Structures and Cytotoxic Properties of Trichoverroids and Their Macrolide Analogues Produced by Saltwater Culture of Myrothecium verrucaria

Abstract

Saltwater culture of Myrothecium verrucaria, separated from a Spongia sp. collected in Hawaii, was a source of three new trichothecenes, 3-hydroxyroridin E (1a), 13′-acetyltrichoverrin B (2), and miophytocen C (3) and nine known related compounds (1b, 4, 5, 6, 7a, 7b, 8, 9a, and 9b). The stereostructures of the new compounds were established on the basis of 1D and 2D NMR spectral analyses and a chemical transformation. At the same time, the stereostructures of known compounds, 1b, 4, and 5 reported previously were also elucidated. All the compounds except 3 showed significant cytotoxicity against murine and human tumor cell lines. Moreover, the structure-activity relationships (SARs) were established from the results of the bioassay data.

Absolute Configuration of New Cytotoxic and Other Bioactive Trichothecene Macrolides

“…This observation suggested that it was most likely a trichothecene compound belonging to the macrocyclic 10,13-cyclotrichothecane group. [1,13] This assumption was subsequently confirmed by a set of 2 D NMR spectroscopic experiments ( 1 H-1 H COSY, NOESY, HMQC, and HMBC spectra) that provided data for the unequivocal assignment of all 1 H and 13 C NMR spectral data (Tables 1 and 2). In the 1 H-1 H COSY spectrum of 1, the coupling sequences from H-2 through H-4, between H-7 and H-8, and of H-10 with H-11 and H-13 were readily recognized and connected to the sesquiterpenol moiety according to the HMBC correlations of (1) H-2 with C-4, C-5, and C-11, (2) H-3a with C-5 and C-12, (3) H-4 with C-5, C-6, and C-12, (4) H-11 with C-9 and C-15, and (5) H-15 with C-1', C-7, and C-11.…”

“…Among this type of secondary metabolite, a number have been demonstrated to play a substantial role in cancer prevention, [1] immunomodulation, [2] plant tissue induction, [3] phytotoxicity, [4] fungus suppression, [5] malaria management, [6] biocontrol agent, [7] and mammalian intoxications. [8] Renewed understanding of the relevant molecular mechanisms of action of these compounds highlighted that the biochemical processes, in most cases, were fascinatingly unique.…”

“…In our continuous characterization of chemically novel and/or biologically potent metabolites produced by fungi harboring in healthy plant tissues [10] or normal animal organs, [11] the presence of trichothecene metabolites was ascertained, prior to the detailed fractionation procedure, by 1 H NMR spectral analysis of extracts derived from a solidsubstrate culture of Myrothecium roridum IFB-E009 and a liquid culture of Myrothecium roridum IFB-E012, which are endophytic fungi residing in two traditional Chinese medicinal plants, Trachelospermum jasminoides (Apocynaceae) and Artemisia annua (Asteraceae), respectively. Subsequent 1 H NMR monitored fractionation of the extracts led to the isolation of three new 10,13-cyclotrichothecane-based macrolides 1-3 in coexistence with the known analogues roridin E (4) and mytoxin B (5).…”

Natural sesquiterpenoids

“…107 Another cyclotrichothecane derivative miophytocen C 132, together with 3-hydroxyroridin E and 13 -acetyltrichoverrin B, were isolated from a saltwater culture of Myrothecium verrucaria, separated from a Spongia sp., collected in Hawaii. 108 GC-MS techniques have been used in the analysis of trichothecene mycotoxins in commercial corn harvested in Brazil. 109 The synthesis of four mycotoxins of this type labelled with carbon-13 and their application as internal standards in stable isotope dilution assays for their determination in foods has been described.…”

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“…Other compounds: Several other anticancerous compounds apart from the above mentioned categories includes steroid, diketopiperazine, terpenes, trichoverroids and peptides. Myrothecium verrucaria derived trichoverroid compounds such as 3-hydroxyroridin E, 13' acetyltrichoverrin B and miophytocen C shows significant cytotoxicity against murine and human tumor cell lines 26 . Aragusterol C, novel chlorinated steroid, was isolated from an Okinawan marine sponge of the genus Xestospongia.…”