Abstract
Background: Exploration of antibiotics from microorganisms became widespread in the academia and the industry with the serendipitous discovery of Penicillin from Penicillium notatum by Sir Alexander Fleming. This embarked the golden era of antibiotics which lasted for over 60 years. However, the traditional phenotypic screening was replaced with more rational and smarter methods of exploration of bioactive compounds from fungi and microorganisms. Fungi have been responsible for providing a variety of bioactive compounds with diverse activities which have been developed into blockbuster drugs such as Cyclosporine, Caspofungin, Lovastatin and Fingolimod etc. It has been reported that ca. 40% of the 1453 New Chemical Entities (NCE’s) approved by USFDA are natural products, natural product inspired or mimics many of which have their origins from fungi. Hence fungal compounds are playing a very important role in drug discovery and development in the pharmaceutical industry.
Methods: We undertook structured searches of bibliographic databases of peer-reviewed research literature which pertained to natural products, medicinal chemistry of natural products and drug discovery from fungi. With the strategic improvement in screening and identification methods, fungi are still a potential resource for novel chemistries. Thus the searches also comprised of bioactive agents from fungi isolated or derived from special ecological groups and lineages. To find different molecules derived or isolated from fungi under clinical studies, clinical trial data from the NIH as well as from pharmaceutical companies were also explored. This comprised of data wherein the pharmaceutical industries have acquired or licensed a fungal bioactive compound for clinical study or a trial.
Results: Natural product chemistry and medicinal chemistry continue to play an important role in converting a bioactive compound into therapeutic moieties or pharmacophores for new drug development.
Conclusion: Thus one can say fungal bioactive compounds are alive and well for development into new drugs as novel ecological groups of fungi as well as novel chemistries are being uncovered. This review further emphasizes the collaboration of fungal biologists with chemists, pharmacologists and biochemists towards the development of newer drugs for taking them into the drug development pipeline.
Keywords: Fungi, secondary metabolites, drug discovery, natural products, endophytes, clinical trials, medicinal chemistry, structure activity relationships.
[1]
Wasson, R.G. Soma-divine mushroom of immortality; Ethno-mycological Studies, 1st ed; Harcourt Brace Jovanovich: Newyork, 1972.
[2]
Rambold, G.; Stadler, M.; Begerow, D. Mycology should be recognized as a field in biology at eye level with other major disciplines—a memorandum. Mycol. Prog., 2013, 12, 455-463.
[3]
Horowitz, N.H.; Berg, P.; Singer, M.; Lederberg, J.; Susman, M.; Doebley, J.; Crow, J.F. A centennial: George W. Beadle, 1903-1989. Genetics, 2004, 166(1), 1-10.
[4]
Osmani, S.A.; Mirabito, P.M. The early impact of genetics on our understanding of cell cycle regulation in Aspergillus nidulans. Fungal Genet. Biol., 2004, 41(4), 401-410.
[5]
Nierman, W.C.; May, G.; Kim, H.S.; Anderson, M.J.; Chen, D.; Denning, D.W. What the Aspergillus genomes have told us. Med. Mycol., 2005, 43(1)(Suppl. 1), S3-S5.
[7]
Eugui, E.M.; Allison, A.C. Immunosuppressive activity of mycophenolate mofetil. Ann. N. Y. Acad. Sci., 1993, 685(1), 309-329.
[8]
Bentley, R. Mycophenolic Acid: a one hundred year odyssey from antibiotic to immunosuppressant. Chem. Rev., 2000, 100(10), 3801-3826.
[9]
Lax, E. The mold in Dr. Florey’s coat: the story of the penicillin miracle; Henry Holt and Company: New York, 2005.
[10]
Bills, G.F.; Gloer, J.B. Biologically active secondary metabolites from the fungi. Microbiol. Spectr., 2016, 4(6)
[11]
Hawksworth, D.L. The fungal dimension of biodiversity: magnitude, significance, and conservation. Mycol. Res., 1991, 95, 641-655.
[13]
Kirk, P.M.; Cannon, P.F.; Minter, D.W.; Stalpers, J.A. Dictionary of the Fungi, 10th ed; CABI: Wallingford, 2008.
[14]
Newton, G.G.F.; Abraham, E.P. Cephalosporin C, a new antibiotic containing sulphur and D-α-aminoadipic acid. Nature, 1955, 175(4456), 548.
[15]
Holten, K.B.; Onusko, E.M. Appropriate prescribing of oral beta-lactam antibiotics. Am. Fam. Physician, 2000, 62(3), 611-620.
[16]
Balkovec, J.M.; Hughes, D.L.; Masurekar, P.S.; Sable, C.A.; Schwartz, R.E.; Singh, S.B. Discovery and development of first in class antifungal caspofungin (CANCIDAS®)-a case study. Nat. Prod. Rep., 2014, 31(1), 15-34.
[17]
Shao, L.; Li, J.; Liu, A.; Chang, Q.; Lin, H.; Chen, D. Efficient bioconversion of echinocandin B to its nucleus by overexpression of deacylase genes in different host strains. Appl. Environ. Microbiol., 2013, 79(4), 1126-1133.
[18]
Fujie, A. Discovery of micafungin (FK463). A novel antifungal drug derived from natural product lead. Pure Appl. Chem., 2007, 79(4), 603-614.
[19]
Butler, M.S. The role of natural product chemistry in drug discovery. J. Nat. Prod., 2004, 67(12), 2141-2153.
[21]
Fleming, A. On the antibacterial action of cultures of Penicillium, with special reference to their use in the isolation of B. influenzae. Br. J. Exp. Pathol., 1929, 10, 226-236.
