This is a review of bioactive secondary metabolites isolated from conifer-associated endophytic fungi from 1990-2014. This includes compounds with antimicrobial, anti-inflammatory, anti-proliferative and cytotoxic activity towards human cancer cell lines, and activity against either plant pathogens or plant insect pests. Compounds that were originally reported without associated activity were included if other studies ascribed activity to these compounds. Compounds were not included if they were exclusively phytotoxic or if they were isolated from active extracts but were not determined to be the active component of that extract.
StierleA, StrobelG, StierleD. (1993) Taxol and taxane production by Taxomyces andreanae an endophytic fungus of Pacific yew. Science, 260, 214–216.
2.
KimuraM, AnzaiH, YamaguchiI. (2001) Microbial toxins in plant-pathogen interactions: Biosynthesis, resistance mechanisms, and significance. Journal of General and Applied Microbiology, 47, 149–160.
HirschGU, BraunU. (1992) Communities of parasitic microfungi. In Handbook of Vegetation Science: Fungi in Vegetation Science. Vol. 19. WinterhoffW. (Ed). Kluwer Academic, Dordrecht, 225–250.
5.
GroveJF, MacMillanJ, MulhollandTPC, RogersMAT. (1952) 762. Griseofulvin. Part IV. Structure. Journal of the Chemical Society (Resumed), 3977–3987.
6.
SchatzA, BugieE, WaksmanS. (1944) Streptomycin: a substance exhibiting antibiotic activity against Gram-positive and Gram-negative bacteria. Proceedings of the Society for Experimental and Biological Medicine, 55, 66–69.
7.
MaieseWM, LechevalierMP, LechevalierHA, KorshallaJ, KuckN, FantiniA, WildeyMJ, ThomasJ, GreensteinM. (1989) Calicheamicins, a novel family of antitumor antibiotics: taxonomy, fermentation and biological properties. Journal of Antibiotics, 42, 558–563.
8.
KharwarRN, MishraA, GondSK, StierleA, StierleD. (2011) Anticancer compounds derived from fungal endophytes: their importance and future challenges. Natural Product Reports, 28, 1208–1228.
9.
SaikkonenK, FaethSH, HelanderM, SullivanTJ. (1998) Fungal endophytes: A continuum of interactions with host plants. Annual Review of Ecology and Systematics, 29, 319–343.
10.
KingstonDGI. (2005) Taxol and its analogues. In Anticancer Agents from Natural Products, CraggGM, KingstonDGI, NewmanDJ. (Eds). Taylor and Francis Group, LLC, CRC Press, Boca Raton, Florida, 89–120.
11.
CraggGM, SnaderKM. (2005) Plants as a source of anti-cancer agents. Journal of Ethnopharmacology, 100, 72–79
12.
WaniMC, TaylorHL, WallME, CoggonP, McPhailAT. (1971) Plant antitumor agents VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. Journal of the American Chemical Society, 93, 2325–2327.
13.
WallME, WaniMC. (1995) Camptothecin and taxol: discovery to clinic—thirteenth Bruce F. Cain Memorial Award Lecture. Cancer Research, 55, 753–760.
14.
SchiffPB, FantJ, HorwitzS. (1979) Promotion of microtubule assembly in vitro by taxol. Nature, 277, 665–667.
15.
StierleA, StierleD, StrobelG, BignamiG, GrothausP. (1995) Bioactive metabolites of the endophytic fungi of Pacific yew, Taxus brevifolia: paclitaxel, taxanes, and other bioactive compounds. In Taxane Anticancer Agents: Basic Science and Current Status. GeorgGI, ChenTT, OjimaI, VyasDM. (Eds). ACS Symposium Series583, Washington, DC, 81–97.
16.
StierleA, StierleD, StrobelG, GrothausP, BignamiG. (1995) The search for a taxol-producing microorganism among the endophytic fungi of the Pacific yew, Taxus brevifolia. Journal of Natural Products, 58, 1315–1324.
17.
StrobelGA, StierleA, StierleD. (1993) Taxomyces andreanae, a proposed new taxon for a bulbilliferous hyphomycete associated with Pacific yew. Mycotaxon, 47, 71–78.
18.
