Nitrostyrene Derivatives of Adenosine 5′‐Glutarates as Selective Inhibitors of the Epidermal Growth Factor Receptor Protein Tyrosine Kinase

Peterli, S.; Stumpf, R.; Schweizer, Marc; Séquin, Urs; Mett, Helmut; Traxler, Peter

doi:10.1002/hlca.19920750304

Cited by 13 publications

(11 citation statements)

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“…The naturally occurring genistein was found to have the most potent dose-dependent effect, even compared to synthetic isoflavones synthesized particularly for their possible growth inhibitory effects. The isoflavones 1, 2, 4, 5, 7, 9 and the ketone 3 (the synthetic precursor of 4 and 5) were synthesized as structural analogues of the naturally occurring genistein and biochanin A. Genistein is a known PTK inhibitor (Peterli et al, 1992) and biochanin A is a non-specific inhibitor of protein kinases (Wang et al, 1997). The oxygenation pattern on the phenyl ring was altered to discover whether simple isomeric alteration (1, 2, 4, 5) or extra methoxylation (7, 9) would affect the biochemistry of the isoflavones.…”

Section: Discussionmentioning

confidence: 99%

Isoflavones inhibit intestinal epithelial cell proliferation and induce apoptosis in vitro

et al. 1999

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The incidence of intestinal cancer is high in Western populations but is relatively uncommon in Asia and Africa (Boyle et al, 1985). It is thought that this variation in incidence is strongly influenced by diet (Armstrong and Doll, 1975;Adlercreutz, 1990) and it is estimated that about 32% of deaths by all cancers, and 70% of deaths from colorectal cancer, could be prevented by a change in diet (Willet, 1995). There is also evidence to suggest that a high intake of soya-based foods (as in populations of Southeast Asia) could contribute to a reduced incidence of mammary (Lee et al, 1995) and prostate (Severson et al 1989) cancer.Soya beans are an abundant source of the isoflavones genistein, daidzein and glyceitin (Wang and Murphy, 1994). These diphenol molecules are structurally similar to the steroidal oestrogens and thus, have been termed phyto-oestrogens. Due to this similarity, attention has focused on the role of phyto-oestrogens in preventing both hormonally mediated (particularly breast) and hormonally independent cancers. Soya metabolites may reduce the risk of colon cancers (Messina et al, 1994). Genistein in particular possesses several anti-tumorigenic activities in vitro, including inhibition of angiogenesis (Fotsis et al, 1993), topoisomerase (Okura et al, 1988) and tyrosine kinase (Ogawara et al, 1989) activity, in addition to having antioxidant properties (Wei et al, 1993). Experiments using colon cancer cell lines have shown that genistein, and the related isoflavone biochanin A, can inhibit cell proliferation and induce apoptosis (Yanagihara et al, 1993;Kuo, 1996), again implying protective effects.No data are available to demonstrate the effects of isoflavones on normal intestinal cell lines. In this study we aimed to investigate the proliferative and apoptotic effects of genistein in vitro on normal intestinal epithelial cells and compare these to the effects on malignant cell lines. We also aimed to examine the effects of some novel isoflavones, which have been synthesized primarily as specific tyrosine kinase inhibitors, upon the same cell lines. The effects of these isoflavones are compared with the effects of oestradiol, the anti-oestrogen tamoxifen, and the specific tyrosine kinase inhibitor, tyrphostin. MATERIALS AND METHODS Cell culture methodsIEC18 and IEC6 cells, related clones isolated from normal neonatal rat small intestine, were originally obtained from A Quaroni (Quaroni and May, 1980). In all assays these lines were used below passage 20. SW620 and HT29 human colon adenocarcinoma lines were obtained from the English Tissue Culture Collection (ETCC, Porton Down, Wilts, UK). All cells were maintained and passaged in Dulbecco's modified Eagles medium (DMEM) (GibcoBRL, Paisley, UK) containing 5% fetal calf serum (FCS) (Sigma, Poole, UK), 0.25 U ml -1 insulin (Hypurin, Fisons, Loughborough, UK), 100 U ml -1 penicillin and 30 µg ml -1 streptomycin (all Sigma, Poole, UK). Charcoal-stripped FCS, phenol red free DMEM, genistein, biochanin A, oestradiol, tamoxifen and tyrphostin 25 were a...