[22]
Crawfoot, D.; Bunn, C.W.; Rogers, L.O.W.; Barbara, W.; Turner-Jones, A. X- ray crystallographic investigation of the structure of Penicillin In: Chemistry of Penicillin; Clarke H.T., Johnson J.R., Robinson, R., Princeton: Princeton University Press, 1949; pp. 310-367.
[23]
Rolinson, G.N. Forty years of β-lactam research. J. Antimicrob. Chemother., 1998, 41(6), 589-603.
[24]
Batchelor, F.R.; Doyle, F.P.; Nayler, J.H.; Rolinson, G.N. Synthesis of penicillin: 6-aminopenicillanic acid in penicillin fermentations. Nature, 1959, 183(4656), 257-258.
[25]
Rolinson, G.N.; Batchelor, F.R.; Butterworth, D.; Cameron-Wood, J.; Cole, M.; Eustace, G.C.; Hart, M.V.; Richards, M.; Chain, E.B. Formation of 6-aminopenicillanic acid from penicillin by enzymatic hydrolysis. Nature, 1960, 187, 236-237.
[26]
Huang, H.T.; English, A.R.; Seto, T.A.; Shull, G.M.; Sobin, B.A. Enzymatic hydrolysis of the side chain of penicillin. J. Am. Chem. Soc., 1960, 82, 3790-3791.
[27]
Sutherland, R.; Rolinson, G.N. Activity of ampicillin in vitro compared with other antibiotics. J. Clin. Pathol., 1964, 17, 461-465.
[28]
Rolinson, G.N.; Sutherland, R. Carbenicillin, a new semisynthetic penicillin active against Pseudomonas aeruginosa. Antimicrob Agents Chemother (Bethesda), 1967, 7, 609-613.
[31]
Knudsen, E.T.; Rolinson, G.N.; Sutherland, R. Carbenicillin: a new semisynthetic penicillin active against Pseudomonas pyocyanea. BMJ, 1967, 3(5557), 75-78.
[32]
Paisley, J.W.; Washington, J.A., II Combined activitiy of clavulanic acid and ticarcillin against ticarcillin-resistant, gram-negative bacilli. Antimicrob. Agents Chemother., 1978, 14(2), 224-227.
[33]
Gin, A.; Dilay, L.; Karlowsky, J.A.; Walkty, A.; Rubinstein, E.; Zhanel, G.G. Piperacillin-tazobactam: a beta-lactam/beta-lactamase inhibitor combination. Expert Rev. Anti Infect. Ther., 2007, 5(3), 365-383.
[34]
Crawford, K.; Heatley, N.G.; Boyd, P.F.; Hale, C.W.; Kelley, B.K.; Miller, G.A.; Smith, N. Antibiotic production by a species of Cephalosporium. J. Gen. Microbiol., 1952, 6(1-2), 47-59.
[35]
Abraham, E.P.; Newton, G.G.F. Purification and some properties of cephalosporin N, a new penicillin. Biochem. J., 1954, 58(1), 94-102.
[36]
Abraham, E.P.; Loder, P.B.; Cephalosporin, C. In: Cephalosporins and Penicillins: chemistry and biology; Flynn, E.H., Ed.; Academic Press: New York, 1972; pp. 1-26.
[37]
Morin, R.B.; Jackson, B.G.; Flynn, E.H.; Roenske, R.W. Chemistry of Cephalosporin antibiotics I. 7-aminocephalosporanic acid from Cephalosporin C. J. Am. Chem. Soc., 1962, 84, 3400-3401.
[38]
Hameed, T.K.; Robinson, J.L. Review of the use of cephalosporins in children with anaphylactic reactions from penicillins. Can. J. Infect. Dis., 2002, 13(4), 253-258.
[39]
Silver, M.S.; Counts, G.W.; Zeleznik, D.; Turck, M. Comparison of in vitro antibacterial activity of three oral cephalosporins: cefaclor, cephalexin, and cephradine. Antimicrob. Agents Chemother., 1977, 12(5), 591-596.
[40]
García-Rodríguez, J.A.; Muñoz Bellido, J.L.; García Sánchez, J.E. Oral cephalosporins: current perspectives. Int. J. Antimicrob. Agents, 1995, 5(4), 231-243.
[41]
Neu, H.C.; Fu, K.P. Cefaclor: in vitro spectrum of activity and β-lactamase stability. Antimicrob. Agents Chemother., 1978, 13(4), 584-588.
[42]
Neu, H.C. β-Lactam antibiotics: structural relationships affecting in vitro activity and pharmacologic properties. Rev. Infect. Dis., 1986, 8(Suppl. 3), S237-S259.
[43]
O’Callaghan, C.H.; Sykes, R.B.; Griffiths, A.; Thornton, J.E. Cefuroxime, a new cephalosporin antibiotic: activity in vitro. Antimicrob. Agents Chemother., 1976, 9(3), 511-519.
[44]
Harding, S.M.; Williams, P.E.; Ayrton, J. Pharmacology of Cefuroxime as the 1-acetoxyethyl ester in volunteers. Antimicrob. Agents Chemother., 1984, 25(1), 78-82.
[45]
Roche, G. Le céfixime, première céphalosporine orale de troisième génération. Presse Med., 1989, 18(32), 1541-1544.
[46]
Garzone, P.; Lyon, J.; Yu, V.L. Third-generation and investigational cephalosporins: I. Structure-activity relationships and pharmacokinetic review. Drug Intell. Clin. Pharm., 1983, 17(7-8), 507-515.
