The Biological Activities of Sesterterpenoid-Type Ophiobolins
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marine drugs Review The Biological Activities of Sesterterpenoid-Type Ophiobolins Wei Tian ID , Zixin Deng and Kui Hong * Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and Wuhan University School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; [email protected] (W.T.); [email protected] (Z.D.) * Correspondence: [email protected]; Tel.: +86-27-6875-2442 Received: 17 May 2017; Accepted: 13 July 2017; Published: 18 July 2017 Abstract: Ophiobolins (Ophs) are a group of tricarbocyclic sesterterpenoids whose structures contain a tricyclic 5-8-5 carbotricyclic skeleton. Thus far, 49 natural Ophs have been reported and assigned into A–W subgroups in order of discovery. While these sesterterpenoids were first characterized as highly effective phytotoxins, later investigations demonstrated that they display a broad spectrum of biological and pharmacological characteristics such as phytotoxic, antimicrobial, nematocidal, cytotoxic, anti-influenza and inflammation-promoting activities. These bioactive molecules are promising drug candidates due to the developments of their anti-proliferative activities against a vast number of cancer cell lines, multidrug resistance (MDR) cells and cancer stem cells (CSCs). Despite numerous studies on the biological functions of Ophs, their pharmacological mechanism still requires further research. This review summarizes the chemical structures, sources, and biological activities of the oph family and discusses its mechanisms and structure–activity relationship to lay the foundation for the future developments and applications of these promising molecules. Keywords: ophiobolins; source; bioactivities; structure–activity relationship; mechanisms 1. Introduction Sesterterpenoids are a group of compounds with C25 carbon frameworks derived from five isoprene units, and exhibit a variety of biological activities including cytotoxic and antimicrobial functions [1–3]. They have been found from widespread sources including fungi, bacteria, plants, insects and marine organisms [4,5]. Marine organisms represent a broad source of potential sesterterpenoids. For example, genus Phyllospongia, one of the most common marine sponges, has been shown to be a prolific producer of various scalarane sesterterpenoids [6], and marine-derived fungi belong to the genus of Aspergillus produced sesterterpenoid ophiobolins [7]. Ophiobolins (Ophs) are a class of sesterpenoids and characterized by the structure of a tricyclic 5-8-5 ring system derived from head to tail linkages of five isoprene units (Figure1). These small molecules, ranged in molecular weight from 338 to 432, are produced by fungi mainly belong to the genus Bipolaris and Aspergillus. The first member of this family named ophiobolin A (compound 1, Figure2) was isolated from the pathogenic plant fungus Ophiobolus miyabeanus by Nakamura and Ishibashi in 1958 [8]. Numerous additional analogs have been reported since then. Here, we summarize 49 natural products of Ophs, which are assigned into 23 subgroups (A–W). There are enormous potential applications of Ophs in different fields due to their wide biological effects. Initially, the researchers focused on the investigations of phytotoxic properties of Ophs, which are produced by pathogenic fungi attacking agricultural crops [9–15]. Later, Ophs have been proven to possess a broad spectrum of other biological properties, such as antimicrobial [15,16], nematocidal [17–19] and cytotoxic activities [1,5,9]. Additionally, MDR reversal effects of Ophs Mar. Drugs 2017, 15, 229; doi:10.3390/md15070229 www.mdpi.com/journal/marinedrugs Mar. Drugs 2017, 15, 229 2 of 21 Mar. Drugs 2017, 15, 229 2 of 21 on multiple tumor cells with a low concentration were proven by both in vitro and in vivo experimentsmultiple tumor[20,21 cells]. Furthermore, with a low concentration Ophs also possess were proven anti-influenza by both [in22 vitro] and and inflammation-promoting in vivo experiments activities[20,21]. [Furthermore,23]. With their Ophs diverse also possess pharmacological anti-influenza properties, [22] and inflammation-promoting Ophs are shown to be aactivities group of promising[23]. With drug theircandidates. diverse pharmacological Although a properti varietyes, of Ophs potential are shown biological to be activitiesa group of of promising Ophs have beendrug widely candidates. investigated, Although their a molecularvariety of targets,potential the biological functional activities mechanisms, of Ophs and have structure–activity been widely investigated, their molecular targets, the functional mechanisms, and structure–activity relationships are still obscure. After Au et al. (2000) reviewed the biology of 23 Ophs [9], 26 more relationships