case of reaction with 1-aminopentane the product contains an unusual C-2/N-18 ring closed, double-hydrate moiety. This electrophilic reactivity also extends to proteins, with lysozyme-discorhabdin C adducts being detected by ESI mass spectrometry. These results prompted further examination of an extract of discorhabdin C-producing sponge, Latrunculia (Latrunculia) trivetricillata, leading to the isolation and characterisation of a new example of a C-1/N-13 linked discorhabdin dimer that shared structural similarities with the 1-aminopentane-discorhabdin C adduct. To definitively assess the influence of the dienone moiety of discorhabdin C on cytotoxicity, a semi-synthetic hydrogenation derivative was prepared, affording a didebrominated ring-closed carbinolamine that was essentially devoid of tumour cell line cytotoxicity. Antiparasitic activity was assessed for a set of 14 discorhabdin alkaloids composed of natural products and semi-synthetic derivatives. Three compounds, (-)-discorhabdin L, a dimer of discorhabdin B and the discorhabdin C hydrogenation carbinolamine, exhibited pronounced activity towards Plasmodium falciparum K1 (IC50 30–90 nM) with acceptable to excellent selectivity (selectivity index 19–510) versus a non-malignant cell line.

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Section: Introductionsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Exploration of the Electrophilic Reactivity of the Cytotoxic Marine Alkaloid Discorhabdin C and Subsequent Discovery of a New Dimeric C-1/N-13-Linked Discorhabdin Natural Product

2020

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“…Sponges of the family Latrunculiidae produce highly condensed and often brominated alkaloids such as makaluvamines, discorhabdins, and tsitsikammamines, collectively known as pyrroloiminoquinones [1,2]. These compounds display a broad range of biological activities, including cytotoxic [3,4,5,6,7], antitumor [8], antimicrobial [9,10], antiplasmodial [11], and antioxidant activities [12], as well as inhibition of topoisomerase I [7,13] and II [6,8], calcineurin, CPP32 [5], and cholinesterase [14]. Recently, pyrroloiminoquinones have attracted a surge of renewed interest as potential anticancer drug leads.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, pyrroloiminoquinones have attracted a surge of renewed interest as potential anticancer drug leads. Several makaluvamines, discorhabdins, and synthetic analogs have shown promising results in anticancer assays [3,4,15,16] and as inhibitors of the formation of the cancer-related HIF-1α/p300 enzyme complex [17].…”

Section: Introductionmentioning

confidence: 99%

Molecular Networking Reveals Two Distinct Chemotypes in Pyrroloiminoquinone-Producing Tsitsikamma favus Sponges

et al. 2019

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The temperate marine sponge, Tsitsikamma favus, produces pyrroloiminoquinone alkaloids with potential as anticancer drug leads. We profiled the secondary metabolite reservoir of T. favus sponges using HR-ESI-LC-MS/MS-based molecular networking analysis followed by preparative purification efforts to map the diversity of new and known pyrroloiminoquinones and related compounds in extracts of seven specimens. Molecular taxonomic identification confirmed all sponges as T. favus and five specimens (chemotype I) were found to produce mainly discorhabdins and tsitsikammamines. Remarkably, however, two specimens (chemotype II) exhibited distinct morphological and chemical characteristics: the absence of discorhabdins, only trace levels of tsitsikammamines and, instead, an abundance of unbranched and halogenated makaluvamines. Targeted chromatographic isolation provided the new makaluvamine Q, the known makaluvamines A and I, tsitsikammamine B, 14-bromo-7,8-dehydro-3-dihydro-discorhabdin C, and the related pyrrolo-ortho-quinones makaluvamine O and makaluvone. Purified compounds displayed different activity profiles in assays for topoisomerase I inhibition, DNA intercalation and antimetabolic activity against human cell lines. This is the first report of makaluvamines from a Tsitsikamma sponge species, and the first description of distinct chemotypes within a species of the Latrunculiidae family. This study sheds new light on the putative pyrroloiminoquinone biosynthetic pathway of latrunculid sponges.

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Varying light intensity can alter metabolic profile and cannabispiradienone content of industrial hemp

Roman

Yuan

et al. 2023

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Exploration of the influence of spiro-dienone moiety on biological activity of the cytotoxic marine alkaloid discorhabdin P

Cited by 9 publications

References 24 publications

Exploration of the Electrophilic Reactivity of the Cytotoxic Marine Alkaloid Discorhabdin C and Subsequent Discovery of a New Dimeric C-1/N-13-Linked Discorhabdin Natural Product

Exploration of the Electrophilic Reactivity of the Cytotoxic Marine Alkaloid Discorhabdin C and Subsequent Discovery of a New Dimeric C-1/N-13-Linked Discorhabdin Natural Product

Molecular Networking Reveals Two Distinct Chemotypes in Pyrroloiminoquinone-Producing Tsitsikamma favus Sponges

Varying light intensity can alter metabolic profile and cannabispiradienone content of industrial hemp

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