Stereochemical Studies of the Karlotoxin Class Using NMR Spectroscopy and DP4 Chemical‐Shift Analysis: Insights into their Mechanism of Action

Waters, Amanda L.; Oh, Joonseok; Place, Allen R.; Hamann, Mark

doi:10.1002/ange.201507418

Cited by 18 publications

(5 citation statements)

References 29 publications

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“…Computational approaches, in conjunction with spectroscopic methods, provide a powerful and emerging method for the assignment of atom connectivity, relative configuration, and absolute configuration of complex molecules. , Highly noteworthy is the protocol developed recently by Martin and Williamson et al incorporating anisotropic NMR parameters with computational approaches to determine the structures of complex natural products. The successful characterization of karlotoxin 2 (KmTx2) followed by KmTx8 and KmTx9 was supported by NMR chemical shift calculation tools including gauge-including atomic orbitals (GIAO) and DP4+ probability studies in conjunction with heteronuclear single quantum coherence (HSQC) spectroscopy studies. − Excited-state time-dependent density functional theory (TDDFT) calculations were applied here in conjunction with experimental electronic circular dichroism (ECD) spectroscopy to determine the absolute configurations of the natural products. − We also used comparison of experimental and calculated 1 H and 13 C NMR chemical shifts of different regioisomers matching the chemical formula of aleutianamine to help verify that the structure was correctly assigned. The protocol presented here involves orchestration of a number of computational methods in combination with spectroscopic analyses, leading to the discovery and establishment of the well-defined structure for aleutianamine.…”

Section: Introductionmentioning

confidence: 99%

Computationally Assisted Discovery and Assignment of a Highly Strained and PANC-1 Selective Alkaloid from Alaska’s Deep Ocean

Zou¹,

Wang

Sims³

et al. 2019

J. Am. Chem. Soc.

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We report here the orchestration of molecular ion networking and a set of computationally assisted structural elucidation approaches in the discovery of a new class of pyrroloiminoquinone alkaloids that possess selective bioactivity against pancreatic cancer cell lines. Aleutianamine represents the first in a new class of pyrroloiminoquinone alkaloids possessing a highly strained multibridged ring system, discovered from Latrunculia (Latrunculia) austini Samaai, Kelly & Gibbons, 2006 (class Demospongiae, order Poecilosclerida, family Latrunculiidae) recovered during a NOAA deep-water exploration of the Aleutian Islands. The molecule was identified with the guidance of mass spectrometry, nuclear magnetic resonance, and molecular ion networking (MoIN) analysis. The structure of aleutianamine was determined using extensive spectroscopic analysis in conjunction with computationally assisted quantifiable structure elucidation tools. Aleutianamine exhibited potent and selective cytotoxicity toward solid tumor cell lines including pancreatic cancer (PANC-1) with an IC 50 of 25 nM and colon cancer (HCT-116) with an IC 50 of 1 μM, and represents a potent and selective candidate for advanced preclinical studies.

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Section: Introductionmentioning

confidence: 99%

Computationally Assisted Discovery and Assignment of a Highly Strained and PANC-1 Selective Alkaloid from Alaska’s Deep Ocean

Zou¹,

Wang

Sims³

et al. 2019

J. Am. Chem. Soc.

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“…This analysis has represented a leap forward in the practice of elucidating structures. It has assisted in the analyses of data sets belonging to bulky molecules and even revision of some wrongly assigned structures. ,− To further validate the results after optical rotation and NMR chemical shift calculations, we fed the experimental and computed data sets of NMR into the DP4 applet by Goodman et al, and the results of DP4 analysis showed that our interpretation of the NMR data and the optical rotation calculation was correct. The DP4 analysis results have been presented in Table .…”

