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Structure and Stereochemical Determination of Hypogeamicins from a Cave-Derived Actinomycete.

Derewacz DK, McNees CR, Scalmani G, Covington CL, Shanmugam G, Marnett LJ, Polavarapu PL, Bachmann BO - J. Nat. Prod. (2014)

Bottom Line: The structures were elucidated using NMR spectroscopy, and the relative stereochemistries of the pyrans were inferred using NOE and comparison to previously reported compounds.Absolute stereochemistry was determined using quantum chemical calculations of specific rotation and vibrational and electronic circular dichroism spectra, after an extensive conformational search and including solute-solvent polarization effects, and comparing with the corresponding experimental data for the monomeric congeners.Interestingly, the dimeric hypogeamicin A (1) was found to be cytotoxic to the colon cancer derived cell line TCT-1 at low micromolar ranges, but not bacteria, whereas the monomeric precursors possessed antibiotic activity but no significant TCT-1 cytotoxicity.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States.

ABSTRACT
Culture extracts from the cave-derived actinomycete Nonomuraea specus were investigated, resulting in the discovery of a new S-bridged pyronaphthoquinone dimer and its monomeric progenitors designated hypogeamicins A-D (1-4). The structures were elucidated using NMR spectroscopy, and the relative stereochemistries of the pyrans were inferred using NOE and comparison to previously reported compounds. Absolute stereochemistry was determined using quantum chemical calculations of specific rotation and vibrational and electronic circular dichroism spectra, after an extensive conformational search and including solute-solvent polarization effects, and comparing with the corresponding experimental data for the monomeric congeners. Interestingly, the dimeric hypogeamicin A (1) was found to be cytotoxic to the colon cancer derived cell line TCT-1 at low micromolar ranges, but not bacteria, whereas the monomeric precursors possessed antibiotic activity but no significant TCT-1 cytotoxicity.

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Chemical thiolysis of hypogeamycin B (2) generatinghypogeamycin A (1).
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fig3: Chemical thiolysis of hypogeamycin B (2) generatinghypogeamycin A (1).

Mentions: Given that the regiochemisty ofthe epoxide opening was previouslyestablished by Tatsuta et al.14 in theBE-52440 series by chemical synthesis and X-ray structure analysis,we propose that the conversion of hypogeamicin B (2)to A (1) likely occurs by ring opening of the epoxideby a sulfur nucleophile (formally H2S) to the less stericallycongested epoxide position C-4a followed by antiperiplanar additionof this intermediate species again to the C-4a epoxide of hypogeamicinB (2) to generate the dimeric natural product (Figure 3). To test this hypothesis, we incubated hypogeamicinB (2) with one molar equivalent of sodium sulfide indioxane in accordance with literature precedent in the BE-52440 series.Notably, the regiochemisty of the epoxide opening was establishedin the BE-52440 series by chemical synthesis and X-ray structure analysis.14 We observed conversion of hypogeamicin B (2) to a new dimeric species, compound 1 (m/z = 785.2605), and subsequent to isolationby C18-HPLC, determined it to be spectroscopically identicalto hypogeamicin A (1) by 1H and 13C NMR analysis (Table S5). On the basisof the likely conservation of epoxide ring opening stereo- and regiochemistryand our stereochemical assignment of hypogeamicin B (2), we propose that hypogeamycin A (1) as shown in Figure 1 possessed the (1R,3R,4aR,10aS,10R,3′R,4a′R,10a′S)-configuration. Notably, this is the same configuration as observedin the BE-52440 series.


Structure and Stereochemical Determination of Hypogeamicins from a Cave-Derived Actinomycete.

Derewacz DK, McNees CR, Scalmani G, Covington CL, Shanmugam G, Marnett LJ, Polavarapu PL, Bachmann BO - J. Nat. Prod. (2014)

Chemical thiolysis of hypogeamycin B (2) generatinghypogeamycin A (1).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4334282&req=5

fig3: Chemical thiolysis of hypogeamycin B (2) generatinghypogeamycin A (1).
Mentions: Given that the regiochemisty ofthe epoxide opening was previouslyestablished by Tatsuta et al.14 in theBE-52440 series by chemical synthesis and X-ray structure analysis,we propose that the conversion of hypogeamicin B (2)to A (1) likely occurs by ring opening of the epoxideby a sulfur nucleophile (formally H2S) to the less stericallycongested epoxide position C-4a followed by antiperiplanar additionof this intermediate species again to the C-4a epoxide of hypogeamicinB (2) to generate the dimeric natural product (Figure 3). To test this hypothesis, we incubated hypogeamicinB (2) with one molar equivalent of sodium sulfide indioxane in accordance with literature precedent in the BE-52440 series.Notably, the regiochemisty of the epoxide opening was establishedin the BE-52440 series by chemical synthesis and X-ray structure analysis.14 We observed conversion of hypogeamicin B (2) to a new dimeric species, compound 1 (m/z = 785.2605), and subsequent to isolationby C18-HPLC, determined it to be spectroscopically identicalto hypogeamicin A (1) by 1H and 13C NMR analysis (Table S5). On the basisof the likely conservation of epoxide ring opening stereo- and regiochemistryand our stereochemical assignment of hypogeamicin B (2), we propose that hypogeamycin A (1) as shown in Figure 1 possessed the (1R,3R,4aR,10aS,10R,3′R,4a′R,10a′S)-configuration. Notably, this is the same configuration as observedin the BE-52440 series.

Bottom Line: The structures were elucidated using NMR spectroscopy, and the relative stereochemistries of the pyrans were inferred using NOE and comparison to previously reported compounds.Absolute stereochemistry was determined using quantum chemical calculations of specific rotation and vibrational and electronic circular dichroism spectra, after an extensive conformational search and including solute-solvent polarization effects, and comparing with the corresponding experimental data for the monomeric congeners.Interestingly, the dimeric hypogeamicin A (1) was found to be cytotoxic to the colon cancer derived cell line TCT-1 at low micromolar ranges, but not bacteria, whereas the monomeric precursors possessed antibiotic activity but no significant TCT-1 cytotoxicity.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States.

ABSTRACT
Culture extracts from the cave-derived actinomycete Nonomuraea specus were investigated, resulting in the discovery of a new S-bridged pyronaphthoquinone dimer and its monomeric progenitors designated hypogeamicins A-D (1-4). The structures were elucidated using NMR spectroscopy, and the relative stereochemistries of the pyrans were inferred using NOE and comparison to previously reported compounds. Absolute stereochemistry was determined using quantum chemical calculations of specific rotation and vibrational and electronic circular dichroism spectra, after an extensive conformational search and including solute-solvent polarization effects, and comparing with the corresponding experimental data for the monomeric congeners. Interestingly, the dimeric hypogeamicin A (1) was found to be cytotoxic to the colon cancer derived cell line TCT-1 at low micromolar ranges, but not bacteria, whereas the monomeric precursors possessed antibiotic activity but no significant TCT-1 cytotoxicity.

Show MeSH
Related in: MedlinePlus