[47]
Pechère, J-C.; Wilson, W.; Neu, H. Laboratory assessment of antibacterial activity of zwitterionic 7-methoxyimino cephalosporins. J. Antimicrob. Chemother., 1995, 36(5), 757-771.
[48]
Hancock, R.E.W.; Bellido, F. Antibacterial in vitro activity of fourth generation cephalosporins. J. Chemother., 1996, 8(Suppl. 2), 31-36.
[49]
Bryskeir, A.; Aszodi, J.; Chantot, J-F. Parenteral cephalosporin classification. Expert Opin. Investig. Drugs, 1994, 3, 145-171.
[50]
Barbhaiya, R.H.; Forgue, S.T.; Gleason, C.R.; Knupp, C.A.; Pittman, K.A.; Weidler, D.J.; Martin, R.R. Safety, tolerance, and pharmacokinetic evaluation of cefepime after administration of single intravenous doses. Antimicrob. Agents Chemother., 1990, 34(6), 1118-1122.
[51]
Giamarellou, H. Fourth generation cephalosporins in the antimicrobial chemotherapy of surgical infections. J. Chemother., 1999, 11(6), 486-493.
[52]
Chahine, E.B.; Nornoo, A.O. Ceftobiprole: The first broad spectrum anti-methicillin resistant Staphylococcus aureus beta lactam. J. Exp. Clin. Med., 2011, 3(1), 9-16.
[53]
Steed, M.E.; Rybak, M.J. Ceftaroline: a new cephalosporin with activity against resistant gram-positive pathogens. Pharmacotherapy, 2010, 30(4), 375-389.
[54]
Ishikawa, T.; Matsunaga, N.; Tawada, H.; Kuroda, N.; Nakayama, Y.; Ishibashi, Y.; Tomimoto, M.; Ikeda, Y.; Tagawa, Y.; Iizawa, Y.; Okonogi, K.; Hashiguchi, S.; Miyake, A. TAK-599, a novel N-phosphono type prodrug of anti-MRSA cephalosporin T-91825: synthesis, physicochemical and pharmacological properties. Bioorg. Med. Chem., 2003, 11(11), 2427-2437.
[55]
Kaushik, D.; Rathi, S.; Jain, A. Ceftaroline: a comprehensive update. Int. J. Antimicrob. Agents, 2011, 37(5), 389-395.
[56]
Godtfredsen, W.O.; Jahnsen, S.; Lorck, H.; Roholt, K.; Tybring, L. Fusidic acid: a new antibiotic. Nature, 1962, 193, 987.
[57]
Spelman, D. Fusidic acid in skin and soft tissue infections. Int. J. Antimicrob. Agents, 1999, 12(2)(Suppl. 2), S59-S66.
[58]
Bush, K.; Page, M.G.P. What we may expect from novel antibacterial agents in the pipeline with respect to resistance and pharmacodynamic principles. J. Pharmacokinet. Pharmacodyn., 2017, 44(2), 113-132.
[59]
Pushkin, R.; Iglesias-Ussel, M.D.; Keedy, K.; MacLauchlin, C.; Mould, D.R.; Berkowitz, R.; Kreuzer, S.; Darouiche, R.; Oldach, D.; Fernandes, P. A randomized study evaluating oral Fusidic acid (CEM-102) in combination with oral Rifampicin compared with standard of care antibiotics for the treatment of prosthetic joint infections: A new identified drug- drug interaction. Clin. Infect. Dis., 2016, 63(12), 1599-1604.
[60]
Farrell, D.J.; Mendes, R.E.; Castanheira, M.; Jones, R.N. Activity of Fusidic acid tested against Staphylococci isolated from patients in US medical centers in 2014. Antimicrob. Agents Chemother., 2016, 60(6), 3827-3831.
[61]
Godtfredsen, W.O.; Von Daehne, W.; Tybring, L.; Vangedal, S. Fusidic acid derivatives. I. Relationship between structure and antibacterial activity. J. Med. Chem., 1966, 9(1), 15-22.
[62]
Kaur, G.; Singh, K.; Pavadi, E.; Njoroge, M. Espinoza- Moraga, M.; De Kock, C.; Smith, P.J.; Wittlin, S.; Chibata, K. Synthesis of Fusidic acid bioisoteres as anti-plasmodial agents and molecular docking studies in the binding site of the elongation factor-G. MedChemComm, 2015, 6, 2023-2028.
[63]
Jones, R.; Fristche, T.; Sadar, H.; Ross, J. Activity of Retapamulin (SB-275833) a novel Pleuromutilin against selected gram +ve cocci. Antimicrob. Agents Chemother., 2006, 50(7), 2583-2586.
[64]
Kavanagh, F.; Hervey, A.; Robbins, W.J. Antibiotic substances from Basidiomycetes VIII. Pleurotus mutilis (Fr.) Sacc. and Pleurotus passeckerianus. Proc. Natl. Acad. Sci. USA, 1951, 37(9), 570-574.
[66]
Birch, A.J.; Holzapfel, C.W.; Rickards, R.W. The structure and some aspects of biosynthesis of pleuromutilins. Tetrahedron, 1966, 22(8), 359-387.
[68]
Boeckmann, R.K., Jr; Springer, D.M.; Alessi, T.R. Synthetic studies directed towards naturally soccurring cycloctanoids 2. A stereo-controlled assembly of (±) - Pleuromutilin via a remarkable sterically demanding oxy-cope rearrangement. J. Am. Chem. Soc., 1989, III(21), 8284-8286.
[69]
Fazakerley, N.J.; Helm, M.D.; Procter, D.J. Total synthesis of (+)-pleuromutilin. Chemistry, 2013, 19(21), 6718-6723.
