Structure-activity relationships and optimisation of the selective MDR modulator 2-(3,4-dimethoxyphenyl)-5-(9-fluorenylamino)-2-(methylethyl) pentanenitrile and its N-methyl derivative.
Several ring-substituted derivatives of previously studied MDR inhibitors 2-(3,4-dimethoxyphenyl)-5-(9-fluorenylamino)-2-(methylethyl)pentanenitrile and 2-(3,4-dimethoxyphenyl)-5-[(9-fluorenyl)-N-methylamino]-2-(methylethyl)pentanenitrile have been synthesised and studied with the aim of optimising activity and selectivity. The results show that MDR inhibition is scarcely sensitive to modulation of the electronic properties of the fluorene ring. Even if dramatic improvement was not obtained, one of the compounds (2) showed improved potency and selectivity with respect to the leads and appears to be a better candidate for drug development.
Dei
S
S
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Via Gino Capponi 9, 50121, Firenze, Italy.
Teodori
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E
Garnier-Suillerot
A
A
Gualtieri
F
F
Scapecchi
S
S
Budriesi
R
R
Chiarini
A
A
D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects; D002850:Chromatography, Gel; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005449:Fluorenes / Q000737:chemistry* / Q000494:pharmacology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D008956:Models, Chemical; D015394:Molecular Structure; D009200:Myocardial Contraction / Q000187:drug effects; D009570:Nitriles / Q000737:chemistry* / Q000494:pharmacology; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014665:Vasodilator Agents / Q000737:chemistry / Q000494:pharmacology
C437565:2-(3,4-dimethoxyphenyl)-5-((9-fluorenyl)-N-methylamino)-2-(methylethyl)pentanenitrile; C437564:2-(3,4-dimethoxyphenyl)-5-(9-fluorenylamino)-2-(methylethyl)pentanenitrile; D018943:Anthracyclines; D005449:Fluorenes; D009570:Nitriles; D014665:Vasodilator Agents; D004317:Doxorubicin; C027260:pirarubicin