Synthesis and antitumor activity of tropolone derivatives. 7. Bistropolones containing connecting methylene chains

Yamato, Masatoshi; Ando, Junko; Sakaki, Katsuhito; Hashigaki, Kuniko; Wataya, Yusuke; Tsukagoshi, Shigeru; Tashiro, Tazuko; Tsuruo, Takashi

doi:10.1021/jm00080a010

Cited by 41 publications

(29 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Bistropolones madeby chemical synthesis have also been reported to possess antitumor activity. 3) This report describes isolation, physico-chemical characterization, biological properties and the structure of eupenifeldin.…”

mentioning

confidence: 99%

Eupenifeldin, a novel cytotoxic bistropolone from Eupenicillium brefeldianum.

et al. 1993

View full text Add to dashboard Cite

Eupenifeldin was isolated from cultures of Eupenicillium brefeldianum ATCC741 84 by extraction and crystallization.The compoundwas identified as a pentacyclic bistropolone on the basis of spectral data and its complete structure was established by single-crystal X-ray analysis. The compound is cytotoxic against the HCT-1 16 cell line and has in vivo antitumor activity in the P388 leukemia model.Ongoing efforts to find new natural products with antitumor activity led to isolation of a novel cytotoxic bistropolone from a culture broth produced by Eupenicillium brefeldianum ATCC74184. The active principle of this culture was purified to homogeneity and namedeupenifeldin. Its spectral data showed that the molecule had partial symmetry due to the presence of two identically substituted tropolone units each fused in the same mannerto dihydropyran rings. The complete structure and relative stereochemical relationships were determined by single crystal X-ray analysis. Only one naturally occuring bistropolone with cytotoxic activity, fusariocin C, has been described previously in the literature.1>2) It was isolated from the culture filtrate of Fusarium moniliforme and had cytotoxic and antitumor activities. Bistropolones madeby chemical synthesis have also been reported to possess antitumor activity.3) This report describes isolation, physico-chemical characterization, biological properties and the structure of eupenifeldin. Materials and Methods Spectral DataMass spectra in the FABmodewere obtained on a Kratos MS25using m-nitrobenzylalcohol as matrix. El spectra were recorded on a Finnigan TSQ70. A Shimadzu UV2100Uspectrophotometer was used for UVspectra and a Perkin-Elmer FTIR Model 1800 spectrometer for IR spectra. All NMRspectra were recorded in CDC13with a drop ofDMSO-d6on a Bruker Model AM-500spectrometer. Proton-proton coupling constants were obtained by selective irradiations, and carbon-proton one-bond coupling constants were measured in the proton coupled carbon spectrum.El mass spectrum: major peaks at m/z 548, 384, 366, 175, 137. IR-spectrum (KBr): 3440, 3260, 2950, 2870, 1630, 1595, 1530, 1445, 1425, 1395, 1280, 1178, 1150, 1082 cm"1. Fermentation ConditionsTo prepare an inoculum for the production phase, 4 rnl of the frozen vegetative stock were transferred to a 500-ml Erlenmeyer flask containing 100ml of vegetative mediumconsisting of soluble starch 0.5%, glucose 0.5%, fishmeat extract 0. 1 %, yeast extract 0.1 %, NZ-case 0.2%, sodium chloride 0.2% and calcium

show abstract

mentioning

confidence: 99%

Eupenifeldin, a novel cytotoxic bistropolone from Eupenicillium brefeldianum.

et al. 1993

View full text Add to dashboard Cite

show abstract

“…The tropone ring has a unique structure and properties and despite their non-benzenoid nature, they are planar and possess aromatic character. Natural and synthetic compounds that have the troponoid core have profound biological activities and have been used as antitumor, [1][2][3] antifungal, 4 and antimicrobial agents. 5 The biological activities of these compounds has been mainly attributed to their inhibitory effect on bimetallic enzymes.…”

Section: Introductionmentioning

confidence: 99%

“…Some examples exist in literature that shows anticancer activity such as thiocolchicin (3), which can act as tubulin 12 or topoisomerase II inhibitor.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Identification of 4-isopropyl–thiotropolone as a novel anti-microbial: regioselective synthesis, NMR characterization, and biological evaluation

et al. 2018

View full text Add to dashboard Cite

We have synthesized and separated tosylated thujaplicin isomers for the first time, and elucidated their structures using 1D, 2D-NMR techniques and X-ray crystallography. The tosylated isomers were used to synthesize 4-isopropyl-thiotropolone and 6-isopropyl-thiotropolone in a regioselective manner. 27853)). 4-Isopropyl-thiotropolone was found to inhibit Staphylococcus aureus in a low micro molar range and exhibit good therapeutic index and ADME properties. This compound can be used for future lead optimization to design inhibitors against Staphylococcus aureus (ATCC 29213).