[70]
Fazakerley, N.J.; Proctor, D.J. Synthesis and synthetic chemistry of Pleuromutilin. Tetrahedron, 2014, 70, 6911-6930.
[71]
Prince, W.T.; Ivezic-Schoenfeld, Z.; Lell, C.; Tack, K.J.; Novak, R.; Obermayr, F.; Talbot, G.H. Phase II clinical study of BC-3781, a pleuromutilin antibiotic, in treatment of patients with acute bacterial skin and skin structure infections. Antimicrob. Agents Chemother., 2013, 57(5), 2087-2094.
[72]
Oxford, A.E.; Raistrick, H.; Simonart, P. Studies in the biochemistry of micro-organisms: Griseofulvin, C(17)H(17)O(6)Cl, a metabolic product of Penicillium griseo-fulvum Dierckx. Biochem. J., 1939, 33(2), 240-248.
[73]
Brian, P.W.; Curtis, P.J.; Hemming, H.G. A substance causing abnormal development of fungal hyphae produced by Penicillium janczewskii. I. Biological Assay, production and isolation of the ‘curling factor’. Trans. Br. Mycol. Soc., 1946, 29, 173-187.
[74]
Grove, J.F. McGOWAN, J.C. Identity of griseofulvin and curling-factor. Nature, 1947, 160(4069), 574.
[75]
Gentles, J.C. Experimental ringworm in guinea pigs: oral treatment with griseofulvin. Nature, 1958, 182(4633), 476-477.
[76]
Finkelstein, E.; Amichai, B.; Grunwald, M.H. Griseofulvin and its uses. Int. J. Antimicrob. Agents, 1996, 6(4), 189-194.
[77]
Keates, R.A.B. Griseofulvin at low concentration inhibits the rate of microtubule polymerization in vitro. Biochem. Biophys. Res. Commun., 1981, 102(2), 746-752.
[78]
Rebacz, B.; Larsen, T.O.; Clausen, M.H.; Rønnest, M.H.; Löffler, H.; Ho, A.D.; Krämer, A. Identification of griseofulvin as an inhibitor of centrosomal clustering in a phenotype-based screen. Cancer Res., 2007, 67(13), 6342-6350.
[79]
Pirrung, M.C.; Brown, W.L.; Rege, S.; Laughton, P. Total synthesis of (+)-griseofulvin. J. Am. Chem. Soc., 1991, 113(22), 8561-8562.
[80]
Petersen, A.B.; Andersen, N.S.; Konotop, G.; Hanafiah, N.H.M.; Raab, M.S.; Krämer, A.; Clausen, M.H. Synthesis and formulation studies of griseofulvin analogues with improved solubility and metabolic stability. Eur. J. Med. Chem., 2017, 130, 240-247.
[81]
Nyfeler, R.; Keller-Schierlein, W.; Nüesch, J.; Treichler, H.; Voser, W.; Nyfeler, R.; Keller-Schierlein, W. Stoffwechselprodukte von Mikroorganismen 143. Mitteilung. Echinocandin B, ein neuartiges Polypeptid-Antibioticum aus Aspergillus nidulans var. echinulatus: Isolierung und Bausteine. Helv. Chim. Acta, 1974, 57(8), 2459-2477.
[82]
C.; Kuhn, A.; Loosli, H.R.; Petcher, T.J.; Weber, H.P.; von Wartburg, A. Struktur des cyclopeptid-antibiotikums sl 7810 (= echinocandinb). Tetrahedron Lett., 1976, 17(46), 4147-4150.
[83]
Schwartz, R.E.; Sesin, D.F.; Joshua, H.; Wilson, K.E.; Kempf, A.J.; Goklen, K.A.; Kuehner, D.; Gailliot, P.; Gleason, C.; White, R.; Inamine, E.; Bills, G.; Salmon, P.; Zitano, L. Pneumocandins from Zalerion arboricola. I. Discovery and isolation. J. Antibiot. (Tokyo), 1992, 45(12), 1853-1866.
[85]
Denning, D.W. Echinocandins and pneumocandins--a new antifungal class with a novel mode of action. J. Antimicrob. Chemother., 1997, 40(5), 611-614.
[86]
Peláez, F.; Cabello, A.; Platas, G.; Díez, M.T.; González del Val, A.; Basilio, A.; Martán, I.; Vicente, F.; Bills, G.E.; Giacobbe, R.A.; Schwartz, R.E.; Onish, J.C.; Meinz, M.S.; Abruzzo, G.K.; Flattery, A.M.; Kong, L.; Kurtz, M.B. The discovery of enfumafungin, a novel antifungal compound produced by an endophytic Hormonema species biological activity and taxonomy of the producing organisms. Syst. Appl. Microbiol., 2000, 23(3), 333-343.
[87]
Heasley, B.H.; Pacofsky, G.J.; Mamai, A.; Liu, H.; Nelson, K.; Coti, G.; Peel, M.R.; Balkovec, J.M.; Greenlee, M.L.; Liberator, P.; Meng, D.; Parker, D.L.; Wilkening, R.R.; Apgar, J.M.; Racine, F.; Hsu, M.J.; Giacobbe, R.A.; Kahn, J.N. Synthesis and biological evaluation of antifungal derivatives of enfumafungin as orally bioavailable inhibitors of β-1,3-glucan synthase. Bioorg. Med. Chem. Lett., 2012, 22(22), 6811-6816.
