Antroalbocin A, an Antibacterial Sesquiterpenoid from Higher Fungus

Nov 29, 2018 - School of Pharmaceutical Sciences, South-Central University for ... possessing a bridged tricyclic system, was isolated from cultures o...
1 downloads 0 Views 707KB Size
Download PDF
Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Antroalbocin A, an Antibacterial Sesquiterpenoid from Higher Fungus Antrodiella albocinnamomea Wei Li,† Juan He,† Tao Feng,* Hui-Xiang Yang, Hong-Lian Ai, Zheng-Hui Li,* and Ji-Kai Liu* School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, China

Org. Lett. Downloaded from pubs.acs.org by UNIV OF WINNIPEG on 11/29/18. For personal use only.

S Supporting Information *

ABSTRACT: Antroalbocin A (1), a sesquiterpenoid possessing a bridged tricyclic system, was isolated from cultures of the higher fungus Antrodiella albocinnamomea (Basidiomycota). The structure with the absolute configuration was determined by extensive spectroscopic methods and single-crystal X-ray diffraction. A plausible biosynthetic pathway for 1 was proposed. Compound 1 was found to inhibit Staphylococcus aureus with an MIC value of 169 μM.

A

mong the secondary metabolites derived from higher fungi (mushroom), sesquiterpenoids are undoubtedly the most diverse type of compound both in terms of their overall number and the range of structural scaffolds.1 The biosynthesis of most sesquiterpenoids, derived from higher fungi, subdivision Basidiomycotina, are supposed to start from humulene with three main pathways, which produces diverse backbones including protoilludane, illudane, tremulane, aromadendrane, drimane, hirsutane, sterpurane, lactarane, marasmane, etc.2 The rich structural variation of sesquiterpenes of higher fungi led to diverse bioactivities as well. For instance, irofulven3 is a semisynthetic derivative of illudin S, a toxic sesquiterpene isolated from the mushroom Omphalotus illudens.4 It has been extensively investigated in numerous clinical trials and displayed significant activity against ovarian, prostate, and gastrointestinal cancers including hepatocellular tumors.5−8 Inspired by the diversity of structure and biological activity, our group focused on sesquiterpene metabolites from higher fungi and also reported a number of sesquiterpenoids. Some of them represented divergent types of new carbon skeletons, such as trefolane A, a sesquiterpenoid possessing a novel 5/6/4 system from cultures of the mushroom Tremella foliacea,9 and conosilane A, a sesquiterpene with an unprecedented carbon skeleton from cultures of the mushroom Conocybe siliginea.10 Antrodiella albocinnamomea, a white-rot fungus belonging to the Basidiomycota, is widely distributed in northeast China.11 In our previous chemical investigations on the cultures of A. albocinnamomea a few sesquiterpenes and steroids were reported. 12−15 Some of them were found to exhibit cytotoxicities and protein tyrosine phosphatase inhibitions.12−15 Antroalbol H, a sesquiterpenoid from A. albocinnamomea, showed promise for the treatment or prevention of diabetes.16 In the current study, a minor modified fermentation of A. albocinnamomea afforded a novel sesquiterpenoid, namely antroalbocin A (1) (Figure 1). The structure was elucidated by extensive spectroscopic methods and confirmed by singlecrystal X-ray diffraction. Compound 1 had a totally new carbon skeleton which fused in a bridged tricyclic system. Its plausible © XXXX American Chemical Society

Figure 1. Structure of antroalbocin A (1).

biosynthetic pathway was proposed. In addition, the bioassay indicated that compound 1 showed certain inhibitory activity against Staphylococcus aureus. Herein, we describe the isolation, structural elucidation, biogenetic pathway, and biological evaluation of 1. Antroalbocin A (1) was isolated as colorless crystals. Its molecular formula C15H24O2 was determined on the basis of the positive high-resolution ESI mass spectrum at m/z 237.18498 [M + H]+ (calcd for C15H25O2 237.18491), corresponding to four degrees of unsaturation. The IR spectrum showed absorption bands for hydroxy (3390 cm−1) and olefinic (1653 cm−1) groups. With the aid of DEPT and HSQC spectra, 15 carbons as displayed by the 13C NMR spectrum could be classified into three sp3 quaternary carbons, three CH (two oxygenated at δC 77.2 and 75.7), four CH2, three CH 3 , and two olefinic carbons (Table 1). In consideration of one double bond and four degrees of unsaturation, these data suggested that compound 1 might be a sesquiterpene with a tricyclic ring system. Three sp3 quaternary carbons at δC 40.7, 50.5, and 65.2 suggested that compound 1 might possess a different carbon skeleton with respect to sesquiterpenes found from the same resource.12−14 According to the 1H−1H COSY spectrum, two spin systems were established as −CH2(2)−CH(3)−CHOH(4) and −CH2(6)−CH2(7)−CHOH(8)− as shown in Figure 2. In the HMBC spectrum, the key correlations from H-3 and H-10 Received: November 9, 2018