StierleAA, StierleDB. (2000) Bioactive compounds from four endophytic Penicillium sp. isolated from the Northwest Pacific yew tree. In Bioactive Natural Products, Volume 24, Atta-Ur-Rahman (Ed), Elsevier Science Publishers, Amsterdam, 933–978.
19.
StrobelG, YangX, SearsJ, KramerR, SidhuRS, HessWM. (1996) Taxol from Pestalotiopsis microspora, an endophytic fungus of Taxus wallachiana. Microbiology, 142, 435–440.
20.
LiJY, StrobelG, SidhuR, HessWM, FordEJ. (1996) Endophytic taxol-producing fungi from bald cypress, Taxodium distichum. Microbiology, 142, 2223–2226.
21.
GangadeviV, MuruganM, MuthumaryJ. (2008) Taxol determination from Pestalotiopsis pauciseta, a fungal endophyte of a medicinal plant. Chinese Journal of Biotechnology, 24, 1433–1438.
22.
GangadeviV, MuthumaryJ. (2009) Taxol production by Pestalotiopsis terminaliae, an endophytic fungus of Terminalia arjuna (arjun tree). Biotechnology and Applied Biochemistry, 158, 675–684.
23.
GangadeviV, MuthumaryJ. (2009) A novel endophytic taxol-producing fungus Chaetomella raphigera isolated from a medicinal plant, Terminalia arjuna. Biotechnology and Applied Biochemistry, 158, 675–684.
24.
GangadeviV, MuthumaryJ. (2008) Taxol, an anticancer drug produced by an endophytic fungus Bartalinia robillardoides Tassi, isolated from a medicinal plant, Aegle marmelos Correa ex Roxb. World Journal of Microbiology Biotechnology, 24, 717–724.
25.
ZhaoJ, ZhouL, WangJ, ShanT, ZhongL, LiuX, GaoX. (2012) Endophytic fungi for producing bioactive compounds originally from their host plants. In Current Research, Technology and Education Topics in Applied Microbiology and Microbial Biotechnology, Volume 1, Mendez-VilasA. (Ed) Formatex Research Center, Badajoz, Spain, 567–576.
26.
ChandraS. (2012) Endophytic fungi: novel sources of anticancer lead molecules. Applied Microbiology and Biotechnology, 95, 47–59.
27.
LeiterJ, DowningV, HartwellJL, ShearJ. (1950) Damage induced in sarcoma 37 with podophyllin, podophyllotoxin alpha-peltatin, beta-peltatin, and quercetin. Journal of the National Cancer Institute, 10, 1273–1293.
28.
StahelinandHF, von WartburgA. (1991) The chemical and biological route from podophyllotoxin glucoside to etoposide: ninth Cain Memorial Award Lecture. Cancer Research, 51, 5–15.
29.
BaldwinEL, OsheroffN. (2005) Etoposide, topoisomerase II and cancer. Current Medicinal Chemistry, Anticancer Agents, 5, 363–372.
30.
PuriSC, NazirA, ChawlaR, AroraR, Riyaz-ul-HasanS, AmnaT, AhmedB, VermaV, SinghS, SagarR, SharmaA, KumarR, SharmaRK, QaziGN. (2006) The endophytic fungus Trametes hirsuta as a novel alternative source of podophyllotoxin and related aryl tetralin lignans. Journal of Biotechnology, 122, 494–510.
31.
EybergerAL, DondapatiR, PorterJR. (2006) Endophyte fungal isolates from Podophyllum peltatum produce podophyllotoxin. Journal of Natural Products, 69, 1121–1124.
32.
LuL, HeJ, YuX, LiG, ZhangX. (2006) Studies on isolation and identification of endophytic fungi strain SC13 from pharmaceutical plant Sabina vulgaris Ant. and metabolites. Acta Botany Boreal-Occident Sinica, 15, 85–89
33.
KourA, ShawlAS, RehmanS, SultanP, QaziPH, SudenP, KhajuriaRK, VermaV. (2008) Isolation and identification of an endophytic strain of Fusarium oxysporum producing podophyllotoxin from Juniperus recurva. World Journal of Microbiology and Biotechnology, 24, 1115–1121.
34.