[88]
Wring, S.A.; Randolph, R.; Park, S.H.; Abrazzo, G.; Chen, Q.; Flattery, A.; Garrett, G.; Peel, M.; Outcalt, R.; Powell, K.; Trucksis, M.; Angulo, D.; Borroto-Esoda, K. SCY-078 A First in Class Orally Active Antifungal Glucan Synthesis Inhibitor: Pre-Clinical Pharmacokinetics and Pharmacodynamic Target in Murine Models of Disseminated Candidiasis. Antimicrob. Agents Chemother., 2017, 61, e02068-e16.
[89]
Bollinger, P.; Sigg, H.P.; Weber, H.P. Die Struktur von Ovalicin. Helv. Chim. Acta, 1973, 56(3), 819-830.
[90]
Lazáry, S.; Stähelin, H. Immunosuppressive and specific antimitotic effects of ovalicin. Experientia, 1968, 24(11), 1171-1173.
[91]
Lazary, S.; Stähelin, H. Immunosuppressive effect of a new antibiotic: ovalicin. Antibiot. Chemother., 1969, 15, 177-181.
[92]
Stähelin, H.F. The history of cyclosporin A (Sandimmune) revisited: another point of view. Experientia, 1996, 52(1), 5-13.
[93]
Petcher, T.J.; Weber, H.; Rüegger, A. Crystal and molecular structure of an iodo-derivative of the cyclic undecapeptide cyclosporin A. Helv. Chim. Acta, 1976, 59(5), 1480-1489.
[94]
Wu, X.; Stockdill, J.L.; Wang, P.; Danishefsky, S.J. Total synthesis of cyclosporine: access to N-methylated peptides via isonitrile coupling reactions. J. Am. Chem. Soc., 2010, 132(12), 4098-4100.
[95]
Angell, Y.M.; Thomas, T.L.; Flentke, G.R.; Rich, D.H. Solid phase synthesis of Cyclosporin peptides. J. Am. Chem. Soc., 1995, 117(27), 7279-7280.
[96]
Smulik, J.A.; Diver, S.T.; Pan, F.; Liu, J.O. Synthesis of cyclosporin A-derived affinity reagents by olefin metathesis. Org. Lett., 2002, 4(12), 2051-2054.
[97]
Wenger, R.M. Synthesis of cyclosporine. Total synthesis of Cyclosporine A and Cyclosporine H, two fungal metabolites from species of Tolypocladium inflatum GAMS. Helv. Chim. Acta, 1984, 67(2), 502-525.
[98]
Alsberg, C.L.; Black, O.F. Contributions to the study of maize deteriorations. Biochemical and toxicological investigations of Penicillium puberlum and Penicillium stoloniferum. USDA Bur. Plant Ind., Bulletin no. 270, Govt. Printing of Washington DC 1913.
[99]
Alsberg, C.L.; Black, O.F. >Contributions to the study of maize deteriorations. Biochemical and toxicological investigations of Penicillium puberlum and Penicillium stoloniferum, 1913.
[100]
Lee, W.A.; Gu, L.; Miksztal, A.R.; Chu, N.; Leung, K.; Nelson, P.H. Bioavailability improvement of mycophenolic acid through amino ester derivatization. Pharm. Res., 1990, 7(2), 161-166.
[101]
Mizumo, K.; Tsujino, M.; Takeda, M.; Hayashi, M.; Atsumi, K. Studies on Brednin I. Isolation, characterization and biological properties. J. Antibiot. (Tokyo), 1974, 27(10), 755-782.
[102]
Kusumi, T.; Tsuda, M.; Katsunuma, T.; Yamamura, M. Dual inhibitory effect of bredinin. Cell Biochem. Funct., 1989, 7(3), 201-204.
[103]
Sakaguchi, K.; Tsujino, M.; Mizuno, K.; Hayano, K.; Ishida, N.; Ishida, N. Effect of bredinin and its aglycone on L5178Y cells. J. Antibiot. (Tokyo), 1975, 28(10), 798-803.
[105]
Nair, V.; Zhang, F. Synthesis of a novel carbocyclic analog of bredinin. Molecules, 2013, 18(9), 11576-11585.
[106]
Asahi Kesai Pharma Corporation. A study to evaluate the efficacy and safety of Mizoribine in the treatment of Lupus Nephritis, [Accessed on October 16, 2016].
[107]
Kluepfel, D.; Bagli, J.; Baker, H.; Charest, M.P.; Kudelski, A. Myriocin, a new antifungal antibiotic from Myriococcum albomyces. J. Antibiot. (Tokyo), 1972, 25(2), 109-115.
[108]
Fujita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sasaki, S.; Toyama, R.; Chiba, K.; Hoshino, Y.; Okumoto, T. Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite. J. Antibiot. (Tokyo), 1994, 47(2), 208-215.
[109]
Fujita, T.; Yoneta, M.; Hirose, R.; Sasaki, S.; Inoue, K.; Kiuchi, M.; Hirase, S.; Adachi, K.; Arita, M.; Chiba, K. Simple compounds, 2-alkyl-2-amino-1,3,- propanediols have potent immunosuppressive activity. Bioorg. Med. Chem. Lett., 1995, 5(8), 847-852.
[110]
Adachi, K.; Kohara, T.; Nakao, N.; Arita, M.; Chiba, K.; Mishina, T.; Sasaki, S.; Fujita, T. Design, Synthesis and structure activity relationships of 2-substituted-2-amino-1,3-propanediols: Discovery of Novel immunosuppressant FTY-720. Bioorg. Med. Chem. Lett., 1995, 5(8), 853-856.
[111]
Keys, A.; Anderson, J.T.; Fidanza, F.; Keys, M.H.; Swahn, B. Effects of diet on blood lipids in man, particularly cholesterol and lipoproteins. Clin. Chem., 1955, 1(1), 34-52.