A

DOI: 10.1021/acs.orglett.8b03595 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. 1H (600 MHz) and 13C (150 MHz) NMR Data for Antroalbocin A (1) in Methanol-d4a δH

no. 1 2α 2β 3 4 5 6α 6β 7α 7β 8 9 10α 10β 11 12 13 14 15

1.24, 1.49, 2.80, 3.84,

m dd (13.4, 12.5) dt (12.5, 7.3) d (7.3)

1.54, 1.20, 1.36, 1.83, 3.28,

m m m m dd (10.8, 5.1)

1.78, d (13.2) 1.62, d (13.2) 1.03, 1.05, 1.02, 4.75, 4.72,

s s s s s

Scheme 1. Proposed Biosynthetic Pathway for 1

δC 40.7 (s) 41.6 (t) 48.1 77.2 50.5 40.4

(d) (d) (s) (t)

30.3 (t) 75.8 (d) 65.2 (s) 43.4 (t) 163.7 29.2 31.7 18.8 101.4

(s) (q) (q) (q) (t)

information, with the aid of the spin system as given by the H−1H COSY spectrum, revealed a seven-membered ring as constructed by C-3, C-4, C-5, C-6, C-7, C-8, and C-9 (Figure 2). Thus far, only two olefinic carbons at δC 101.4 (t, C-15) and 163.7 (s, C-11) were not assigned. They constructed a terminal double bond that was easily confirmed by their 1H and 13C NMR data. In the HMBC spectrum, the weak correlations from H-3, H-8, and H-10 to C-11 suggested the connection from C-9 and C-11, which allowed C-9 to be an sp3 quaternary carbon at δC 65.2 (s). The connection between C-5 and C-11 has been proved by the HMBC correlation from H14 to C-11 as given above. Therefore, a bridged carbon bond of C-5−C-11−C-9 was established, which cut the sevenmembered ring into a five-membered ring B and a sixmembered ring C (Figure 2). Detailed analysis of other 2D NMR data established the final planar structure of 2, which affords a novel carbon skeleton as depicted. Because three nonprotonated carbons C-5, C-9, and C-11 were inextricably linked, the HMBC correlations, as well as other 2D NMR data, could not give solid evidence for the novel backbone. A gross structure of 1 was, temporarily, established as given in Figure 2. As a bridged tricyclic ring system as elucidated, the framework of 1 was rigid so that the relative configuration could be readily characterized by the ROESY experiment (Figure 2). In that configuration, the ROESY correlations of H-7α with H-3 and H-4 suggested that H-3 and H-4 were on the same side and assigned as α orientation, which allowed OH-4 to be β oriented. On the basis of the above analysis, the ROESY correlations of H-4/H-6α and H-6β/H-8 indicated that the OH-8 was α oriented. These ROESY data, on the other hand, helped with the NMR data assignments (Figure 2 and Table 1). Therefore, compound 1 was elucidated as a novel sesquiterpenoid with a bridged tricyclic ring system. Fortunately, a single crystal of 1 was obtained from a mixture of petroleum ether/acetone (9:1), and an X-ray diffraction not only confirmed the structure as elucidated above but also determined the absolute configuration (Figure 3, CCDC 1876453, Flack parameter = −0.11(6)). Antroalbocin A (1) displayed a completely different carbon skeleton. Structurally, the carbon skeleton of 1 was a nonisoprenyl sesquiterpenoid that should be converted via 1

a Data were assigned by HSQC, HMBC, 1H−1H COSY, and ROESY spectra.

Figure 2. Key 2D NMR correlations of antroalbocin A (1).

Figure 3. ORTEP diagram of antroalbocin A (1).

to C-9 suggested the connections between C-3 and C9 and between C-10 and C-9, while the HMBC correlations from H12 and H-13 to C-1, C-2, and C-10 revealed a gem-dimethyl moiety. These data further revealed a five-membered carbon ring A as established by C-1, C-2, C-3, C-10, and C-9 (Figure 2). In the HMBC spectrum, a singlet for the Me-14 at δH 1.02 (3H, s, H-14) showed correlations to C-4, C-6, C-11, and the sp3 quaternary carbon C-5. This was very important for the establishment of three C−C bonds of C-4, C-6, C-11 with C-5, respectively. In addition, the key HMBC correlation from H-8 to C-9 suggested the connection between C-8 and C-9. This B

DOI: 10.1021/acs.orglett.8b03595 Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

■

alkyl migration. As shown in Scheme 1, a cyclization of humulene built a backbone of triquinane-type sesquiterpene, which was isolated from the same fungus13 and proposed as the key precursor of 1. A tertiary carbocation formed at C-9 might lead to an alkyl migration and generate a new C−C bond between C-8 and C-9. After deprotonation and oxidation, an unprecedented carbon skeleton was built. Antroalbocin A (1) was evaluated for its bioactivities on NO production inhibition, cytotoxicity, and antibacterial activity. As a result, compound 1 showed certain antibacterial activity to Staphylococcus aureus with an MIC of 169 μM. In conclusion, antroalbocin A, isolated from cultures of the basidiomycete A. albocinnamomea, has a new carbon skeleton furnishing a bridged tricyclic ring system. Its novel carbon skeleton and antibacterial activity make it a good scaffold for further chemistry studies and pharmacological investigations.

