10'-Desmethoxystreptonigrin, a novel analog of streptonigrin.

Liu, W. C.; Barbacid, Mariano; Bulgar, M.; Clark, Junius M.; Crosswell, Alfred R.; Dean, Loretta D.; Doyle, Terrence W.; Fernandes, Prabhavathi; Huang, Stella; Manne, Veeraswamy; Pirnik, Dolores M.; Wells, John G.; Meyers, and Edward A.

doi:10.7164/antibiotics.45.454

Cited by 37 publications

(25 citation statements)

References 2 publications

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“…Therefore, inhibition of FT is currently one of the main foci of anticancer drug development [Schafer et al, 1989;Manne et al, 1991;Gibbs, 19911 in an attempt to inhibit andior reverse ras mediated malignant transformation in human cancers. Several classes of FT inhibitors have been reported in the literature, including CAAX h x based tetrapeptide analogs [Goldstein et al, 1991;., 1993; James et al, 1993;Garcia ct a]., 1993; Nigam et al, 1993;Leftheris et al, 19941, FPP analogs [ I'ompliano et al, 1992;Gillbs et al, 1993;Tarnanoi, 19931, bisubstrate analogs [Patel et a]., 19941, and natural products [Crowcll ct al., 1991;Liu et …”

Section: Introductionmentioning

confidence: 99%

Ras farnesylation as a target for novel antitumor agents: Potent and selective farnesyl diphosphate analog inhibitors of farnesyltransferase

Manne

Ricca

Brown

et al. 1995

Drug Development Research

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Protein prenylation is increasingly recognized as an important mechanism by which functional association of proteins t o membranes is mediated. Ras proteins, regulators of cell proliferation and differentiation, are among the proteins that undergo farnesylation, one of the two prenylation modifications known. Since ras proteins are activated into hyperactive oncogenic versions in a wide variety of human cancers, agents that d o w n modulate ras activity could be antineoplastic. Therefore, inhibitors of farnesyltransferase have the potential t o be of therapeutic value as anticancer agents due t o their ability t o block ras processing and hence its function. W e describe the identification of two farnesyl pyrophosphate (FPP) analogs that are potent and selective inhibitors of farnesyltransferase. While showing n o toxicity t o untransformed cells, a pivaloyloxyrnethyl ester of one of these inhibitors blocked ras mediated transformation of NIH 3T3 cells. In addition, both the ester and its parent acid inhibited ras farnesylation as measured by incorporation of labeled mevalonate into ras proteins in whole cells. Thus, this i s the first report of an FPP analog t o show biological activity by inhibiting ras processing i n whole cells. (0 1995 Wile"-Liss, Inc.

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Section: Introductionmentioning

confidence: 99%

Ras farnesylation as a target for novel antitumor agents: Potent and selective farnesyl diphosphate analog inhibitors of farnesyltransferase

Manne

Ricca

Brown

et al. 1995

Drug Development Research

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“…These include chaetomellic acids, actinoplanic acids, preussomerins, cylindrols, barceloneic acid, fusidienol, and oreganic acid . Other inhibitors have been reported by several groups and include pepticinnamins, gliotoxin, 10‘-desmethoxystreptonigrin, and manumycin analogs . Our continued interest in finding potent and novel inhibitors of FPTase led to the isolation of fusidienol A ( 1a ) from Phoma sps.…”

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confidence: 99%

Fusidienol A: A Novel Ras Farnesyl-Protein Transferase Inhibitor from Phoma sp.

et al. 1997

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“…The search for inhibitors of FPTase, based on either natural products or the CAAX tetrapeptide, has intensified. The natural product inhibitors reported to date fall into three main classes: (a) Inhibitors that are competitive with farnesyl diphosphate (FDP), including chaetomellic acids, actinoplanic acids, and manumycin analogs; (b) inhibitors that are competitive with Ras-peptide such as the pepticinnamins; and (c) those inhibitors that are either not competitive with either of the FPTase substrates or their mechanism of inhibition is not yet known; this class of inhibitors includes fusidienol, preussomerins, gliotoxin, and 10‘-desmethoxystreptonigrin . We have continued screening for novel inhibitors of FPTase and recently reported yet another class of novel inhibitor, cylindrol A ( 1a ), from Cylindrocarpon lucidum (Ascomycotina, Hypocreales).…”

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Chemistry and Biology of Cylindrols: Novel Inhibitors of Ras Farnesyl-Protein Transferase from Cylindrocarpon lucidum

et al. 1996

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Farnesyl-protein transferase (FPTase) is an enzyme responsible for the farnesylation of Ras protein. Farnesylation is required for cell-transforming activity in several tumor-types, and therefore, inhibition of FPTase activity may be a potential target for anticancer drugs. Our continued search for novel inhibitors led to the isolation of a number of bicyclic resorcinaldehyde cyclohexanone derivatives named here cylindrols A(1) to A(4), cylindrols B and B(1), and a number of known compounds, from Cylindrocarpon lucidum. The compounds were isolated by bioassay-guided separation using Sephadex LH-20, silica gel, and reverse phase HPLC. Structures were elucidated by extensive application of 2D NMR and X-ray crystallography. The determination of absolute stereochemistry was accomplished by CD measurements. Chemical transformations of the most abundant compound resulted in a number of key derivatives which were critical for the evaluation of structure activity relationship. These compounds are members of ascochlorin family and showed a wide range of inhibitory activity (0.7 &mgr;M to >140 &mgr;M) against FPTase. The FPTase activity was noncompetitive with respect to both substrates. Isolation, structures, chemical transformations, and FPTase activity are discussed in detail.

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10'-Desmethoxystreptonigrin, a novel analog of streptonigrin.

Cited by 37 publications

References 2 publications

Ras farnesylation as a target for novel antitumor agents: Potent and selective farnesyl diphosphate analog inhibitors of farnesyltransferase

Ras farnesylation as a target for novel antitumor agents: Potent and selective farnesyl diphosphate analog inhibitors of farnesyltransferase

Fusidienol A: A Novel Ras Farnesyl-Protein Transferase Inhibitor from Phoma sp.

Chemistry and Biology of Cylindrols: Novel Inhibitors of Ras Farnesyl-Protein Transferase from Cylindrocarpon lucidum

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