[112]
Dietschy, J.M.; Wilson, J.D. Regulation of cholesterol metabolism. N. Engl. J. Med., 1970, 282(21), 1179-1183.
[113]
Altschul, R.; Hoffer, A.; Stephen, J.D. Influence of nicotinic acid on serum cholesterol in man. Arch. Biochem. Biophys., 1955, 54(2), 558-559.
[114]
Thorp, J.M.; Waring, W.S. Modification of metabolism and distribution of lipids by ethyl chlorophenoxyisobutyrate. Nature, 1962, 194, 948-949.
[115]
Bergen, S.S., Jr; Van Itallie, T.B.; Tennent, D.M.; Sebrell, W.H. Effect of an anion exchange resin on serum cholesterol in man. Proc. Soc. Exp. Biol. Med., 1959, 102, 676-679.
[116]
Endo, A.; Kuroda, M.; Tsujita, Y. ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium. J. Antibiot. (Tokyo), 1976, 29(12), 1346-1348.
[117]
Fears, R.; Richards, D.H.; Ferres, H. The effect of compactin, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme-A reductase activity, on cholesterogenesis and serum cholesterol levels in rats and chicks. Atherosclerosis, 1980, 35(4), 439-449.
[118]
Alberts, A.W. Chen, J.; Kurori, G.; Hunt, V.; Huff, J.; Hoffman, C.; Rothrock, J.; Lopez, M.; Joshua, H.; Harris, E.; Patchett, A.; Mongham, R.; Currie, S.; Stapely, E.; Albers-Schonberg, G.; Hensens, O.; Hirshfield, J.; Hoogsten, K.; Liesch, J.; Springer, J. Mevinolin: a highly potent competitive inhibitor of hydroxyl-methylglutaryl-Coenzyme A reductase and a cholesterol lowering agent. Proc. Natl. Acad. Sci. USA, 1980, 77(7), 3957-3961.
[119]
Tobert, J.A. Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nat. Rev. Drug Discov., 2003, 2(7), 517-526.
[120]
Hoffman, W.F.; Alberts, A.W.; Anderson, P.S.; Chen, J.S.; Smith, R.L.; Willard, A.K. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 4. Side chain ester derivatives of mevinolin. J. Med. Chem., 1986, 29(5), 849-852.
[121]
Willard, A.K.; Smith, R.L. Incorporation of 2(s)-methylbutanoic acid-1-14C into the structure of Mevinolin. J. Labelled Comp. Radiopharm., 1982, 19(3), 337-344.
[122]
Tsujita, Y.; Kuroda, M.; Shimada, Y.; Tanzawa, K.; Arai, M.; Kaneko, I.; Tanaka, M.; Masuda, H.; Tarumi, C.; Watanabe, Y.; Fuji, S. CS-514, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase: tissue-selective inhibition of sterol synthesis and hypolipidemic effect on various animal species. Biochim. Biophys. Acta, 1986, 877(1), 50-60.
[123]
Andersen, P.L.; Kathawala, F.G.; Paolella, N.A.; Wattanasin, S. Preparation of azaindole and indolizine derivatives as anticholesteremics. WO 1988001997A2 1988.
[124]
Repic, O.; Prasad, K.; Lee, G.T. The story of Lescol: from research to production. Org. Process Res. Dev., 2001, 5(5), 519-527.
[125]
Ballantyne, C.M.; Corsini, A.; Davidson, M.H.; Holdaas, H.; Jacobson, T.A.; Leitersdorf, E.; März, W.; Reckless, J.P.; Stein, E.A. Risk for myopathy with statin therapy in high-risk patients. Arch. Intern. Med., 2003, 163(5), 553-564.
[126]
Roth, B.D.; Blankley, C.J.; Chucholowski, A.W.; Ferguson, E.; Hoefle, M.L.; Ortwine, D.F.; Newton, R.S.; Sekerke, C.S.; Sliskovic, D.R.; Stratton, C.D. Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus. J. Med. Chem., 1991, 34(1), 357-366.
[127]
Roth, B.D. The discovery and development of atorvastatin, a potent novel hypolipidemic agent. Prog. Med. Chem., 2002, 40, 1-22.
[128]
McGarth, N.A.; Brichacek, M.; Njardarson, J.T. A graphical journey of innovative organic architectures that have improved our lives. J. Chem. Educ., 2010, 87(12), 1348-1349.
[129]
Watanabe, M.; Koike, H.; Ishiba, T.; Okada, T.; Seo, S.; Hirai, K. Synthesis and biological activity of methanesulfonamide pyrimidine- and N-methanesulfonyl pyrrole-substituted 3,5-dihydroxy-6-heptenoates, a novel series of HMG-CoA reductase inhibitors. Bioorg. Med. Chem., 1997, 5(2), 437-444.
[130]
Flores, N.A. Pitavastatin Nissan/Kowa Yakuhin/Novartis/Sankyo. Curr. Opin. Investig. Drugs, 2002, 3(9), 1334-1341.
[131]
Mukhtar, R.Y.A.; Reid, J.; Reckless, J.P.D. Pitavastatin. Int. J. Clin. Pract., 2005, 59(2), 239-252.
[132]
Nicolette, R.; Fiorentino, A. Antitumor metabolites of Fungi. Curr. Bioact. Compd., 2014, 10, 207-244.
[133]
Lawal, T.O.; Wicks, S.M.; Mahady, G.B. Ganoderma lucidum (Ling_Zhi): The impact of Chemistry on Biological Activity in Cancer. Curr. Bioact. Compd., 2017, 13, 28-40.
