Sesterterpenoids with Anticancer Activity.

Terpenes have received a great deal of attention in the scientific literature due to complex, synthetically challenging structures and diverse biological activities associated with this class of natural products. Based on the number of C5 isoprene units they are generated from, terpenes are classified as hemi- (C5), mono- (C10), sesqui- (C15), di- (C20), sester- (C25), tri (C30), and tetraterpenes (C40). Among these, sesterterpenes and their derivatives known as sesterterpenoids, are ubiquitous secondary metabolites in fungi, marine organisms, and plants. Their structural diversity encompasses carbotricyclic ophiobolanes, polycyclic anthracenones, polycyclic furan-2-ones, polycyclic hydroquinones, among many other carbon skeletons. Furthermore, many of them possess promising biological activities including cytotoxicity and the associated potential as anticancer agents. This review discusses the natural sources that produce sesterterpenoids, provides sesterterpenoid names and their chemical structures, biological properties with the focus on anticancer activities and literature references associated with these metabolites. A critical summary of the potential of various sesterterpenoids as anticancer agents concludes the review.

[1]  Daniel E. Johnson.  The ubiquitin-proteasome system: opportunities for therapeutic intervention in solid tumors. , 2015, Endocrine-related cancer.

[2]  N. Donato,et al.  Emerging potential of therapeutic targeting of ubiquitin-specific proteases in the treatment of cancer. , 2014, Cancer research.

[3]  R. Kiss,et al.  Incorporation of Ophiobolin A into Novel Chemoembolization Particles for Cancer Cell Treatment , 2014, Pharmaceutical Research.

[4]  A. Cimmino,et al.  Phytotoxic Terpenes Produced by Phytopathogenic Fungi and Allelopathic Plants , 2014, Natural product communications.

[5]  A. Arnold,et al.  Secoemestrin D, a cytotoxic epitetrathiodioxopiperizine, and emericellenes A-E, five sesterterpenoids from Emericella sp. AST0036, a fungal endophyte of Astragalus lentiginosus1. , 2013, Journal of natural products.

[6]  J. Frisvad,et al.  Bio-Activity and Dereplication-Based Discovery of Ophiobolins and Other Fungal Secondary Metabolites Targeting Leukemia Cells , 2013, Molecules.

[7]  Cuiting Lv,et al.  Ophiobolin-O Reverses Adriamycin Resistance via Cell Cycle Arrest and Apoptosis Sensitization in Adriamycin-Resistant Human Breast Carcinoma (MCF-7/ADR) Cells , 2013, Marine drugs.

[8]  Liangdong Guo,et al.  Ophiobolins P-T, five new cytotoxic and antibacterial sesterterpenes from the endolichenic fungus Ulocladium sp. , 2013, Fitoterapia.

[9]  W. Berger,et al.  Ophiobolin A, a sesterterpenoid fungal phytotoxin, displays higher in vitro growth-inhibitory effects in mammalian than in plant cells and displays in vivo antitumor activity. , 2013, International journal of oncology.

[10]  R. Kiss,et al.  Therapeutic agents triggering nonapoptotic cancer cell death. , 2013, Journal of medicinal chemistry.

[11]  S. Spiegl-Kreinecker,et al.  Ophiobolin A induces paraptosis-like cell death in human glioblastoma cells by decreasing BKCa channel activity , 2013, Cell Death and Disease.

[12]  Li-lian Liu,et al.  Cytotoxic Sesterterpenoids from a Sponge Hippospongia sp. , 2012, Marine drugs.

[13]  M. Maiuri,et al.  Cacospongionolide and Scalaradial, Two Marine Sesterterpenoids as Potent Apoptosis-Inducing Factors in Human Carcinoma Cell Lines , 2012, PloS one.

[14]  A. Arnold,et al.  Geopyxins A-E, ent-kaurane diterpenoids from endolichenic fungal strains Geopyxis aff. majalis and Geopyxis sp. AZ0066: structure-activity relationships of geopyxins and their analogues. , 2012, Journal of natural products.