KusariS, LamshöftM, SpitellerM. (2009) Aspergillus fumigatus Fresenius, an endophytic fungus from Juniperus communis L. Horstmann as a novel source of the anticancer pro-drug deoxypodophyllotoxin. Journal of Applied Microbiology, 107, 1019–1030.
35.
OxfordAE, RaistrickH, SimonartP. (1939) XXIX. Studies in the biochemistry of microorganisms. Griseofulvin, C17H17O6Cl, a metabolic product of P'enicillium griseo-fulvum Dierckx. Biochemistry Journal, 33, 240–248.
36.
BrianPW, CurtisPJ, HemmingHG. (1946) A substance causing abnormal development of fungal hyphae produced by P'enicillium janczewskii Zal. I. Biological assay, production and isolation of “curling factor.”Transactions of the British Mycological Society, 29, 173–187.
37.
GroveJF, MacmillanJ, MulhollandTPC, ZealleyJ. (1952) Griseofulvin. Part III. The structures of the oxidation products C9H9O5CI and C14H1507C1. Journal of the Chemical Society, 3967–3977.
38.
GroveJF, MacMillanJ, MulhollandTPC, Thorold RogersMA. (1952) Griseofulvin. Part IV. Structure. Journal of the Chemical Society, 3977–3987.
39.
ParkJH, ChoiGJ, LeeSW, LeeHB, KimKM, JungHS, JangKS, ChoKY, KimJC. (2005) Griseofulvin from Xylaria sp. strain F0010, an endophytic fungus of Abies holophylla and its antifungal activity against plant pathogenic fungi. Journal of Microbiology and Biotechnology, 15, 112–117.
40.
RichardsonSN, WalkerAK, NsiamaTK, McFarlaneJ, SumarahMW, IbrahimA, MillerJD. (2014) Griseofulvin-producing Xylaria endophytes of Pinus strobus and Vaccinium angustifolium: evidence for a conifer-understory species endophyte ecology. Fungal Ecology, 11, 107–113.
41.
ZabalaAO, ChooiYH, ChoiMS, LinHC, TangY. (2014) Fungal polyketide synthase product chain-length control by partnering thiohydrolase. ACS Chemical Biology, 9, 1576–1586
42.
WangJ, HuangY, FangM, ZhangY, ZhengZ, ZhaoY, SuW. (2002) Brefeldin A, a cytotoxin produced by Paecilomyces sp. and Aspergillus clavatus isolated from Taxus mairei and Torreya grandis. FEMS Immunology and Medical Microbiology, 34, 51–57.
43.
HardE, LoefflerW, SiggHP, StaehelinS, TammC. (1963) Uber die isolierung der stoffwech selprodukte aus Penicillium brefel- dianum Dodge. Helvetica Chimica Acta, 46, 1235–1244.
44.
SingletonVL, BohonosN, UllstrupAJ. (1958) Decumbin, a new compound from a species of Penicillium. Nature, 181, 1072–1073.
45.
BetinaV, BarathZ, NemecP, DobiasJ. (1962) Cyanein, a new antibiotic from Penicillium cyaneum. Folia Biologica, 7, 353–357.
46.
SuzukiY, TanakaH, AokiH, TamuraT. (1970) Ascotoxin (decumbin), a metabolite of Ascochyta imperfecta Peck. Agricultural and Biological Chemistry, 34, 395–413.
47.
CoombeRG, FossPS, JacobsJJ, WatsonTR. (1969) The biosynthesis of brefeldin A. Australian Journal of Chemistry, 22, 1943–50.
48.
Bu'LockJD, ClayPT (1969) Fatty acid cyclization in the biosynthesis of brefeldin-A: a new route to some fungal metabolites. Journal of the Chemical Society. D: Chemical Communications, 237–238.
49.
StierleAA, StierleDB, BugniT. (1999) Sequoiatones A and B: novel antitumor metabolites isolated from a redwood endophyte. Journal of Organic Chemistry, 64, 5479–5484
50.
StierleA, StierleDB, BugniT. (2001) Sequoiatones C-f, constituents of the redwood endophyte Aspergillus parasiticus. Journal of Natural Products, 64, 1350–1353.
51.
