Synthesis of the novel analogues of dysidiolide and their structure–activity relationship

Takahashi, Masato; Dodo, Kosuke; Sugimoto, Yoshikazu; Aoyagi, Yoshimi; Yamada, Yuji; Hashimoto, Yuichi; Shirai, Ryuichi

doi:10.1016/s0960-894x(00)00527-8

Cited by 65 publications

(35 citation statements)

References 11 publications

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“…Cdc25A and Cdc25B have also been shown to be overexpressed in several types of cancer cells (43)(44)(45)(46)(47)(48)(49)(50). Importantly, it has also been shown that treatment of tumor cell lines with Cdc25 inhibitors inhibits tumor growth or causes cell cycle arrest (15,16,(51)(52)(53), which validates Cdc25 as a drug target and makes inhibitors of Cdc25 very valuable. It has been known for some time that suramin treatment increases the tyrosine phosphorylation levels of Cdc2, a cyclin-dependent kinase responsible for initiation of mitosis (54).…”

Section: Resultsmentioning

confidence: 94%

Suramin Derivatives as Inhibitors and Activators of Protein-tyrosine Phosphatases

McCain

Nickel

et al. 2004

Journal of Biological Chemistry

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Protein-tyrosine phosphatases (PTPs) are important signaling enzymes that have emerged within the last decade as a new class of drug targets. It has previously been shown that suramin is a potent, reversible, and competitive inhibitor of PTP1B and Yersinia PTP (YopH). We therefore screened 45 suramin analogs against a panel of seven PTPs, including PTP1B, YopH, CD45, Cdc25A, VHR, PTP␣, and LAR, to identify compounds with improved potency and specificity. Of the 45 compounds, we found 11 to have inhibitory potency comparable or significantly improved relative to suramin. We also found suramin to be a potent inhibitor (IC 50 ‫؍‬ 1.5 M) of Cdc25A, a phosphatase that mediates cell cycle progression and a potential target for cancer therapy. In addition we also found three other compounds, NF201, NF336, and NF339, to be potent (IC 50 < 5 M) and specific (at least 20 -30-fold specificity with respect to the other human PTPs tested) inhibitors of Cdc25A. Significantly, we found two potent and specific inhibitors, NF250 and NF290, for YopH, the phosphatase that is an essential virulence factor for bubonic plague. Two of the compounds tested, NF504 and NF506, had significantly improved potency as PTP inhibitors for all phosphatases tested except for LAR and PTP␣. Surprisingly, we found that a significant number of these compounds activated the receptor-like phosphatases, PTP␣ and LAR. In further characterizing this activation phenomenon, we reveal a novel role for the membrane-distal cytoplasmic PTP domain (D2) of PTP␣: the direct intramolecular regulation of the activity of the membrane-proximal cytoplasmic PTP domain (D1). Binding of certain of these compounds to PTP␣ disrupts D1-D2 basal state contacts and allows new contacts to occur between D1 and D2, which activates D1 by as much as 12-14-fold when these contacts are optimized.

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Section: Resultsmentioning

confidence: 94%

Suramin Derivatives as Inhibitors and Activators of Protein-tyrosine Phosphatases

McCain

Nickel

et al. 2004

Journal of Biological Chemistry

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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%

Small molecule inhibitors of dual specificity protein phosphatases

et al. 2000

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“…Indolyldihydroxiquinones have been shown to effectively compete with CDC25 substrate in vitro and to inhibit cell proliferation (23). A few other products such as the steroidal derivative dithiocarboxy cholestanol (24) and natural products such as dysidiolide have also been reported to inhibit CDC25 activity in vitro and to cause inhibition of HL60 cell proliferation (25,26).…”

Section: Introductionmentioning

confidence: 99%

A Novel Synthetic Inhibitor of CDC25 Phosphatases

et al. 2004

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CDC25 dual-specificity phosphatases are essential regulators that dephosphorylate and activate cyclin-dependent kinase/cyclin complexes at key transitions of the cell cycle. CDC25 activity is currently considered to be an interesting target for the development of new antiproliferative agents. Here we report the identification of a new CDC25 inhibitor and the characterization of its effects at the molecular and cellular levels, and in animal models.BN82002 inhibits the phosphatase activity of recombinant human CDC25A, B, and C in vitro. It impairs the proliferation of tumoral cell lines and increases cyclin-dependent kinase 1 inhibitory tyrosine phosphorylation. In synchronized HeLa cells, BN82002 delays cell cycle progression at G 1 -S, in S phase and at the G 2 -M transition. In contrast, BN82002 arrests U2OS cell cycle mostly in the G 1 phase. Selectivity of this inhibitor is demonstrated: (a) by the reversion of the mitotic-inducing effect observed in HeLa cells upon CDC25B overexpression; and (b) by the partial reversion of cell cycle arrest in U2OS expressing CDC25. We also show that BN82002 reduces growth rate of human tumor xenografts in athymic nude mice.BN82002 is a original CDC25 inhibitor that is active both in cell and animal models. This greatly reinforces the interest in CDC25 as an anticancer target.

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Synthesis of the novel analogues of dysidiolide and their structure–activity relationship

Cited by 65 publications

References 11 publications

Suramin Derivatives as Inhibitors and Activators of Protein-tyrosine Phosphatases

Suramin Derivatives as Inhibitors and Activators of Protein-tyrosine Phosphatases

Small molecule inhibitors of dual specificity protein phosphatases

A Novel Synthetic Inhibitor of CDC25 Phosphatases

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