The Total Synthesis and Biological Properties of the Cytotoxic Macrolide FD‐891 and Its Non‐Natural (<i>Z</i>)‐C12 Isomer

Garcı́a-Fortanet, Jorge; Murga, Juan; Cardá, Miguel; Marco, J. Alberto; Matesanz, Ruth; Díaz, J. Fernando; Barasoaín, Isabel

doi:10.1002/chem.200700342

Cited by 19 publications

(10 citation statements)

References 68 publications

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“…However, non-apoptotic cells harboring two nuclei apparently accumulated in FD-891-treated cells (unpublished observation). Therefore, as previously reported, 19 it seems that FD-891 induces cell cycle arrest at the G 2 /M phase, and this biological effect may also contribute to its inhibitory effect on cell proliferation. In this study, the molecular mechanism underlying FD-891-induced apoptosis in Jurkat cells was further addressed.…”

Section: Fd-891 Induces Caspase-8-dependent Apoptosis S Inaba Et Alsupporting

confidence: 77%

“…It has been shown that FD-891 inhibits cell proliferation in cancer cell lines. 12,19 Consistent with these findings, we have shown that FD-891 is able to inhibit cell proliferation in many human cancer cell lines at IC 50 values of 0.03 to 1 mM. Human leukemia cell lines, such as Jurkat cells and HeLa cells, were highly sensitive to FD-891 and underwent rapid apoptosis upon treatment with FD-891.…”

Section: Fd-891 Induces Mitochondrial Release Of Cytochrome Csupporting

confidence: 75%

“…12,19 (Table 1). In Jurkat cells, FD-891 decreased cell viability by more than 80% at concentrations higher than 100 nM when incubated for 72 h (Figure 1b).…”

Section: Fd-891 Inhibits Proliferation Of Human Cancer Cell Linesmentioning

confidence: 99%

“…[17][18][19] It has been shown that FD-891 exerts cytotoxicity toward several cancer cell lines. 12,19 Moreover, as regards immunosuppressive activity, FD-891 prevents cytotoxic T lymphocyte (CTL) mediated killing pathway. 20 In this study, we investigated the molecular mechanism underlying the cytotoxicity of FD-891.…”

Section: Introductionmentioning

confidence: 99%

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The cytotoxic macrolide FD-891 induces caspase-8-dependent mitochondrial release of cytochrome c and subsequent apoptosis in human leukemia Jurkat cells

et al. 2009

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The 16-membered macrolide FD-891 exerts cytotoxicity toward several cancer cell lines. In this study, we showed that FD-891 induces apoptosis in various human cancer cell lines. Human leukemia Jurkat cells were highly sensitive to FD-891, exhibiting caspase activation and mitochondrial release of cytochrome c into the cytosol at early time points after exposure to FD-891. By contrast, Jurkat cells deficient in caspase-8 were resistant to FD-891-induced apoptosis and manifested little induction of cytochrome c release as well as caspase-9 processing. Consistent with these results, the overexpression of the Bcl-2 family member Bcl-x L or the caspase-8 modulator c-FLIP L markedly prevented FD-891-induced apoptosis. These results clearly demonstrate that FD-891 triggers caspase-8-dependent mitochondrial release of cytochrome c and subsequent apoptosis in Jurkat cells.

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Section: Fd-891 Induces Caspase-8-dependent Apoptosis S Inaba Et Alsupporting

confidence: 77%

Section: Fd-891 Induces Mitochondrial Release Of Cytochrome Csupporting

confidence: 75%

“…12,19 (Table 1). In Jurkat cells, FD-891 decreased cell viability by more than 80% at concentrations higher than 100 nM when incubated for 72 h (Figure 1b).…”

Section: Fd-891 Inhibits Proliferation Of Human Cancer Cell Linesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The cytotoxic macrolide FD-891 induces caspase-8-dependent mitochondrial release of cytochrome c and subsequent apoptosis in human leukemia Jurkat cells

et al. 2009

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“…Cell cycle arrest at G 2 /M phase by FD-891 was also suggested to contribute to the FD-891-induced apoptosis. [3] FD-891 also prevents cytotoxic T lymphocyte (CTL)-mediated killing pathway as an immunosuppressive activity. [4] However, in contrast to a structurally related concanamycin A, which blocks the perforin-dependent killing pathway in CTLmediated cytotoxicity, FD-891 did not affect the vacuolar acidification and only slightly decreased perforin activity.…”