[15]  V. Nizet,et al.  Novel Bacterial Metabolite Merochlorin A Demonstrates in vitro Activity against Multi-Drug Resistant Methicillin-Resistant Staphylococcus aureus , 2012, PloS one.

[16]  Shanjian Wei,et al.  The novel agent ophiobolin O induces apoptosis and cell cycle arrest of MCF-7 cells through activation of MAPK signaling pathways. , 2012, Bioorganic & medicinal chemistry letters.

[17]  P. Sung,et al.  Cytotoxic C21 and C22 terpenoid-derived metabolites from the sponge Ircinia sp. , 2011, Journal of natural products.

[18]  Motomasa Kobayashi,et al.  Concise synthesis and structure–activity relationship of furospinosulin-1, a hypoxia-selective growth inhibitor from marine sponge , 2011 .

[19]  K. Oh,et al.  Sesterterpenes from the tropical sponge Coscinoderma sp. , 2011, Journal of natural products.

[20]  Y. Yi,et al.  Hippolides A-H, acyclic manoalide derivatives from the marine sponge Hippospongia lachne. , 2011, Journal of natural products.

[21]  D. Hawksworth,et al.  Naming Aspergillus species: progress towards one name for each species. , 2011, Medical mycology.

[22]  J. Frisvad,et al.  Distribution of sterigmatocystin in filamentous fungi. , 2011, Fungal biology.

[23]  K. Oh,et al.  Scalarane sesterterpenes from the sponge Hyatella sp. , 2011, Journal of natural products.

[24]  D. Curran,et al.  Novel agents in the management of lung cancer. , 2010, Current medicinal chemistry.

[25]  A. Setiawan,et al.  Hypoxia‐Selective Growth Inhibition of Cancer Cells by Furospinosulin‐1, a Furanosesterterpene Isolated from an Indonesian Marine Sponge , 2010, ChemMedChem.

[26]  Johan Bussink,et al.  PET-CT for response assessment and treatment adaptation in head and neck cancer. , 2010, The Lancet. Oncology.

[27]  R. Riccio,et al.  Chemical proteomics discloses petrosapongiolide M, an antiinflammatory marine sesterterpene, as a proteasome inhibitor. , 2010, Angewandte Chemie.

[28]  P. Proksch,et al.  Bioactive Sesterterpenes and Triterpenes from Marine Sponges: Occurrence and Pharmacological Significance , 2010, Marine drugs.

[29]  Serge Eifes,et al.  Heteronemin, a spongean sesterterpene, inhibits TNF alpha-induced NF-kappa B activation through proteasome inhibition and induces apoptotic cell death. , 2010, Biochemical pharmacology.

[30]  J. Schnitzler,et al.  Poplar volatiles - biosynthesis, regulation and (eco)physiology of isoprene and stress-induced isoprenoids. , 2009, Plant biology.

[31]  Miguel A. González.  Scalarane Sesterterpenoids , 2010 .

[32]  N. Lemoine,et al.  Pancreatic cancer: molecular pathogenesis and new therapeutic targets , 2009, Nature Reviews Gastroenterology &Hepatology.

[33]  A. Tosco,et al.  Sesterterpenes as tubulin tyrosine ligase inhibitors. First insight of structure-activity relationships and discovery of new lead. , 2009, Journal of medicinal chemistry.

[34]  C. Pirker,et al.  The sodium pump α1 sub-unit: a disease progression–related target for metastatic melanoma treatment , 2009, Journal of cellular and molecular medicine.

[35]  C. Cavasotto,et al.  The binding mode of petrosaspongiolide M to the human group IIA phospholipase A(2): exploring the role of covalent and noncovalent interactions in the inhibition process. , 2009, Chemistry.

[36]  A. Osbourn,et al.  Plant-derived natural products : synthesis, function, and application , 2009 .

