Hormones and Mammary Carcinogenesis

Baseline separation of ten new, substituted [1-(imidazo-1-yl)-1-phenylmethyl)] benzothiazolinone and benzoxazolinone derivatives with one chiral center was achieved using cyclodextrin-capillary zone electrophoresis (CD-CZE). A method for the enantiomeric resolution of these compounds was developed using neutral CDs (native alpha-, beta-, gamma-CDs or alpha-, beta-, gamma-hydroxypropyl (HP)-CDs) as chiral selectors. Operational parameters including the nature and concentration of the chiral selectors, pH, ionic strength, organic modifiers, temperature, and applied voltage were investigated. The use of neutral CDs provides enantiomeric resolution by inclusion of compounds in the CD cavity. The HP-alpha-CD and HP-beta-CD were found to be the most effective complexing agents and allowed efficient enantiomeric resolutions. Optimal separation of N-imidazole derivatives was obtained using 50 mM phosphate buffer at pH 2.5 containing either HP-alpha-CD or HP-beta-CD (7.5-12.5 mM) at 25 degrees C, with an applied field of 0.50 kV.cm(-1) giving resolution factors Rs superior to 1.70 with migration times of the second enantiomer less than 13 min. The same enantiomer migration order observed for all molecules can be related to a close interaction mechanism with CDs. The influence of structural features of the solutes on Rs and tm was studied. The lipophilic character (log kw) of the solutes and the apparent and averaged association constants of inclusion complexes for four compounds with the six different CDs led us to rationalize the enantioseparation mechanisms. The conclusions were corroborated with reversed-phase high-performance liquid chromatography (HPLC) on chiral stationary phases (CSPs) based on CDs.

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“…Concerning the a-CD and HP-a-CD, binding constants (K 1 , respectively. Moreover, no enantioseparation is observed.…”

Section: Determination Of Apparent and Averaged Binding Constantsmentioning

confidence: 99%

Chiral separation of N‐imidazole derivatives, aromatase inhibitors, by cyclodextrin‐capillary zone electrophoresis. Mechanism of enantioselective recognition

et al. 2004

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“…1) [1] have been developed as inhibitors of P450 aromatase [2,3] and are useful in second-line therapy of estrogen-dependent breast cancer in postmenopausal women [4]. The need for clinical drugs with increased specificity, clinical efficiency, and tolerability remains a challenge in the development of new compounds [3,5] and lead us to synthesize new benzoxazolinone (1, 3, 5-10) and benzothiazolinone (2, 4) derivatives ( Fig. 1) [6,7] which present higher in vitro activities than fadrozole.…”

Section: Introductionmentioning

confidence: 99%

Enantioseparation of chiralN-imidazole derivatives by electrokinetic chromatography using highly sulfated cyclodextrins: Mechanism of enantioselective recognition

et al. 2005

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Baseline separation of ten new substituted [1-(imidazo-1-yl)-1-phenylmethyl)] benzothiazolinone and benzoxazolinone derivatives, with one chiral center, was achieved by CD-EKC using highly sulfated CDs (alpha, beta, gamma highly S-CDs) as chiral selectors. The influence of the type and concentration of the chiral selectors on the enantioseparations was investigated. The highly S-CDs exhibit a very high enantioselectivity power since they allow excellent enantiomeric resolutions compared to those obtained with the neutral CDs. The enantiomers were resolved with analysis times inferior to 2.5 min and resolution factors R(s) of 3.73, 3.90, 1.40, and 4.35 for compounds 1, 2, 3, and 5, respectively, using 25 mM phosphate buffer at pH 2.5 containing either highly S-alpha-CD, highly S-beta-CD, and highly S-gamma-CD (3 or 4% w/v) at 298 K, with an applied field of 0.30 kV/cm. The determination of the enantiomer migration order for the various analytes and the study of the analyte structure-enantioseparation relationships display the high contribution of the interactions between the analytes phenyl ring and the CDs to the enantiorecognition process. The thermodynamic study of the analyte-CD affinities permits us to improve our knowledge about the enantioseparation mechanism.

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“…Animal studies and clinical trials of anti-oestrogens and inhibitors of oestrogen biosynthesis have confirmed that oestrogens are the most important hormones involved in supporting growth of hormone-dependent breast cancers (Segaloff, 1978;Kirschner, 1979). Indeed, oestrogen deprivation by these means results in objective tumour regression.…”

mentioning

confidence: 97%

Intratumoral oestrone sulphatase activity as a prognostic marker in human breast carcinoma

Evans

Rowlands²,

Law³

et al. 1994

Br J Cancer

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Hormones and Mammary Carcinogenesis

Cited by 21 publications

References 28 publications

Chiral separation of N‐imidazole derivatives, aromatase inhibitors, by cyclodextrin‐capillary zone electrophoresis. Mechanism of enantioselective recognition

Chiral separation of N‐imidazole derivatives, aromatase inhibitors, by cyclodextrin‐capillary zone electrophoresis. Mechanism of enantioselective recognition

Enantioseparation of chiralN-imidazole derivatives by electrokinetic chromatography using highly sulfated cyclodextrins: Mechanism of enantioselective recognition

Intratumoral oestrone sulphatase activity as a prognostic marker in human breast carcinoma

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