[134]
Kanoh, K.; Kohno, S.; Asari, T.; Harada, T.; Katada, J.; Muramatsu, M.; Kawashima, H.; Sekiya, H.; Uno, I. (−) -Phenylahistin: A new mammalian cell cycle inhibitor produced by Aspergillus ustus. Bioorg. Med. Chem. Lett., 1997, 7, 2847-2852.
[135]
Kanoh, K.; Kohno, S.; Katada, J.; Hayashi, Y.; Muramatsu, M.; Uno, I. Antitumor activity of phenylahistin in vitro and in vivo. Biosci. Biotechnol. Biochem., 1999, 63(6), 1130-1133.
[136]
Kanoh, K.; Kohno, S.; Katada, J.; Takahashi, J.; Uno, I. (-)-Phenylahistin arrests cells in mitosis by inhibiting tubulin polymerization. J. Antibiot. (Tokyo), 1999, 52(2), 134-141.
[137]
Nicholson, B.; Lloyd, G.K.; Miller, B.R.; Palladino, M.A.; Kiso, Y.; Hayashi, Y.; Neuteboom, S.T.C. NPI-2358 is a tubulin-depolymerizing agent: in-vitro evidence for activity as a tumor vascular-disrupting agent. Anticancer Drugs, 2006, 17(1), 25-31.
[138]
Federico, K.C. Phase 1/2 study of vascular disrupting agent NPI- 2358 in pa-tients with advanced solid tumors or lymphoma. Nereus Pharmaceuticals Inc., [Accessed on October 18, 2016].,
[139]
Huang, L.; Schooley, G.L. Assessment of Docetaxel + Plinabulin compared to Docet-axel+ placebo in patients with advanced NSCLC with at least one measurable Lung Lesion. BeyondSpring Pharma Inc., [Accessed on October 20, 2016].,
[140]
Krohn, K.; Michel, A.; Florke, U.; Aust, H.J.; Draeger, S.; Schulz, B. Biologically active metabolites from fungi 4. Palmarumycins CP1-CP4 from Coniothyrium palmuram: Isolation, structure elucidation and biological activity. Eur. J. Org. Chem., 1994, 11(28), 1093-1097.
[141]
Powis, G.; Wipf, P.; Lynch, S.M.; Birmingham, A.; Kirkpatrick, D.L. Molecular pharmacology and antitumor activity of palmarumycin-based inhibitors of thioredoxin reductase. Mol. Cancer Ther., 2006, 5(3), 630-636.
[142]
Wipf, P.; Lynch, S.M.; Powis, G.; Birmingham, A.; Englund, E.E. Synthesis and biological activity of prodrug inhibitors of the thioredoxin-thioredoxin reductase system. Org. Biomol. Chem., 2005, 3(21), 3880-3882.
[143]
Banerjee, S.; Paruthy, S.B. Preclinical and Clinical perspective on fungal metabolites and their analogs as anti-cancer agents from bench to bedside. In: Fungal Metabolites; Merellion, J.M.; Ramawat, K.G., Eds.; Springer: New York, 2016; pp. 1-32.
[144]
Yang, T.; Lu, Z.; Meng, L.; Wei, S.; Hong, K.; Zhu, W.; Huang, C. The novel agent ophiobolin O induces apoptosis and cell cycle arrest of MCF-7 cells through activation of MAPK signaling pathways. Bioorg. Med. Chem. Lett., 2012, 22(1), 579-585.
[145]
Sun, W.; Lv, C.; Zhu, T.; Yang, X.; Wei, S.; Sun, J.; Hong, K.; Zhu, W.; Huang, C. Ophiobolin-O reverses adriamycin resistance via cell cycle arrest and apoptosis sensitization in adriamycin-resistant human breast carcinoma (MCF-7/ADR) cells. Mar. Drugs, 2013, 11(11), 4570-4584.
[146]
Dasari, R.; Masi, M.; Lisy, R.; Ferdérin, M.; English, L.R.; Cimmino, A.; Mathieu, V.; Brenner, A.J.; Kuhn, J.G.; Whitten, S.T.; Evidente, A.; Kiss, R.; Kornienko, A. Fungal metabolite ophiobolin A as a promising anti-glioma agent: In vivo evaluation, structure-activity relationship and unique pyrrolylation of primary amines. Bioorg. Med. Chem. Lett., 2015, 25(20), 4544-4548.
[147]
Charudattan, R.; Rao, K.V. Bostrycin and 4-deoxybostrycin: two nonspecific phytotoxins produced by Alternaria eichhorniae. Appl. Environ. Microbiol., 1982, 43(4), 846-849.
[148]
Xie, G.; Zhu, X.; Li, Q.; Gu, M.; He, Z.; Wu, J.; Li, J.; Lin, Y.; Li, M.; She, Z.; Yuan, J. SZ-685C, a marine anthraquinone, is a potent inducer of apoptosis with anticancer activity by suppression of the Akt/FOXO pathway. Br. J. Pharmacol., 2010, 159(3), 689-697.
[149]
Yuan, J.; He, Z.; Wu, J.; Lin, Y.; Zhu, X. A novel adriamycin analogue derived from marine microbes induces apoptosis by blocking Akt activation in human breast cancer cells. Mol. Med. Rep., 2011, 4(2), 261-265.
[150]
Kasettrathat, C.; Ngamrojanavanich, N.; Wiyakrutta, S.; Mahidol, C.; Ruchirawat, S.; Kittakoop, P. Cytotoxic and antiplasmodial substances from marine-derived fungi, Nodulisporium sp. and CRI247-01. Phytochemistry, 2008, 69(14), 2621-2626.
