Novel CDC25A Phosphatase Inhibitors from Pyrolysis of 3-α-Azido-B-homo-6-oxa-4-cholesten-7-one on Silica Gel

Peng, Hairuo; Zalkow, Leon H.; Abraham, Robert T.; Powis, Garth

doi:10.1021/jm980500r

Cited by 24 publications

(9 citation statements)

References 13 publications

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“…Presumably the anti-Cdc25 activity found in the original dysidiolide preparation was an unidenti®ed contaminant in the extract. Nonetheless, using dysidiolide as a pharmacophore, Takahashi et al (2000) and Peng et al (1998) synthesized compounds that mimicked substructures of dysidiolide. Pyrolysis of a cholesteryl acetate derivative produced Compound 7, which inhibited Cdc25A activity in the low mM range (Peng et al, 1998).…”

Section: Small Molecule Inhibitors Of Cdc25mentioning

confidence: 99%

“…Nonetheless, using dysidiolide as a pharmacophore, Takahashi et al (2000) and Peng et al (1998) synthesized compounds that mimicked substructures of dysidiolide. Pyrolysis of a cholesteryl acetate derivative produced Compound 7, which inhibited Cdc25A activity in the low mM range (Peng et al, 1998). Several derivatives of Compound 7 were developed in an e ort to produce a simpler inhibitor structure.…”

Section: Small Molecule Inhibitors Of Cdc25mentioning

confidence: 99%

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Small molecule inhibitors of dual specificity protein phosphatases

et al. 2000

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Section: Small Molecule Inhibitors Of Cdc25mentioning

confidence: 99%

Section: Small Molecule Inhibitors Of Cdc25mentioning

confidence: 99%

Small molecule inhibitors of dual specificity protein phosphatases

et al. 2000

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“…Except for the widely used broad-spectrum protein phosphatase inhibitor vanadate (Baratte et al, 1992), few dual speci®city protein phosphatase inhibitors have been reported (Peng et al, 1998). Although the natural products dnacin, dysidiolide, a RK-682 analogue and a cholestenone analog appear to inhibit Cdc25 dual speci®city phosphatase (Gunasekera et al, 1996;Hamaguchi et al, 1995;Horiguchi et al, 1994;Peng et al, 1998), there is little information on the nature of their inhibition and selectivity, and these analogs are generally in limited supply.…”

Section: Discussionmentioning

confidence: 99%

“…Although the natural products dnacin, dysidiolide, a RK-682 analogue and a cholestenone analog appear to inhibit Cdc25 dual speci®city phosphatase (Gunasekera et al, 1996;Hamaguchi et al, 1995;Horiguchi et al, 1994;Peng et al, 1998), there is little information on the nature of their inhibition and selectivity, and these analogs are generally in limited supply. Moreover, the e ects of these compounds on cell cycle transition are not known.…”

Section: Discussionmentioning

confidence: 99%

Dual G1 and G2/M phase inhibition by SC-ααδ9, a combinatorially derived Cdc25 phosphatase inhibitor

et al. 1999

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The Cdc25 dual speci®city phosphatase family has a central role in controlling cell cycle progression and has been implicated in the etiology of cancer. One compound, 4-(benzyl-(2-[(2, 5-diphenyl-oxazole-4-carbonyl)-amino]-ethyl)-carbamoyl)-2-decanoylamino butyric acid (SC-aad9), was previously identi®ed as the most potent reported synthetic inhibitor of Cdc25 phosphatases in vitro. In the present study, we demonstrate that SC-aad9 inhibited Cdc25-dependent cell cycle progression at both G1 and G2/M phase using tsFT210 cells, which express a temperature-sensitive Cdc2 mutant. SCaad9 blocked both G2/M transition and dephosphorylation of Cdc2 in a concentration-dependent manner. SCaad9 also enhanced tyrosine phosphorylation of both Cdk2 and Cdk4, and decreased Cdk4 kinase activity. Both of the kinases are potent regulators of G1 transition. Furthermore, closely related chemical analogs that lacked Cdc25 inhibitory activity failed to block cell cycle progression at both G1 and G2/M, and did not a ect Cdc2 phosphorylation or Cdk4 kinase activity. SC-aad9 did not alter p53, p21 or p16 levels. Our results support the hypothesis that the disruption in cell cycle transition caused by SC-aad9 was due to intracellular Cdc25 inhibition. We propose that the SC-aad9 pharmacophore could be useful in further clarifying the role of Cdc25 phosphatase-dependent pathways in checkpoint control, oncogenesis, and apoptosis.

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“…2). 10 Recently, our group reported the solid-phase synthesis and biological evaluation of a combinatorial library of small-molecule phosphatase inhibitors. 11,12 The library was structured around a pharmacophore (IV) designed with the aid of SAR available for the microcystins and calyculin A natural products (Fig.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of a targeted library of protein phosphatase inhibitors

Wipf

Aslan

Luci

et al. 2000

Biotechnol. Bioeng.

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Phosphorylation of serine, threonine, and tyrosine controls fundamental mammalian cell events and is achieved by kinases which, in turn, are in dynamic relationship with phosphatases. Few selective inhibitors of protein tyrosine and dual specificity phosphatases are readily available. Based on SAR studies of naturally occurring phosphatase inhibitors and following up on previously published research, we have designed a new pharmacophore model V and synthesized a new library of functional analogues of V. All synthetic steps were carried out and optimized employing combinatorial chemistry methods on Wang resin. All compounds were tested in vitro for their ability to inhibit recombinant human protein tyrosine (PTP1B) and dual‐specificity (Cdc25B2 and VHR) phosphatases. Three of the approximately 70 compounds in our library inhibited Cdc25B2 by 50% at 375–490 μM. No compounds inhibited PTP1B, and only one blocked VHR. Cell‐culture studies revealed no toxicity to human breast cancer cells with two of the phosphatase inhibitors. © 2000 John Wiley & Sons, Inc. Biotechnol Bioeng (Comb Chem) 71:58–70, 2000.

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Novel CDC25A Phosphatase Inhibitors from Pyrolysis of 3-α-Azido-B-homo-6-oxa-4-cholesten-7-one on Silica Gel

Cited by 24 publications

References 13 publications

Small molecule inhibitors of dual specificity protein phosphatases

Small molecule inhibitors of dual specificity protein phosphatases

Dual G1 and G2/M phase inhibition by SC-ααδ9, a combinatorially derived Cdc25 phosphatase inhibitor

Synthesis and biological evaluation of a targeted library of protein phosphatase inhibitors

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