We report the isolation and characterization of three new nybomycins (nybomycins B-D, 1-3) and six known compounds (nybomycin, 4; deoxynyboquinone, 5; α-rubromycin, 6; β-rubromycin, 7; γ-rubromycin, 8; and [2α(1E,3E),4β]-2-(1,3-pentadienyl)-4-piperidinol, 9) from the Rock Creek (McCreary County, KY) underground coal mine acid reclamation site isolate Streptomyces sp. AD-3-6. Nybomycin D (3) and deoxynyboquinone (5) displayed moderate (3) to potent (5) cancer cell line cytotoxicity and displayed weak to moderate anti-Gram-(+) bacterial activity, whereas rubromycins 6-8 displayed little to no cancer cell line cytotoxicity but moderate to potent anti-Gram-(+) bacterial and antifungal activity. Assessment of the impact of 3 or 5 cancer cell line treatment on 4E-BP1 phosphorylation, a predictive marker of ROS-mediated control of cap-dependent translation, also revealed deoxynyboquinone (5)-mediated downstream inhibition of 4E-BP1p. Evaluation of 1-9 in a recently established axolotl embryo tail regeneration assay also highlighted the prototypical telomerase inhibitor γ-rubromycin (8) as a new inhibitor of tail regeneration. Cumulatively, this work highlights an alternative nybomycin production strain, a small set of new nybomycin metabolites, and previously unknown functions of rubromycins (antifungal activity and inhibition of tail regeneration) and also provides a basis for revision of the previously proposed nybomycin biosynthetic pathway.
|Number of pages||8|
|Journal||Journal of Natural Products|
|State||Published - Dec 27 2019|
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health Grant Nos. R24 OD21479 (S.R.V., J.S.T.), R01 CA203257 (Q.B.S., J.S.T.), R01 CA175105 (Q.B.S.), and R01 GM115261 (J.S.T.), the University of Kentucky College of Pharmacy, the University of Kentucky Markey Cancer Center, and the National Center for Advancing Translational Sciences (UL1TR000117 and UL1TR001998). We thank the College of Pharmacy NMR Center (University of Kentucky) for NMR support.
© 2019 American Chemical Society and American Society of Pharmacognosy.
ASJC Scopus subject areas
- Analytical Chemistry
- Molecular Medicine
- Pharmaceutical Science
- Drug Discovery
- Complementary and alternative medicine
- Organic Chemistry