Waol B, a New Trihydrofuran Derivative with Cytocidal Activity, isolated from Myceliophthora lutea.

Nozawa, Osamu; Okazaki, Tetsuji; Morimoto, Shigeo; Chen, Zeng-Xiang; He, Bi-Mei; Mizoue, Kazutoshi

doi:10.7164/antibiotics.53.1296

Cited by 14 publications

(9 citation statements)

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“…In continuation of the search for producers of biologically active compounds among marine isolates of microscopic fungi, we determined that the fungus Myceliophthora lutea Costantin [4], which was isolated from marine sediments of Sakhalin Bay (Sea of Okhotsk), synthesizes compounds with antibacterial and cytotoxic activities. Little is known about secondary metabolites from fungi of the genus Myceliophthora although these fungi are often encountered and can be isolated from various substrates [5][6][7][8]. Herein we present data on the isolation and identification of known acremine A (2) [9] and previously unknown compounds called by us isoacremine D (1) and spiroacremines A (3) and B (4).…”

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confidence: 99%

Biologically active metabolites from the marine isolate of the fungus Myceliophthora lutea

et al. 2011

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The new compound isoacremine D (1) and acremine A (2) that was previously unknown for marine organisms were isolated from the marine isolate of the fungus Myceliophthora lutea. It was found that acremine A in CHCl 3 was converted through the action of light into spirocompounds called by us spiroacremines A (3) and B (4). The structures of the compounds were elucidated based on NMR spectroscopic and high-resolution mass spectrometric data. The absolute stereochemistry of the spiroacremines was determined by Mosher's method. It was shown that isoacremine D exhibited antimicrobial activity against Staphylococcus aureus at a concentration of 200 Pg/mL and cytotoxic activity against embryos of the sea urchin Strongylocentrotus nudus. It was found that 1-4 exhibited cytotoxic activity against sea urchin sperm cells.Keywords: acremines, marine isolate of the fungus Myceliophthora lutea, NMR data, 1-oxaspiro [4,5]decenes.Facultative and obligate marine microscopic fungi are sources of biologically active secondary metabolites [1][2][3]. In continuation of the search for producers of biologically active compounds among marine isolates of microscopic fungi, we determined that the fungus Myceliophthora lutea Costantin [4], which was isolated from marine sediments of Sakhalin Bay (Sea of Okhotsk), synthesizes compounds with antibacterial and cytotoxic activities. Little is known about secondary metabolites from fungi of the genus Myceliophthora although these fungi are often encountered and can be isolated from various substrates [5][6][7][8]. Herein we present data on the isolation and identification of known acremine A (2) [9] and previously unknown compounds called by us isoacremine D (1) and spiroacremines A (3) and B (4). The last two compounds are apparently artifacts of the isolation process.The fungus was cultivated on solid medium for 21 d at 22°C in order to produce the metabolites. The dried EtOAc extract of the biomass produced a CHCl 3 extract, separation of which over silica gel and Sephadex LH-20 afforded pure 1 and 2 ( Fig. 1) in addition to 3 and 4, which were not present in the starting total EtOAc extract according to TLC (Fig. 2).The empirical formula of 1 was determined as C 12 H 14 O 3 on the basis of the high-resolution mass spectrum and NMR spectra. The PMR spectrum of 1 contained three 3H-singlets in the range 1.55-2.27 ppm, indicative of three tertiary methyls in its structure. The DEPT and HSQC spectra of 1 confirmed the presence of three methyls (G C 17.6, 31.0, 31.0 ppm) and also indicated that three methine groups were present (G C 101.2, 106.5, 113.4). The remaining six C atoms were classified as quaternary (G C 165.9, 153.0, 150.8, 128.6, 123.1, 69.7). Figure 1 shows the key HMBC-correlations of 1.

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Biologically active metabolites from the marine isolate of the fungus Myceliophthora lutea

et al. 2011

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“…23 When the same group subsequently isolated a closely related compound from the same strain, termed waol B, FD-211 was renamed to waol A. 25 Both showed activity against a range of tumour cell lines, including adriamycin-resistant HL-60 cells. Soon after, the synthesis of a key intermediate of the proposed waol A structure was reported.…”

Section: Massarilactonesmentioning

confidence: 99%

“…The furo [3,4-b]pyran scaffold is found in only a handful of known natural products, including TAN-2483A and B, 16 the fusidilactones, 17,18 the massarilactones, [19][20][21][22] and waol A 23,24 and B. 25 The biological activity of these natural products is broad, and includes cytotoxic, antibacterial, antifungal and antialgal properties.…”