are still obscure. After Au et al. (2000) reviewed the biology of 23 Ophs [9], 26 more Ophs have been reported/added to the family. In this review, we summarize the chemical structures, Ophs have been reported/added to the family. In this review, we summarize the chemical structures, sources, and biological properties of 49 reported Ophs. Furthermore, we will focus on the cytotoxic sources, and biological properties of 49 reported Ophs. Furthermore, we will focus on the cytotoxic properties, mechanism of action, and structure–activity relationship of Ophs to demonstrate their properties, mechanism of action, and structure–activity relationship of Ophs to demonstrate their pervasivenesspervasiveness and and importance importance in in drug drug discovery. discovery. 2. Chemical Structure and Source of Ophs 2. Chemical Structure and Source of Ophs TheseThese small small molecules molecules are are characterizedcharacterized by a core structure of of 5-8-5 5-8-5 tricyclic tricyclic carbon carbon skeletons skeletons (Figure(Figure1) and1) and assigned assigned into into A–W A–W subgroups. subgroups. All All reportedreported Ophs, numbered numbered from from 1–49, 1–49, are are shown shown in in FigureFigure2. The2. The original original names names of of the the biological biological sources sources ofof OphsOphs are listed in in Table Table 11.. WithWith many many structurally structurally similar similar analogs, analogs, Ophs Ophs family family needed needed an approach an approach to distinguish to distinguish between thembetween [24,25 them]. Kildgaard [24,25]. Kildgaard et al. (2014) et al. reported (2014) reported that Ophs that canOphs be can dereplicated be dereplicated accurately accurately by usingby ultra-highusing ultra-high performance performance liquid chromatography–diode liquid chromatography–diode array detection–quadrupole array detection–quadrupole time of flight time massof spectrometryflight mass spectrometry (UHPLC-DAD-QTOFMS) (UHPLC-DAD-QTOFMS) with a tandem with high a tandem resolution high MS resolution (MS/HRMS) MS (MS/HRMS) Library and eightLibrary Ophs and were eight available Ophs were as standards available andas standards included and in theincluded library in at the present library [ 25at ].present [25]. FigureFigure 1.1. CarbonCarbon skeleton of of Ophs. Ophs. In the earlier studies, different research groups adopted different taxonomical nomenclatures forIn the the same earlier pathogenic studies, fungi, different which research caused groups confusions. adopted Therefore, different some taxonomical of the fungi nomenclatures have been forreclassified. the same pathogenic For example, fungi, Drechslera which oryzae caused and confusions. Helminthosporium Therefore, oryzae some have of been the fungireclassified have beenin reclassified.Bipolaris oryzae For. example, Drechslera oryzae and Helminthosporium oryzae have been reclassified in BipolarisThe oryzae majority. of Ophs were discovered from the fungi genera of Bipolaris and Aspergillus. For example,The majority genus Bipolaris of Ophs produces were discoveredophiobolins fromA–B, I–J, the and fungi L–M, genera while ofgenusBipolaris Aspergillusand producesAspergillus . Forophiobolins example, genus C, F–H,Bipolaris K, N, producesand U–W ophiobolins(Table 1). Marine-derived A–B, I–J, and L–M, fungi while belong genus to AspergillusAspergillus produceproduces ophiobolinsvarious Ophs. C, F–H, For example, K, N, and Aspergillus U–W (Table sp. 1(Taxonomy). Marine-derived ID: 5065) fungi produces belong ophiobolins to Aspergillus G, H, produceK and variousO [4] (Table Ophs. 1); For and example, EmericellaAspergillus variecolorsp. (reclassified (Taxonomy in ID:Aspergillus 5065) produces stellatu, Taxonomy ophiobolins ID: G, 1549217) H, K and O[produces4] (Table ophiobolins1); and Emericella C, G, H, variecolor K and N (reclassified[26,27] (Table in1).Aspergillus The other genera stellatu including, Taxonomy Drechslera ID: 1549217) [28], producesUlocladium ophiobolins [29], Penicillium C, G, H,[30], K andMollisia N [ 26[31],,27 ]and (Table Cephalosporium1). The other [32], genera were including producersDrechslera of a part of[28 ], Ulocladiumthe discovered[29], Penicillium structures[30. ],Moreover,Mollisia [ 31ophiobolin], and Cephalosporium A lactone [and32], wereophiobolin producers B lactone of a part were of the discoveredtransformed structures. from ophiobolin Moreover, A ophiobolinby the bacteria A lactone Polyangium and ophiobolincellulosum and B lactone Pseudomonas were transformedaeruginosa, fromrespectively ophiobolin [30]. A by the bacteria Polyangium cellulosum and Pseudomonas aeruginosa, respectively [30]. Mar. Drugs 2017, 15, 229 3 of 21 Mar. Drugs 2017, 15, 229 3 of 21 ItIt is is not not yet yet known known whether whether the the similarities similarities