[151]
Dai, J.Q.; Krohn, K.; Draeger, S.; Schulz, B. New naphthalene –chroman coupling products from the endophytic fungus Nodulisporium sp. from Erica arborea. Eur. J. Org. Chem., 2009, 10, 1564-1569.
[152]
Zheng, Q.C.; Chen, G.D.; Kong, M.Z.; Li, G.Q.; Cui, J.Y.; Li, X.X.; Wu, Z.Y.; Guo, L.D.; Cen, Y.Z.; Zheng, Y.Z.; Gao, H. Nodulisporisteriods A and B, the first 3,4-seco-4-methyl-progesteroids from Nodulisporium sp. Steroids, 2013, 78(9), 896-901.
[153]
Sawada, H.; Nishimura, N.; Suzuki, E.; Zhuang, J.; Hasegawa, K.; Takamatsu, H.; Honda, K.; Hasumi, K. SMTP-7, a novel small-molecule thrombolytic for ischemic stroke: a study in rodents and primates. J. Cereb. Blood Flow Metab., 2014, 34(2), 235-241.
[154]
Meshram, V.; Saxena, S. Potential fibrinolytic activity of an endophytic Lasiodiplodia pseudotheobromae species. 3Biotech, 2016, 6, 114.
[155]
Meshram, V.; Saxena, S.; Paul, K. Xylarinase: a novel clot busting enzyme from an endophytic fungus Xylaria curta. J. Enzyme Inhib. Med. Chem., 2016, 31(6), 1502-1511.
[156]
Gupta, M.; Saxena, S.; Goyal, D. Potential pancreatic lipase inhibitory activity of an endophytic Penicillium species. J. Enzyme Inhib. Med. Chem., 2015, 30(1), 15-21.
[157]
Kapoor, N.; Saxena, S. Potential xanthine oxidase inhibitory activity of endophytic Lasiodiplodia pseudotheobromae. Appl. Biochem. Biotechnol., 2014, 173(6), 1360-1374.
[158]
Kapoor, N.; Saxena, S. Xanthine oxidase inhibitory and antioxidant potential of Indian Muscodor Species. 3Biotech, 2016, 6, 248.
[159]
Guo, B.; Dai, J.R.; Ng, S.; Huang, Y.; Leong, C.; Ong, W.; Carté, B.K. Cytonic acids A and B: novel tridepside inhibitors of hCMV protease from the endophytic fungus Cytonaema species. J. Nat. Prod., 2000, 63(5), 602-604.
[160]
Bhagat, J.; Kaur, A.; Kaur, R.; Yadav, A.K.; Sharma, V.; Chadha, B.S. Cholinesterase inhibitor (Altenuene) from an endophytic fungus Alternaria alternata: optimization, purification and characterization. J. Appl. Microbiol., 2016, 121(4), 1015-1025.
[161]
Cui, H.; Liu, Y.; Nie, Y.; Liu, Z.; Chen, S.; Zhang, Z.; Lu, Y.; He, L.; Huang, X.; She, Z. Polyketides from the mangrove-derived endophytic fungus Nectria sp. HN001 and their α-Glucosidase Inhibitory Activity. Mar. Drugs, 2016, 14(5), E86.
[162]
Aly, A.H.; Debbab, A.; Kjer, J.; Proksch, P. Fungal endophytes from higher plants: a prolific source of phytochemicals and other bioactive natural products. Fungal Divers., 2010, 41, 1-16.
[163]
Kaul, S.; Gupta, S.; Ahmed, M.; Dhar, K. Endophytic fungi from medicinal plants: a treasure hunt for bioactive metabolites. Phytochem. Rev., 2012, 11(4), 487-505.
Call for Papers in Thematic Issues
31 December, 2025
Antioxidants: Unveiling their Power in Health and Disease
Antioxidants have captured significant interest for decades due to their potential role in preventing chronic diseases. These molecules combat free radicals and unstable molecules that damage cells and contribute to the development of conditions like metabolic diseases, heart disease, cancer, and neurodegenerative diseases. This thematic issue will explore the cutting-edge ...read more
31 December, 2025
Bioactive Compounds: An Ideal Source for Drug Discovery, Design, Development and Target Identification
The Special Issue "Bioactive Compounds: Discovery, Design, Development, and Target Identification" aims to bring together innovative research and critical reviews on bioactive molecules that show therapeutic potential across diverse diseases. Discovery of novel bioactive compounds will focus on uncovering new molecules from natural or synthetic sources, expanding the library of ...read more
Related Journals
Anti-Cancer Agents in Medicinal Chemistry
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry
Current Analytical Chemistry
Current Computer-Aided Drug Design
Current Cancer Drug Targets
Combinatorial Chemistry & High Throughput Screening
Current Cancer Therapy Reviews
Current Diabetes Reviews
Current Drug Safety
Current Drug Targets
Related Books
AI Innovations in Drug Delivery and Pharmaceutical Sciences; Advancing Therapy through Technology
2-Deoxy-D-Glucose: Chemistry and Biology
Chiral Ionic Liquids: Applications in Chemistry and Technology
Anthocyanins: Pharmacology and Nutraceutical Importance
Therapeutic Insights into Herbal Medicine through the Use of Phytomolecules
Computer-Aided Drug Discovery Methods: A Brief Introduction
The Roles and Responsibilities of Clinical Pharmacists in Hospital Settings
Bioactive Compounds from Medicinal Plants for Cancer Therapy and Chemoprevention
Biochar - Solid Carbon for Sustainable Agriculture
DFT-Based Studies On Atomic Clusters
Article Metrics
72
5
1
2