Section: Resultsmentioning

confidence: 99%

Determination of the Absolute Configuration of Ballonigrin Lactone A Using Density Functional Theory Calculations

et al. 2023

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We report the determination of the absolute configuration of a diterpenoid, namely, ballonigrin lactone A (BLA), by comparison of the computed optical rotations, [α]D, of its two diastereomers using density functional theory (DFT) calculations to the experimental [α]D value of +22.4. One of the diastereomers having configurations 4S, 5R, 6S, 10S, 15S was named “α-BLA,” and the other one with configuration 4S, 5R, 6S, 10S, 15R was called “β-BLA”. Six conformers for each diastereomer (α-BLA and β-BLA) of BLA were identified through their conformational analysis. [α]D values of these six conformations for each diastereomer were calculated using DFT at the mPW1PW91/6-311G(d,p)/SMDChloroform level of theory, leading to the conformationally averaged [α]D values of −96.8 for α-BLA and +65.1 for β-BLA. Thus, it was found that the experimental [α]D value of +22.4 was of 4S, 5R, 6S, 10S, 15R, i.e., β-BLA. Experimental and computed nuclear magnetic resonance (NMR) data were also compared, and this comparison was in accordance with the conclusion drawn from the comparison of [α]D values. Finally, the results were augmented with the calculation of the DP4 analysis, and the probability obtained also endorsed our earlier calculations.

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“…The karlotoxin family stands out as a unique and well-studied group of fish-killing toxins. Their modes of action have been proposed (Waters et al, 2015), providing a foundation for understanding the putative toxins we identified in this study. This apparent connection with the karlotoxin family not only expands our understanding of leadbeaterins, but also provides a valuable reference point for further investigations into their biological activities.…”

Section: Discussionmentioning

confidence: 99%

“…Despite progress in characterization of the chemical structures of the toxins of Karlodinium parvum (karlotoxins), Prymnesium parvum (prymnesins), and Karenia brevisulcata (brevisulcenals), the exact mechanisms by which these microalgae cause finfish mortality are not yet fully elucidated (Manning and La Claire, 2010; Van Wagoner et al, 2010; Deeds et al, 2015; Rasmussen et al, 2016; Binzer et al, 2019). However, the fact that the mode of action of karlotoxins has been suggested to be related to the disruption of the gill cell membrane by specific binding to, for instance, cholesterol, supports that they facilitate creation of pores in the membrane (Waters et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Insights into the nature of the microalgal toxins from theChrysochromulina leadbeateriblooms in Northern Norwegian fjords

Wang,

Fon,

Andersen

et al. 2024

Preprint

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In May-June 2019, the microalga Chrysochromulina leadbeateri caused a massive fish-killing event in several fjords in Northern Norway, resulting in the largest direct impact ever on aquaculture in northern Europe due to toxic algae. Motivated by the fact that no algal toxins have previously been described from C. leadbeateri, we set out to investigate the chemical nature and toxicity of secondary metabolites in extracts of two strains (UIO 393, UIO 394) isolated from the 2019 bloom, as well as one older strain (UIO 035) isolated during a bloom in Northern Norway in 1991. Initial LC-DAD-MS/MS-based molecular networking analysis of the crude MeOH extracts of the cultivated strains showed that their profiles of small organic molecules, including a large number of known lipids, were very similar, suggesting that the same class of toxin(s) were likely the causative agents of the two harmful algal bloom (HAB) events. Next, bioassay-guided fractionation using the RTgill-W1 cell line and metabolomics analysis pointed to a major compound affording [M+H]+ ions at m/z 1399.8333 as a possible toxin, corresponding to a compound with the formula C67H127ClO27. Moreover, our study unveiled a series of minor analogues exhibiting distinct patterns of chlorination and sulfation, together defining a new family of compounds, which we propose to name leadbeaterins. Remarkably, these suspected toxins were detected in situ in samples collected during the 2019 bloom close to Tromsø, thereby substantiating their likely role in fish kills. The elemental compositions of the putative C. leadbeateri ichthyotoxins strongly indicate them to be long linear polyhydroxylated polyketides, structurally similar to sterolysins, reported from a number of dinoflagellates.

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Stereochemical Studies of the Karlotoxin Class Using NMR Spectroscopy and DP4 Chemical‐Shift Analysis: Insights into their Mechanism of Action

Cited by 18 publications

References 29 publications

Computationally Assisted Discovery and Assignment of a Highly Strained and PANC-1 Selective Alkaloid from Alaska’s Deep Ocean

Computationally Assisted Discovery and Assignment of a Highly Strained and PANC-1 Selective Alkaloid from Alaska’s Deep Ocean

Determination of the Absolute Configuration of Ballonigrin Lactone A Using Density Functional Theory Calculations

Insights into the nature of the microalgal toxins from theChrysochromulina leadbeateriblooms in Northern Norwegian fjords

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