■

REFERENCES

(1) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2016, 79, 629−661. (2) Fraga, B. M. Nat. Prod. Rep. 2013, 30, 1226−1264. (3) McMorris, T. C.; Kelner, M. J.; Wang, W.; Yu, J.; Estes, L. A.; Taetle, R. J. Nat. Prod. 1996, 59, 896−899. (4) McMorris, T. C.; Anchel, M. J. Am. Chem. Soc. 1963, 85, 831− 832. (5) Staake, M. D.; Kashinatham, A.; McMorris, T. C.; Estes, L. A.; Kelner, M. J. Bioorg. Med. Chem. Lett. 2016, 26, 1836−1838. (6) Alexandre, J.; Raymond, E.; Kaci, M. O.; Brain, E. C.; Lokiec, F.; Kahatt, C.; Faivre, S.; Yovine, A.; Goldwasser, F.; Smith, S. L.; MacDonald, J. R.; Misset, J.-L.; Cvitkovic, E. Clin. Cancer Res. 2004, 10, 3377−3385. (7) Raymond, E.; Kahatt, C.; Rigolet, M. H.; Sutherland, W.; Lokiec, F.; Alexandre, J.; Tombal, B.; Elman, M.; Lee, M. S.; MacDonald, J. R.; Cullen, M.; Misset, J.-L.; Cvitkovic, E. Clin. Cancer Res. 2004, 10, 7566−7574. (8) Senzer, N.; Arsenau, J.; Richards, D.; Berman, B.; MacDonald, J. R.; Smith, S. Am. J. Clin. Oncol. 2005, 28, 36−42. (9) Ding, J.-H.; Feng, T.; Li, Z.-H.; Yang, X.-Y.; Guo, H.; Yin, X.; Wang, G.-Q.; Liu, J.-K. Org. Lett. 2012, 14, 4976−4978. (10) Yang, X.-Y.; Feng, T.; Li, Z.-H.; Sheng, Y.; Yin, X.; Leng, Y.; Liu, J.-K. Org. Lett. 2012, 14, 5382−5384. (11) Yuan, H.-S.; Dai, Y.-C.; Steffen, K. Mycology 2012, 3, 100−108. (12) Chen, Z.-M.; Fan, Q.-Y.; Yin, X.; Yang, X.-Y.; Li, Z.-H.; Feng, T.; Liu, J.-K. Nat. Prod. Bioprospect. 2014, 4, 207−211. (13) Chen, Z.-M.; Chen, H.-P.; Wang, F.; Li, Z.-H.; Feng, T.; Liu, J.K. Fitoterapia 2015, 102, 61−66. (14) Chen, Z.-M.; Wang, S.-L. Nat. Prod. Res. 2015, 29, 1985−1989. (15) Chen, Z.-M.; Yang, X.-Y.; Fan, Q.-Y.; Li, Z.-H.; Wei, K.; Chen, H.-P.; Feng, T.; Liu, J.-K. Steroids 2014, 87, 21−25. (16) Liu, J.-K.; Xiong, W.-Y.; Wang, F.; Yang, X.-Y. Antroalbol H, Pharmaceutical Composition, Its Preparation Method and Application for Treating or Preventing Diabetes. Chinese patent CN105566088A, May 11, 2016.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03595. General experimental procedures, fungal materials, extraction and isolation, bioactivity assay, and spectroscopic data (PDF) Accession Codes

CCDC 1876453 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

■

Letter

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Tao Feng: 0000-0002-1977-9857 Zheng-Hui Li: 0000-0003-1284-0288 Ji-Kai Liu: 0000-0001-6279-7893 Author Contributions †

W.L. and J.H. contributed equally to this work.

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (81872762, 31870513, 81561148013, 21502239), the Key Projects of Technological Innovation of Hubei Province (2016ACA138), and the Fundamental Research Funds for the Central University, South-Central University for Nationalities (CZP18005, CZT18013, CZT18014). The authors thank Analytical & Measuring Centre, South-Central University for Nationalities, for the spectral measurements. C

DOI: 10.1021/acs.orglett.8b03595 Org. Lett. XXXX, XXX, XXX−XXX