[37]  M. Sasaki,et al.  The Inhibitory Action of Kohamaic Acid A Derivatives on Mammalian DNA Polymerase β , 2008, Molecules.

[38]  A. Schimmer,et al.  Anoikis resistance and tumor metastasis. , 2008, Cancer letters.

[39]  Paola Chiarugi,et al.  Anoikis: a necessary death program for anchorage-dependent cells. , 2008, Biochemical pharmacology.

[40]  R. Andersen,et al.  Scalarane-based metabolites isolated from the antimitotic extract of the marine sponge Hyrtios erectus , 2008, Natural product research.

[41]  R. Ueoka,et al.  Aplysinoplides A-C, cytotoxic sesterterpenes from the marine sponge Aplysinopsis digitata. , 2008, Journal of natural products.

[42]  M. Slevin,et al.  Anti-angiogenic activity of sesterterpenes; natural product inhibitors of FGF-2-induced angiogenesis , 2008, Angiogenesis.

[43]  A. Arnold,et al.  Understanding the diversity of foliar endophytic fungi: progress, challenges, and frontiers , 2007 .

[44]  D. Nagle,et al.  Hypoxia-selective antitumor agents: norsesterterpene peroxides from the marine sponge Diacarnus levii preferentially suppress the growth of tumor cells under hypoxic conditions. , 2007, Journal of natural products.

[45]  M. Garson,et al.  Mooloolabenes A-E, norsesterterpenes from the Australian sponge Hyattella intestinalis. , 2006, Journal of natural products.

[46]  M. Fracchiolla,et al.  Ophiobolin E and 8-epi-ophiobolin J produced by Drechslera gigantea, a potential mycoherbicide of weedy grasses. , 2006, Phytochemistry.

[47]  Yu-Chi Lin,et al.  Novel linear C22-sesterterpenoids from sponge Ircinia formosana , 2006 .

[48]  Isabelle Camby,et al.  Present and potential future issues in glioblastoma treatment , 2006, Expert review of anticancer therapy.

[49]  M. Fracchiolla,et al.  Herbicidal potential of ophiobolins produced by Drechslera gigantea. , 2006, Journal of agricultural and food chemistry.

[50]  H. Gross,et al.  Terpenoids from Marine Organisms: Unique Structures and their Pharmacological Potential , 2006, Phytochemistry Reviews.

[51]  R. Kiss,et al.  Gastrin exerts pleiotropic effects on human melanoma cell biology. , 2005, Neoplasia.

[52]  R. Kiss,et al.  Are syngeneic mouse tumor models still valuable experimental models in the field of anti-cancer drug discovery? , 2005, International journal of oncology.

[53]  R. Kiss,et al.  Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[54]  P. Proksch,et al.  New luffariellolide derivatives from the Indonesian sponge Acanthodendrilla sp. , 2004, Journal of natural products.

[55]  R. Kiss,et al.  Development of a chemoresistant orthotopic human nonsmall cell lung carcinoma model in nude mice , 2004, Cancer.

[56]  M. Kinoshita,et al.  Cytotoxic sesterterpenes, 6-epi-ophiobolin G and 6-epi-ophiobolin N, from marine derived fungus Emericella variecolor GF10 , 2004 .

[57]  S. Lowe,et al.  Apoptosis and melanoma chemoresistance , 2003, Oncogene.

[58]  R. Croteau,et al.  Strategies for transgenic manipulation of monoterpene biosynthesis in plants. , 2002, Trends in plant science.

[59]  M. Boyd,et al.  Thorectandrols C, D, and E, new sesterterpenes from the marine sponge Thorectandra sp. , 2002, Journal of natural products.

[60]  M. Wink.  Medicinal Natural Products. A Biosynthetic Approach , 2002 .

[61]  K. Suenaga,et al.  Kohamaic Acids A and B, Novel Cytotoxic Sesterterpenic Acids, from the Marine Sponge Ircinia sp. , 2010 .

