Synthesis and cytotoxicity of shikimate analogues. Structure

Activity studies based on 1-crotonyloxymethyl-3R,4R,5R-trihydroxycyclohex-2-enone

O. Aghil, M. C. Bibby, S. J. Carrington, J. Double, K. T. Douglas, R. M. Phillips, Tony Kung Ming Shing

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Syntheses are described for and structure:activity studies undertaken of the anti-tumour activity of (2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone) (1) and its analogues 1-crotonyloxymethyl-(3R,4S,5R) -3,4,5-trihydroxycyclohex-1-ene (3), 1-crotonyloxymethyl- (3R,4S,5S)-3,4,5-trihydroxycyclohexene (4) and 2-crotonyloxymethyl-2-cyclohexenone (5), which differ from 1 in the presence/absence of the cyclic keto group and/or the stereochemistry at one of the -OH bearing carbon atoms. None of the above compounds, including 1, directly inhibited glyoxalase I,isolated for the first time to homogeneity from rat Yoshida sarcomas and for which a purification protocol was developed. The apparent inhibition of glyoxalase 1 by 1 and 5 (but not detected for 4 or 3) could be explained by reaction of 1 and 5 with the glutathione present in the assay buffer and the consequent depletion of substrate. 1 and 5 were found to react readily with glutathione whereas 4 and 3 did not react. In vitro chemosensitivity studies against a panel of tumour cell lines of both mouse and human origin showed that in parallel with their thiol reactivity, 1 and 5 exhibited significant in vitro cytotoxicity whereas 4 and 3 did not. Concentrations of drug required to cause 50% cell kill (ID50 values) were in the range 0.5-19 μM (0.1-2.8 μg/ml) for 5, and 3-44 μM (0.7-10 μg/ml) for 1. The structural features causing the differences in antitumour effects were localized on this basis to the α,β- unsaturated ketone linkage as opposed to the stereochemistry of the (trihydroxy) alcoholic sites.

Original languageEnglish
Pages (from-to)67-82
Number of pages16
JournalAnti-Cancer Drug Design
Volume7
Issue number1
Publication statusPublished - 1992 Jan 1
Externally publishedYes

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Stereochemistry
Cytotoxicity
Glutathione
Tumors
Bearings (structural)
Lactoylglutathione Lyase
Yoshida Sarcoma
Tumor Cell Line
Ketones
Sulfhydryl Compounds
Purification
Rats
Assays
Buffers
Carbon
Cells
Atoms
Substrates
Pharmaceutical Preparations
Neoplasms

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Organic Chemistry
  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Aghil, O., Bibby, M. C., Carrington, S. J., Double, J., Douglas, K. T., Phillips, R. M., & Shing, T. K. M. (1992). Synthesis and cytotoxicity of shikimate analogues. Structure: Activity studies based on 1-crotonyloxymethyl-3R,4R,5R-trihydroxycyclohex-2-enone. Anti-Cancer Drug Design, 7(1), 67-82.

Synthesis and cytotoxicity of shikimate analogues. Structure : Activity studies based on 1-crotonyloxymethyl-3R,4R,5R-trihydroxycyclohex-2-enone. / Aghil, O.; Bibby, M. C.; Carrington, S. J.; Double, J.; Douglas, K. T.; Phillips, R. M.; Shing, Tony Kung Ming.

In: Anti-Cancer Drug Design, Vol. 7, No. 1, 01.01.1992, p. 67-82.

Research output: Contribution to journalArticle

Aghil, O, Bibby, MC, Carrington, SJ, Double, J, Douglas, KT, Phillips, RM & Shing, TKM 1992, 'Synthesis and cytotoxicity of shikimate analogues. Structure: Activity studies based on 1-crotonyloxymethyl-3R,4R,5R-trihydroxycyclohex-2-enone', Anti-Cancer Drug Design, vol. 7, no. 1, pp. 67-82.
Aghil, O. ; Bibby, M. C. ; Carrington, S. J. ; Double, J. ; Douglas, K. T. ; Phillips, R. M. ; Shing, Tony Kung Ming. / Synthesis and cytotoxicity of shikimate analogues. Structure : Activity studies based on 1-crotonyloxymethyl-3R,4R,5R-trihydroxycyclohex-2-enone. In: Anti-Cancer Drug Design. 1992 ; Vol. 7, No. 1. pp. 67-82.
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abstract = "Syntheses are described for and structure:activity studies undertaken of the anti-tumour activity of (2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone) (1) and its analogues 1-crotonyloxymethyl-(3R,4S,5R) -3,4,5-trihydroxycyclohex-1-ene (3), 1-crotonyloxymethyl- (3R,4S,5S)-3,4,5-trihydroxycyclohexene (4) and 2-crotonyloxymethyl-2-cyclohexenone (5), which differ from 1 in the presence/absence of the cyclic keto group and/or the stereochemistry at one of the -OH bearing carbon atoms. None of the above compounds, including 1, directly inhibited glyoxalase I,isolated for the first time to homogeneity from rat Yoshida sarcomas and for which a purification protocol was developed. The apparent inhibition of glyoxalase 1 by 1 and 5 (but not detected for 4 or 3) could be explained by reaction of 1 and 5 with the glutathione present in the assay buffer and the consequent depletion of substrate. 1 and 5 were found to react readily with glutathione whereas 4 and 3 did not react. In vitro chemosensitivity studies against a panel of tumour cell lines of both mouse and human origin showed that in parallel with their thiol reactivity, 1 and 5 exhibited significant in vitro cytotoxicity whereas 4 and 3 did not. Concentrations of drug required to cause 50{\%} cell kill (ID50 values) were in the range 0.5-19 μM (0.1-2.8 μg/ml) for 5, and 3-44 μM (0.7-10 μg/ml) for 1. The structural features causing the differences in antitumour effects were localized on this basis to the α,β- unsaturated ketone linkage as opposed to the stereochemistry of the (trihydroxy) alcoholic sites.",
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