StierleDB, StierleAA, BugniT. (2003) Sequoiamonascins A-D: novel anticancer metabolites isolated from a redwood endophyte. Journal of Organic Chemistry, 68, 4966–49699.
52.
LeeJC, StrobelGA, LobkovskyE, ClardyJ. (1996) Torreyanic acid: a selectively cytotoxic quinone dimer from the endophytic fungus Pestalotiopsis microspore. Journal of Organic Chemistry, 61, 3232–3233.
53.
DaiJ, KrohnK, FlörkeU, DraegerS, SchulzB, Kiss-SzikszaiA. (2006) Metabolites from the endophytic fungus Nodulisporium sp. from Juniperus cedrus. European Journal of Organic Chemistry, 3498–3506.
54.
DaiJ, KrohnK, DraegerS, SchulzB. (2009) New naphthalenechroman coupling products from the endophytic fungus, Nodulisporium sp. from Erica arborea. European Journal of Organic Chemistry, 1564–1569.
55.
GroveJFJ. (1985) Metabolic products of Phomopsis oblonga. Part 2. Phomopsolides A and B, tiglic esters of two 6-substituted 5,6-dihydo-5-hydroxypyran-2-ones. Journal of the Chemical Society, Perkin Transactions1, 865–869.
56.
StierleDB, StierleAA, GanserB. (1997) New phomopsolides from a Penicillium sp. Journal of Natural Products, 60, 1207–1209.
57.
CalhounLA, FindlayJA, MillerDJ, WhitneyNJ. (1992) Metabolites toxic to spruce budworm from balsam fir needle endophytes. Mycological Research, 96, 281–286.
58.
UenoY, SatoN, ItoT, UenoI, EnomotoM, TsunodaH. (1980) Chronic toxicity and hepatocarcinogenicity of (+) rugulosin, an anthraquinoid mycotoxin from Penicillium species: preliminary surveys in mice. Journal of Toxicological Sciences, 5, 295–302.
59.
SumarahMW, KestingJR, SorensenD, MillerJD. (2011) Antifungal metabolites from fungal endophytes of Pinus strobus. Phytochemistry, 72, 1833–1837.
60.
HatakeyamaT, KosekiT, MurayamaT, ShionoY. (2010) Eremophilane sesquiterpenes from the endophyte Microdiplodia sp. KS 75-land revision of the stereochemistries of phomadecalins C and D. Phytochemistry Letters, 3, 148–151.
61.
HuZY, LiYY, HuangYJ, SuWJ, ShenYM. (2008) Three new sesquiterpenoids from Xylaria sp. NCY2. Helvetica Chimica Acta, 91, 46–52.
62.
XuR, WangMZ, LuCH, ZhengZH, ShenYM. (2009) Tuberculariols A-C, new sesquiterpenes from the mutant strain M-741 of Tubercularia sp. TF 5. Helvetica Chimica Acta, 92, 1514–1519.
63.
PelaezF, CabelloA, PlatasG, DiezMT, Gonzalez del ValA, BasilioA, MartanI, VicenteF, BillsGF, GiacobbeRA, SchwartzRE, OnishiJC, MeinzMS, AbruzzoGK, FlatteryAM, KongL, KurtzMB. (2000) The discovery of enfumafungin, a novel antifungal compound produced by an endophytic Hormonema species biological activity and taxonomy of the producing organisms. Systematic and Applied Microbiology, 23, 333–343.
KimS, ShinDS, LeeT, OhKB. (2004) Periconicins, two new fusicoccane diterpenes produced by an endophytic fungus Periconia sp. with antibacterial activity. Journal of Natural Products, 67, 448–450.
66.
ShinDS, OhMN, YangHC, OhKB. (2005) Biological characterization of periconicins, bioactive secondary metabolites, produced by Periconia sp. OBW-15. Journal of Microbiology and Biotechnology, 15, 216–219.
67.
CalhounLA, FindlayJA, MillerJ, WhitneyNJ. (1992) Metabolites toxic to spruce budworm from balsam fir needle endophytes. Mycological Research, 96, 281–286.
68.
EndoA, HasumiK, SakaiK, KanbeT. (1985) Specific inhibition of glyceraldehyde-3-phosphate dehydrogenase by konigic acid (heptelidic acid). Journal of Antibiotics, 38, 920–925.
