CC BY
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Vestnik FEB RAS. 2018. № 6 Supplement
UDC 547.995:593.6+547.996:593.4+57.012.7 DOI: 10.25808/08697698.2018.202.6S.041 E.V. LESHCHENKO, SH.SH. AFIYATULLOV, D.V. BERDYSHEV
Seagrass-derived fungi
as a source of bioactive compounds
Five new eudesmane-type sesquiterpenes — thomimarines A-E (1-5) and 12 new polyketides with "decalin" moiety — zosteropenillines A-L (6-17) were isolated from the ethylacetate extract of the fungi Penicillium thomii associated with the seagrass Zostera marina. Their structures were established based on spectroscopic methods. The absolute configurations of 1—5 and 7-10 were determined by time-dependent density functional theory (TD-DFT) calculations of ECD spectra. The absolute configuration of zosteropenilline A (6) was determined by a combination of the modified Mosher's method, X-ray analysis, and NOESY data. The effect ofselected compounds on the viability of human drug-resistant prostate cancer cells PC3 as well as on autophagy in these cancer cells and inhibitory effects of selected compounds on NO production in LPS-inducedRAW 264.7 murine macrophages were evaluated.
Key words: Penicillium thomii, Zostera marina, NMR, X-ray, ECD spectra,TD-DFT, Mosher's method, autophagy, NO, sesquiterpenes, polyketides.
Marine-derived fungi are a prolific source of new secondary metabolites many of
which are biologically active [4-6].As part of our ongoing search for structurally novel and bioactive metabolites we have isolated 17 new compounds from two fungi Penicillium thomii, associated with seagrass Zostera marina (Troitsa bay, Sea of Japan), including five new eudesmanetype sesquiterpenes - thomimarines A-E (1-5) [1, 2] (Figure 1) from the P. thomii KMM 4667 and 12 new polyketides with "decalin" moiety - zosteropenillines A-L (6-17) (Figure 2) from the P thomii KMM 4674 [3] (Figure 1). Their structures were established based on spectroscopic methods. The absolute configurations of thomimarines A-E (1-5) and zosteropenillines B-D (79) were determined by time-dependent density functional theory (TD-DFT) calculations of ECD spectra. The absolute configuration of zosteropenilline A (6) was determined by a combination of the modified Mosher's method, X-ray analysis and NOESY data (Figure 3).
Figure 1. Chemical structures of thomimarines A-E (1-5)
* LESHCHENKO Elena Vladislavovna - PhD, Researcher (Far Eastern Federal University, Vladivostok, Russia; G.B. Elyakov Pacific Institute of Bioorganic Chemistry, FEB RAS, Vladivostok, Russia), AFIYATULLOV Shamil Sheribzyanovish - PhD, The Head of The Laboratory, BERDYSHEV Dmitrii Vitalievich - Researcher(G.B. Elyakov Pacific Institute of Bioorganic Chemistry, FEB RAS, Vladivostok, Russia). *E-mail: bykadorovachem@gmail.com
OH
HO
14
It was found that compounds 1, 4, 5, 6, 13 and 15 at concentration of 10.0 ^M induced a moderate down-regulation of NO production in macrophages stimulated with LPS. NO level in these cells was decreased by 24.9%±0.9, 20.9%±5.7, 22.5±5.1%, 27.7%±1.8, 20.6%±1.2 and 22.3%±3.8, respectively, compare to control cells pretreated with LPS.
OH
OH H 8
H 9
H ^ OH OH
10
OH
OH
OH
H -OH OH
13
H
OH
OH
OH
HO
H
14 15
Figure 2. Chemical structures of zosteropenillines A-L (6-17)
16
OH
OH
HO
17
OH
7
6
The most effective substance was compound 2 exhibited the maximal pronounced inhibition of NO formation in LPS-stimulated RAW 264.7 cells by 43.4%±L5. The effect of zosteropenillines 6-8, 12, 13, 15 and 16 on the viability of human drug-resistant prostate cancer cells PC3 as well as on autophagy in these cancer cells was examined. The results suggest that the investigated compounds are able to inhibit autophagy at non-cytotoxic concentrations and may sensibilize human cancer cells to cytotoxic anticancer drugs.
Figure 3. (A) Key HMBC and COSY correlations of 6; (B) AS(SS- SR) values (in ppm) for the (S)- and (R)-MPTA esters of 6; (C) Crystal structure of 6
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