Section: Introductionmentioning

confidence: 99%

Cloning and Characterization of the Biosynthetic Gene Cluster of 16‐Membered Macrolide Antibiotic FD‐891: Involvement of a Dual Functional Cytochrome P450 Monooxygenase Catalyzing Epoxidation and Hydroxylation

et al. 2010

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FD‐891 is a 16‐membered cytotoxic antibiotic macrolide that is especially active against human leukemia such as HL‐60 and Jurkat cells. We identified the FD‐891 biosynthetic (gfs) gene cluster from the producer Streptomyces graminofaciens A‐8890 by using typical modular type I polyketide synthase (PKS) genes as probes. The gfs gene cluster contained five typical modular type I PKS genes (gfsA, B, C, D, and E), a cytochrome P450 gene (gfsF), a methyltransferase gene (gfsG), and a regulator gene (gfsR). The gene organization of PKSs agreed well with the basic polyketide skeleton of FD‐891 including the oxidation states and α‐alkyl substituent determined by the substrate specificities of the acyltransferase (AT) domains. To clarify the involvement of the gfs genes in the FD‐891 biosynthesis, the P450 gfsF gene was inactivated; this resulted in the loss of FD‐891 production. Instead, the gfsF gene‐disrupted mutant accumulated a novel FD‐891 analogue 25‐O‐methyl‐FD‐892, which lacked the epoxide and the hydroxyl group of FD‐891. Furthermore, the recombinant GfsF enzyme coexpressed with putidaredoxin and putidaredoxin reductase converted 25‐O‐methyl‐FD‐892 into FD‐891. In the course of the GfsF reaction, 10‐deoxy‐FD‐891 was isolated as an enzymatic reaction intermediate, which was also converted into FD‐891 by GfsF. Therefore, it was clearly found that the cytochrome P450 GfsF catalyzes epoxidation and hydroxylation in a stepwise manner in the FD‐891 biosynthesis. These results clearly confirmed that the identified gfs genes are responsible for the biosynthesis of FD‐891 in S. graminofaciens.

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TheJulia–Kocienski Olefination

Blakemore¹,

Sephton

Ciganek

2018

Organic Reactions

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The Julia–Kocienski olefination is a direct connective synthesis of alkenes via the addition of metalated aryl alkyl sulfones to carbonyl compounds. The activating aromatic group associated with the sulfone must possess electrophilic character, and alkene formation occurs via β‐alkoxy sulfone formation, transfer of the aryl group from sulfur to oxygen via a Smiles rearrangement, and then elimination of sulfur dioxide and an aryloxide anion from the resulting β‐aryloxy sulfinate anion. The olefination process itself and the methods used to prepare the requisite sulfone substrates are tolerant of a wide variety of functional groups, and a variety of alkene targets can be prepared. Stereoselectivity is dependent on the nature of the sulfone, the carbonyl compound, the activating aryl moiety, and the reaction conditions. This chapter describes theoretical and operational aspects of the Julia–Kocienski olefination such that the reader will be able to obtain optimal results in his/her own research. A detailed mechanistic overview is included to account for the factors that influence stereoselectivity and yield. Methods for introducing sulfone activators into fragments of interest, best practices for generating sulfone anions, and optimal strategies for targeting different classes of alkene targets are discussed. Functional group compatibilities, reaction variants, and a comparison to other methods of alkene synthesis are also presented. Tabular surveys are organized according to type of alkene synthesized, with an emphasis on the degree of substitution and the level of conjugation about the newly formed double bond. The literature is covered from the initial disclosure of the Julia–Kocienski olefination in 1991 to the first quarter of 2016.

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The Total Synthesis and Biological Properties of the Cytotoxic Macrolide FD‐891 and Its Non‐Natural (Z)‐C12 Isomer

Abstract: El artículo seleccionado no se encuentra disponible por ahora a texto completo por no haber sido facilitado todavía por el investigador a cargo del archivo del mismo.

Cited by 19 publications

References 68 publications

The cytotoxic macrolide FD-891 induces caspase-8-dependent mitochondrial release of cytochrome c and subsequent apoptosis in human leukemia Jurkat cells

The cytotoxic macrolide FD-891 induces caspase-8-dependent mitochondrial release of cytochrome c and subsequent apoptosis in human leukemia Jurkat cells

Cloning and Characterization of the Biosynthetic Gene Cluster of 16‐Membered Macrolide Antibiotic FD‐891: Involvement of a Dual Functional Cytochrome P450 Monooxygenase Catalyzing Epoxidation and Hydroxylation

TheJulia–Kocienski Olefination

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