Section: Introductionmentioning

confidence: 99%

Toward the Synthesis of (–)-TAN-2483B Lactam Analogues

Stirrat¹

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<p>Natural products continue to be an abundant source of lead compounds for drug discovery and development. (–)-TAN-2483A and (–)-TAN-2483B, isolated from the culture of a filamentous fungus, incorporate an unusual furo[3,4-b]pyran-5-one scaffold. TAN-2483A was initially reported to inhibit the c-Src tyrosine kinase enzyme, a potential anticancer target, and parathyroid hormone-induced bone resorption. TAN-2483B, on the other hand, was not isolated in sufficient quantities for biological testing. The synthesis of TAN-2483B is therefore desirable from a drug discovery perspective. Several analogues of TAN-2483B that are functionalised at the propenyl sidechain have previously been synthesised in the Harvey group and have shown promising biological activity. For example, the (Z)-ethyl ester analogue showed micromolar inhibition of HL-60 cells and Bruton’s tyrosine kinase, a protein involved in B-cell maturation that is implicated in certain cancers. The lactone moiety of TAN-2483B and its sidechain analogues, however, appears to be unstable to nucleophilic attack. The aim of this thesis was to investigate the viability of a synthetic route toward lactam analogues of TAN-2483B. It was proposed that substituting the lactone for a lactam would increase the stability of the compound in nucleophilic media. Moreover, the lactam nitrogen may provide a site for further functionalisation of the compound for future structure-activity relationship studies. Because installation of the (Z)-ethyl ester sidechain via Wittig conditions has previously been found to be more facile than installation of the (E)-propenyl sidechain found in the natural product, investigations into forming the lactam ring system were carried out on the ethyl ester advanced intermediates. Reductive amination of a ketone intermediate was envisaged to install the amine prior to a palladium-catalysed carbonylation/lactam formation step. The promising bioactivity of the (Z)-ethyl ester analogue was anticipated to be retained in the target lactam analogues. It was found that the substrates of the proposed reductive amination, the advanced ketone intermediates, were incompatible with the tested conditions, presumably due to base sensitivity. Three by-products from the reductive amination experiments were isolated and tentatively characterised by NMR spectroscopy and HRMS. An alternative route toward lactam analogues of TAN-2483B, via intermediate amines accessed by the substitution of an activated alcohol, was briefly investigated with encouraging results. Further optimisation of the synthetic route toward analogues of TAN-2483B was also achieved. Removal of a purification step enabled the more expedient two-step synthesis of a diol intermediate. The two-step transformation to (Z)- and (E)-ethyl ester intermediates, via sodium periodate-mediated diol cleavage and Wittig olefination, proceeded in the highest yield obtained to date. Investigations into the desilylation of a trimethylsilyl-protected acetylene were also conducted. Although lactam analogues of TAN-2483B were not obtained in this study, progress was made toward their synthesis. The alternative route toward amines that was briefly explored here appears promising, and work is ongoing in the Harvey group to access lactam (and other) analogues of TAN-2483B, in addition to the natural product itself.</p>

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“…FD-211 was later termed waol A, when a close relative, waol B (156) was later isolated from the same fungal species. 84 Later, a preliminary paper reported the partial synthesis of structure 155. The Snider group has published the only known reports on the total synthesis of these furo [3,4-b]pyran-5-one natural products.…”

Section: Waol Compoundsmentioning

confidence: 99%

“…86 More recently, the Snider group have published work indicating that waol A and B do not have structures 155 and 156, and the correct structures of waol A and B were confirmed by synthesis to be 157 and 158 respectively.87Figure 1.11 Initial and revised structures of waol A and B83,84,87 …”

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Investigations of Ring-Opening Reactions of Cyclopropanated Carbohydrates: Towards the Synthesis of the Natural Product (--)-TAN-2483B

Hewitt¹

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<p>Cyclopropanes and carbohydrates are materials of great interest to chemists. Ring opening reactions of cyclopropanated carbohydrates have excellent potential for synthesis, due to the many diverse structures that may be obtained. The work described in this thesis explores the scope of such ring opening reactions, and extends to the synthesis and reactions of several novel cyclopropanated carbohydrates, in which synthesis of a natural product was also investigated. Several bicyclic gem-dihalocyclopropanes, including 97, were synthesised. Base-mediated cyclopropane ring opening of 97 in the presence of nucleophiles afforded a series of 2-C-branched glycosides 389 and 390 (Chapter 2), whereas silver-promoted ring expansion provided access to seven-membered rings (255 and 256) (Chapter 3). Studies on the mechanisms of the ring opening processes were also carried out. Ring-opening reactions of carbohydrate-derived gem-dihalocyclopropanes were also applied to the exploration of possible routes to the natural product (--)-TAN-2483B (154). Attempts to convert d-galactose and d-xylose into the dihydropyran 193 are the subject of Chapter 4, while the transformation of d-mannose into 193 and subsequent efforts to prepare the natural product 154 are discussed in Chapter 5.</p>

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Waol B, a New Trihydrofuran Derivative with Cytocidal Activity, isolated from Myceliophthora lutea.

Cited by 14 publications

References 4 publications

Biologically active metabolites from the marine isolate of the fungus Myceliophthora lutea

Biologically active metabolites from the marine isolate of the fungus Myceliophthora lutea

Toward the Synthesis of (–)-TAN-2483B Lactam Analogues

Investigations of Ring-Opening Reactions of Cyclopropanated Carbohydrates: Towards the Synthesis of the Natural Product (--)-TAN-2483B

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