show abstract

“…1,2) BT has a wide variety of biological functions, including antibacterial and antifungal activity, 3) acting as an iron chelator for Salmonella typhimurium, 4) anti-tumor activity, 5) and induction of differentiation. 6) Thus far, however, the molecular mechanisms by which BT exerts such a broad spectrum of biological effects have not been elucidated.…”

mentioning

confidence: 99%

Human Metallothionein Gene Expression Is Upregulated by .BETA.-Thujaplicin: Possible Involvement of Protein Kinase C and Reactive Oxygen Species

Nakano

Ikenaga

Aizu

et al. 2006

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

b-Thujaplicin (BT), also known as hinokitiol, is a tropolone-related compound found in the heart wood in several cupressaceous plants such as the Hinoki cypress, Chamaecyprais obtuse, and the western red cedar, Thuja Plicata DON.1,2) BT has a wide variety of biological functions, including antibacterial and antifungal activity, 3) acting as an iron chelator for Salmonella typhimurium, 4) anti-tumor activity, 5) and induction of differentiation. 6) Thus far, however, the molecular mechanisms by which BT exerts such a broad spectrum of biological effects have not been elucidated.Metallothioneins (MT) are ubiquitously distributed, low molecular weight proteins with a high cysteine content and high binding capacity for metals such as zinc and cadmium. 7)MT function in zinc homeostasis 7) and detoxification of heavy metals. 8,9) Several experiments have also shown that MT acts as a reactive oxygen species (ROS) scavenger, 10,11) and MT induction has protective effects against oxidative stresses such as anticancer drugs 12) and ultraviolet (UV). 13)MT gene expression is induced not only by heavy metals but also by a wide variety of stress-inducing agents such as ultraviolet, 14) X-ray, 15) hypoxia, 16) hydrogen peroxide, 17) and a number of cytokines including interferon-a and b, TNF-a, and interleukin 1 and 6. [18][19][20][21][22] Recently, we found that BT induces cellular metallothionein in mouse keratinocytes in vitro and in vivo, resulting in reduction of apoptotic cell formation caused by UV-B irradiation. 23)The molecular mechanism underlying MT gene regulation has been extensively investigated (reviewed in ref. 24). In the proximal promoters of MT genes, multiple copies of metal response elements (MREs) reside, and these cis-elements are essential for MT gene induction by zinc and cadmium. MREs were shown to mediate the transcriptional response of MT genes to oxidative stress in mouse hepatoma cells.25) A metal-responsive transcription factor, termed MTF-1, which binds to MREs and activates MT gene transcription, has been cloned from mouse and human. 26,27) Recently, the involvement of protein kinase-C (PKC) has been demonstrated in zinc-and cadmium-induced MT gene expression, as determined by Northern analyses using a specific PKC inhibitor, chelerythrin. 28) However, the precise regulation of MT gene expression by other inducing agents has yet to be elucidated.In the present study, we report the first evidence for BT as a potent transactivator for the human MT-IIA gene. Moreover, inhibition experiments revealed a possible involvement of protein kinase C and reactive oxygen species in the transduction mechanism. MATERIALS AND METHODSChemicals BT was a kind gift from Takasago (Tokyo, Japan). Cycloheximide, H7, chelerythrin, HA1004, and Nacetylcysteine (NAC) were all purchased from Sigma (St. Louis, MO, U.S.A.).Cell Culture The spontaneously transformed human epidermal keratinocyte cell line, HaCaT, (kindly provided by Dr. Husenig) was cultured in Dulbecco's modified minimal essential medium (DMEM) supplemented...

show abstract

Synthesis and antitumor activity of tropolone derivatives. 7. Bistropolones containing connecting methylene chains

Cited by 41 publications

References 0 publications

Eupenifeldin, a novel cytotoxic bistropolone from Eupenicillium brefeldianum.

Eupenifeldin, a novel cytotoxic bistropolone from Eupenicillium brefeldianum.

Identification of 4-isopropyl–thiotropolone as a novel anti-microbial: regioselective synthesis, NMR characterization, and biological evaluation

Human Metallothionein Gene Expression Is Upregulated by .BETA.-Thujaplicin: Possible Involvement of Protein Kinase C and Reactive Oxygen Species

Contact Info

Product

Resources

About