Enantioselective Divergent Syntheses of Several Polyhalogenated <i>Plocamium</i> Monoterpenes and Evaluation of Their Selectivity for Solid Tumors

Vogel, Carl V.; Pietraszkiewicz, Halina; Sabry, Omar M.; Gerwick, William H.; Valeriote, Frederick A.; Vanderwal, Christopher D.

doi:10.1002/ange.201407726

Cited by 11 publications

(3 citation statements)

References 36 publications

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“…We have observed one particularly relevant case of selectivity reversal in a homoallylic alcohol superimposed on a cyclohexene ring, 45 and others wherein transient installation of electron-deficient acyl groups markedly improved reaction behavior. 46,47 In the case of 32 , the most interesting outcome came from a one-pot trifluoroacetylation/dichlorination sequence that provided a nearly equimolar mixture of expected diaxial and unexpected diequatorial dichlorides 33 (not separated at this stage). Of course, the formation of the latter contravenes the Fürst–Plattner principle and provides access to the naturally occurring configurations at C2 and C3 as found in DCL and hatA.…”

Section: Resultsmentioning

confidence: 99%

Synthesis facilitates an understanding of the structural basis for translation inhibition by the lissoclimides

et al. 2017

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The lissoclimides are unusual succinimide-containing labdane diterpenoids that were reported to be potent cytotoxins. Our short semi-synthesis and analogue-oriented synthesis approaches have provided a series of lissoclimide natural products and analogues that expanded the structure-activity relationships in this family. The semi-synthesis approach yielded significant quantities of chlorolissoclimide that permitted evaluation against the NCI’s 60 cell line panel and allowed us to obtain an X-ray co-crystal structure of the synthetic secondary metabolite with the eukaryotic 80S ribosome. While it shares a binding site with other imide-based natural product translation inhibitors, chlorolissoclimide engages in a particularly interesting and novel face-on halogen-π interaction between the ligand’s alkyl chloride and a guanine residue. Our analogue-oriented synthesis provided many more lissoclimide compounds, which were tested against aggressive human cancer cell lines, and for protein synthesis inhibitory activity. Finally, computational modeling was used to explain the SAR of certain key compounds, setting the stage for structure-guided design of better translation inhibitors.

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Section: Resultsmentioning

confidence: 99%

Synthesis facilitates an understanding of the structural basis for translation inhibition by the lissoclimides

et al. 2017

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“…[1] A prominent example is the cytotoxic polyhalogenated monoterpene halomon isolated from the red algae Portieria hornemannii. [2] It is one of only few substances showing activity against all 60 tumor cell lines of the National Cancer Institute. [3] Enantiopure alkylchlorides are also valuable synthetic substrates for S N 2 type reactions.…”

Section: Introductionmentioning

confidence: 99%

Catalytic Asymmetric Chlorination of Isoxazolinones

et al. 2022

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Organic compounds featuring a chlorine substituted stereocenter are frequently found in nature and are interesting for pharmaceutical applications and as synthetic building blocks. Catalytic methods to generate such stereocenters by C,H bond functionalization are still relatively rare. Here we report the first catalytic asymmetric chlorination of isoxazolinones, a synthetically and biologically interesting class of heterocycles, which can be considered as precursors for β-aminoacids. The title reaction was catalyzed with high enantioselectivity by a planar chiral ferrocene based palladacycle in high to excellent yields. It is showcased that the products are valuable for post-synthetic transformations. An S N 2 reaction proceeded with smooth inversion of the absolute configuration. The substitution product could then be transformed into an α-azido β-aminoacid derivative via a reductive, diastereoselective ring opening.

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“…Polyhalogenated monoterpenes vary for the given species depending on collection, location and season (Fuller et al, 1992). Research on this genus has yielded a number of halogenated metabolites that display considerable biological activities such as cytotoxic activity (Naylor et al, 1983; Ortega et al, 1997; Wessels et al, 2000; Vogel et al, 2014), anti-feedant activity (Argandona et al, 2002), anti-fungal activity, molluscicidal activity and insecticidal activity (Watanabe et al, 1989). These secondary metabolites can be categorized into two predominant skeletal types, the 2,6-dimethyloctanes and cyclohexanes (Mynderse and Faulkner, 1975; Crews 1977).…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic halogenated monoterpenes from Plocamium cartilagineum

Sabry

Goeger

Valeriote

et al. 2016

Natural Product Research

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As a result of our efforts to identify bioactive agents from marine algae, we have isolated and identified one new halogenated monoterpene 1 [(−)-(5E,7Z)-3,4,8-trichloro-7-dichloromethyl-3-methyl-1,5,7-octatriene] in addition to three known compounds (2, 3 and 4) from the red alga Plocamium cartilagineum collected by hand from the eastern coast of South Africa. Compound 1 was found to be active as a cytotoxic agent in human lung cancer (NCI-H460) and mouse neuro-2a cell lines (IC50 4 μg/ml). Two of these compounds (3 and 4) were found to have cytotoxic activity in other cell line assays, especially against human leukemia and human colon cancers (IC50 1.3 μg/ml). None of these metabolites were active as sodium channel blockers or activators. All structures were determined by spectroscopic methods (UV, IR, LRMS, HRMS, 1D NMR and 2D NMR). 1D and 2D NOE experiments were carried out on these compounds to confirm the geometry of the double bonds.

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Enantioselective Divergent Syntheses of Several Polyhalogenated Plocamium Monoterpenes and Evaluation of Their Selectivity for Solid Tumors

Cited by 11 publications

References 36 publications

Synthesis facilitates an understanding of the structural basis for translation inhibition by the lissoclimides

Synthesis facilitates an understanding of the structural basis for translation inhibition by the lissoclimides

Catalytic Asymmetric Chlorination of Isoxazolinones

Cytotoxic halogenated monoterpenes from Plocamium cartilagineum

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