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Section: Discussionmentioning

confidence: 99%

Isoflavones inhibit intestinal epithelial cell proliferation and induce apoptosis in vitro

et al. 1999

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“…The P-nitrostyrene derivative 24 used as tyrosine mimic was found to be a moderately potent inhibitor of the EGF-R PTK [13]. No significant increase of kinase inhibition was observed when the glutaryl moiety was added to the nitrostyrene unit [14]. Thus, the acid 25 showed an IC,, value comparable to that of the parent compound 24 [14].…”

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confidence: 85%

“…Based on this transition-state, multisubstrate-complex analogues were designed that contained a P-nitrostyrene part as a tyrosine mimic, the sulfonylbenzoyl or the glutaryl ( = pentanedioyl) moiety as the triphosphate substitute, and adenosine as nucleoside [13] [ 141. The thus obtained transition-state analogues were highly potent bisubstrate-type inhibitors of the EGF-R PTK (IC,, = 0.7 p~) and showed selectivity with respect to other PTK's such as c-src or v-abl as well as to serine kinases such as protein kinase C (PKC) or cyclic AMP-dependent protein kinase (PKA) [14].…”

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“…When we started our work using the glutaryl moiety as a triphosphate substitute [14], no crystal structure data on either a serine or a tyrosine kinase were available. we used was derived from NMR NOE measurements using the protein kinase PKA.…”

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“…-Starting from 4-hydroxybenzaldehyde (l), the chain-elongated aldehydes 2-4 were prepared by base-catalyzed reaction with 2-chloroethanol (5), 3-chloropropanol (6), and 4-chlorobutanol (7), respectively, following a procedure by Stoddart and coworkers [ 161 (Scheme I ). Starting from benzene-l,6dicarbaldehyde (8), [14]. The free acids 19 and 20 were synthesized by reaction of the corresponding nitrostyrenes 11 and 13 with glutaric anhydride following our previously published procedure [ 141.…”

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Nitrostyrene Derivatives of Adenosine 5′‐Glutarates Modified with an Alkyl Spacer and their inhibitory activity on epidermal growth factor receptor protein tyrosine kinase

Peterli

Hubmann

Séquin

et al. 1994

Helvetica Chimica Acta

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B-Nitrostyrene derivatives of adenosine 5'-glutarates are potent and selective bisubstrate-type inhibitors of the epidermal growth factor receptor protein tyrosine kinase (EGF-R PTK). In an attempt to improve the inhibitory activity, this type of compounds was modified with alkyl spacers of varying length between the nitrostyrene and the glutaryl units. The spacers consisted of 1, 3,4, and 5 atoms to give compounds of the benzyl, oxyethyl, oxypropyl, and oxybutyl series, respectively (Schemes 1 and 2). Adenosine 5'-esters were prepared in the benzyl and oxypropyl series only. Compared to the compounds in the parent series without spacer (ICs0 = 0.7-12 p~) , most of the modified compounds inhibited the EGF-R PTK only marginally or were inactive (K5, 2 100 VM). The only exceptions were the free acids 19 and 20 with IC,, values of ca. 5 PM. It is noteworthy that esterification of these two hydrogen glutarates with either MeOH or adenosine yielded inactive compounds, which is in contrast to the corresponding substances without spacers.

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Organische Synthese und biologische Signaltransduktion

Hinterding¹,

Alonso-Díaz²,

Waldmann³

1998

Angewandte Chemie

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Das Verständnis zellulärer Kommunikationswege im molekularen Detail ist ein wichtiges Ziel bioorganischer Forschung. Die Synthese von Wirkstoffanaloga (z. B. 1) zum Studium der Regulation der Muskelkontraktion oder die spezifische Lipidmodifizierung repräsentativer Peptide (→2) zur Untersuchung ihrer subzellulären Adressierung zu intrazellulären Membranen – dies sind Beispiele für die Leistungsfähigkeit der organischen Synthese bei der Erforschung biologischer Signaltransduktionsmechanismen.

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Nitrostyrene Derivatives of Adenosine 5′‐Glutarates as Selective Inhibitors of the Epidermal Growth Factor Receptor Protein Tyrosine Kinase

Cited by 13 publications

References 19 publications

Isoflavones inhibit intestinal epithelial cell proliferation and induce apoptosis in vitro

Isoflavones inhibit intestinal epithelial cell proliferation and induce apoptosis in vitro

Nitrostyrene Derivatives of Adenosine 5′‐Glutarates Modified with an Alkyl Spacer and their inhibitory activity on epidermal growth factor receptor protein tyrosine kinase

Organische Synthese und biologische Signaltransduktion

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