69.
YamaguchiY, ManitaD, TakeuchiT, KuramochiK, KuriyamaI, SugawaraF, YoshidaH, MizushinaY. (2010) Novel terpenoids, trichoderonic acids A and B isolated from Trichoderma virens, are selective inhibitors of family X DNA polymerases. Bioscience Biotechnology and Biochemistry, 74, 793–801.
70.
KimJH, ChoongHL. (2009) Heptelidic acid, a sesquiterpene lactone, inhibits etoposide-induced apoptosis in human leukemia U937 Cells. Journal of Microbiology and Biotechnology, 19, 787–791.
71.
TanakY, ShiomiK, KamaeiK, Sugoh-HaginoM, EnomotoY, FangF, YamaguchiY, MasumaR, ZhangCG, ZhangXW, OmuraS. (1998) Antimalarial activity of radicicol, heptelidic acid and other fungal metabolites. Journal of Antibiotics, 51, 153–160.
72.
FindlayJA, LiG, PennerPE. (1995) Novel diterpenoid insect toxins from a conifer endophyte. Journal of Natural Products, 58, 197–200.
73.
FindlayJA, ButheleziS, LavoieR, RodriguezL. (1995) Bioactive isocoumarins and related metabolites from conifer endophytes. Journal of Natural Products, 58, 1759–1766.
74.
MuthW, NashCH. (1975) Biosynthesis of mycophenolic acid: purification and characterization of s-adenosyl-1-methionine: demethylmycophenolic acid o-methyltransferase. Antimicrobial Agents and Chemotherapy, 321–327.
75.
ClutterbuckPW, OxfordAE, RaistrickH, SmithG. (1932) CLXXI. Studies in the biochemistry of microorganisms. XXIV. The metabolic products of the Penicillium brevi-compactum series. Biochemistry Journal, 26, 1442–1458
76.
AndoK, SuzukiS, TamuraG, AumaK. (1968) Antiviral activity of mycophenolic acid. Journal of Antibiotics, 21, 649–652.
77.
GilliverK. (1946) The inhibitory action of antibiotics on plant pathogenic bacteria and fungi. Annals of Botany, 10, 271–282.
78.
WilliamsRH, LivelyDH, DelongDC, ClineJC, SweeneyJ, PooreGA, ParsonSH. (1968) Mycophenolic acid: antiviral and antitumor properties. Journal of Antibiotics, 21, 463–464.
79.
MitsuiA, SuzukiS. (1969) Immunosuppressive effect of mycophenolic acid. Journal of Antibiotics, 22, 358–363.
80.
JohnsonIS. (1972) Pharmaceuticals containing mycophenolic acid for treatment of psoriasis. Chemical Abstracts, 77, 92853.
81.
MimouniD, AnhaltGJ, CumminsDL, KoubaDJ, ThorneJE, NousariHC. (2003) Treatment of Pemphigus vulgaris and Pemphigus foliaceus with mycophenolate mofetil. Archives of Dermatology, 139, 739–742.
82.
DiamondMS, ZachariahM, HarrisE. (2002) Mycophenolic acid inhibits dengue virus infection by preventing replication of viral RNA. Virology, 304, 211–221
83.
BlochP, TammC, BollingerP, PetcherT, WeberHP. (1976) Pseurotin, a new metabolite of Pseudeurotium ovalis Stolk having an unusual hetero-spirocyclic system. Helvetica Chimica Acta, 59, 133–137.
84.
Schmeda-HirschmannG, HormazabalE, RodriguezJA, TheodulozC. (2008) Cycloaspeptide A and pseurotin A from the endophytic fungus Penicillium janczewskii. Zeitschrift für Naturforschung C, 63, 383–388.
85.
IshikawaM, NinomiyaT, AkabanH, KushidaN, TsujiuchiG, OhyamaM, GomiSShitoKMurataT. (2009) Pseurotin A and its analogues as inhibitors of immunoglobuline E production. Bioorganic & Medicinal Chemistry Letters, 19, 1457–1460.
86.