[62]  B. H. Bae,et al.  New cytotoxic sesterterpenes from the sponge Sarcotragus species. , 2001, Journal of natural products.

[63]  Y. Ohizumi,et al.  Ophiobolin A, a Novel Apoptosis‐inducing Agent from Fungus Strain f‐7438 , 2000 .

[64]  W. S. Chick,et al.  The biology of ophiobolins. , 2000, Life sciences.

[65]  Y. Kashman,et al.  Bilosespens A and B: two novel cytotoxic sesterpenes from the marine sponge Dysidea cinerea. , 1999, Organic letters.

[66]  Z. Cichacz,et al.  Antineoplastic agents. 397: Isolation and structure of sesterstatins 4 and 5 from Hyrtios erecta (the Republic of Maldives). , 1998, Bioorganic & medicinal chemistry letters.

[67]  A. Carotenuto,et al.  Antiproliferative sesterterpenes from the Caribbean sponge Cacospongia cf. linteiformis. , 1998, Comparative biochemistry and physiology. Part C, Pharmacology, toxicology & endocrinology.

[68]  S. D. Rosa,et al.  Further Bioactive Sesterterpenes from the Tyrrhenian Sponge Fasciospongia Cavernosa , 1997 .

[69]  A. Randazzo,et al.  New cytotoxic sesterterpenes from the New Caledonian marine sponge Petrosaspongia nigra (Bergquist) , 1997 .

[70]  S. Matsunaga,et al.  Three new cytotoxic sesterterpenes from the marine sponge Hyrtios cf. erectus. , 1996, Journal of natural products.

[71]  M. Ishibashi,et al.  Luffariolides F and G, new manoalide derivatives from the Okinawan marine sponge Luffariella sp. , 1993, Journal of natural products.

[72]  D. Faulkner,et al.  Phospholipase A2 inhibitors from marine organisms. , 1992, Journal of natural products.

[73]  H. Li,et al.  New cytotoxic scalarane sesterterpenes from the Dictyoceratid sponge Strepsichordaia lendenfeldi. , 1992, Journal of natural products.

[74]  Takuma Sasaki,et al.  Luffariolides A-E, new cytotoxic sesterterpenes from the Okinawan marine sponge Luffariella sp , 1992 .

[75]  K. Glaser,et al.  Manoalide: structure-activity studies and definition of the pharmacophore for phospholipase A2 inactivation. , 1989, Molecular pharmacology.

[76]  S. D. Rosa,et al.  Cacospongionolide a new antitumoral sesterterpene from the marine sponge cacospongia mollior , 1988 .

[77]  S. Morgutti,et al.  Effects of ophiobolin A on potassium permeability, transmembrane electrical potential and proton extrusion in maize roots , 1983 .

[78]  F. Schmitz,et al.  Marine natural products: cembrene-A and cembrene-C from a soft coral, Nephthea species , 1978 .

[79]  C. L. Tipton,et al.  Effects of ophiobolin a on ion leakage and hexose uptake by maize roots. , 1977, Plant physiology.

[80]  G. Cordell.  Biosynthesis of sesquiterpenes , 1976 .

[81]  D. V. Banthorpe,et al.  The biosynthesis of monoterpenes. , 1972, Sogo kango. Comprehensive nursing, quarterly.

[82]  T. Sassa,et al.  Production and Characterization of a New Fungal Metabolite, Cotylenol , 1972 .

[83]  S. Okuda,et al.  The isolation of an acyclic C25-isoprenoid alcohol, geranylnerolidol, and a new ophiobolin , 1968 .

[84]  A. Itai,et al.  The structure of cephalonic acid, a pentaprenyl terpenoid. , 1967, Tetrahedron letters.

[85]  M. Kienle,et al.  The constitution of cochliobolin , 1966 .

[86]  C. Barnes,et al.  The Structure of Polygodial: A New Sesquiterpene Dialdehyde from Polygonum hydropiper L , 1962 .