KawashimaK, NakanishiK, NishikawaH. (1964) Structure of tauranin and a note on the “C-16-Acids” obtained from di- and triterpenoids. Chemical and Pharmaceutical Bulletin, 12, 796–803.
87.
WijeratneEMK, ParanagamaPA, MarronMT, GunatilakaMK, ArnoldAE, GunatilakaAAL. (2008) Sesquiterpene quinones and related metabolites from Phyllosticta spinarum, a fungal strain endophytic in Platycladus orientalis, of the Sonoran desert. Journal of Natural Products, 71, 218–222.
88.
AraiT, MikamiY, FushimaK, UtsumiT, YazawaK. (1973) A new antibiotic, leucinostatin, derived from Penicillium lilacinum. Journal of Antibiotics, 26, 157–161.
89.
KawadaM, InoueH, OhbaSI, MasudaT, MomoseI, IkedaD. (2010) Leucinostatin A inhibits prostate cancer growth through reduction of insulinlike growth factor-I expression in prostate stromal cells. International Journal of Cancer, 126, 810–818.
90.
StrobelGA, HessWM. (1997) Glucosylation of the peptide leucinostatin A, produced by an endophytic fungus of European yew, may protect the host from leucinostatin toxicity. Chemistry and. Biology, 4, 529–536.
91.
NobleHM, LangleyD, SidebottomPJ, LaneSJ, FisherPJ. (1991) An echinocandin from an endophytic Cryptosporiopsis sp. and Pezicula sp. in Pinus sylvestris and Fagus sylvatica. Mycological Research, 95, 1439–1440.
92.
ChapmanSW, SullivanDC, ClearyJD. (2008) In search of the Holy Grail of antifungal therapy. Transactions of the American Clinical and Climatological Association, 119, 197–216.
93.
KobayashiR, SamejinaY, NakajimaS, KawaiK, UdagawaS. (1987), Studies on fungal products XI. Isolation and structures of novel cyclic pentapeptides from Aspergillus sp. NE-45. Chemical and Pharmaceutical Bulletin, 35, 1347–1352.
94.
DalsgaardPW, LarsenTO, ChristophersenC. (2005) Bioactive cyclic peptides from the psychrotolerant fungus Penicillium algidum. Journal of Antibiotics, 58, 141–144.
95.
SunHH, BarrowCJ, SedlockDM, GillumAM, CooperR. (1994) Benzomalvins, new substance P inhibitors from a Penicillium sp. Journal of Antibiotics, 47, 515–522.
96.
WongSM, MuszaLL, KyddGC, KullnigR, GillumAM, CooperRJ. (1993) Fiscalins: new substance P inhibitors produced by the fungus Neosartorya fischeri. Taxonomy, fermentation, structures, and biological properties. Journal of Antibiotics, 46, 545–53.
97.
RegoliD, DrapeauG, DionS. (1988) New selective agonists for neurokinin receptors: pharmacological tools for receptor characterization. Trends in Pharmacological Sciences, 9, 290–295.
98.
PernowB. (1983) Substance P. Pharmacology Reviews, 35, 85–141.
99.
NagelDW, PachlerKGR, SteynPS, VleggaarR, WesselsPL (1976) The chemistry and 13C NMR assignments of oxaline, a novel alkaloid from Penicillium oxalicum. Tetrahedron, 32, 2625–2631.
100.
KoizumiY, AraiM, TomodaH, OmuraS. (2004) Oxaline, a fungal alkaloid, arrests the cell cycle in M phase by inhibition of tubulin polymerization. Biochimica et Biophysica Acta, 1693, 47–55
101.
PolonskyJ, MerrienMA, ScottPM. (1977) Roquefortine and isofumigaclavine A, alkaloids from Penicillium roqueforti. Annates de la nutrition et de Valimentation, 31, 963–968.
102.
MantlePG, PereraKP, MaishmanNJ, MundyGR. (1983) Biosynthesis of penitrems and roquefortine by Penicillium crustosum. Applied Environmental Microbiology, 45, 1486–1490.
103.
SteynPS, VleggaarR. (1983) Roquefortine, an intermediate in the biosynthesis of oxaline in cultures of Penicillium oxalicum. Journal of the Chemical Society: Chemical Communications, 560–561.