Synthesis of a library of 3-oxopiperazinium and perhydro-3-oxo-1,4-diazepinium derivatives and identification of bioactive compounds.
The design and synthesis of a library of novel families of 3-oxopiperazinium and perhydro-3-oxo-1,4-diazepinium derivatives is reported. The library was composed of 44 3-oxopiperazinium derivatives (11 of these compounds had a spiranic skeleton) and 22 perhydro-3-oxo-1,4-diazepinium compounds. The synthetic procedure involved a 6-step sequence carried out in solution, along with the use of solid-phase linked scavengers and microwave activation for the rapid removal of the excess of amine reagents. A final cyclization step performed under mild conditions led to the charged heterocyclic moiety. Screening of this library in two biological assays identified active compounds that inhibit the activity of the vanilloid receptor TRPV1 and modulators of the multidrug resistance phenomenon. Thus, this synthetic sequence represents a facile and convenient entry to unprecedented libraries of this sort of tetraalkylammonium derivatives that may be of use for identification of novel scaffolds of diverse biological activity.
Masip
Isabel
I
Department of Biological Organic Chemistry, IIQAB, CSIC. J. Girona, 18, 08034 Barcelona, Spain. ampqob@iiqab.csic.es
Ferrándiz-Huertas
Clotilde
C
García-Martínez
Carolina
C
Ferragut
José A
JA
Ferrer-Montiel
Antonio
A
Messeguer
Angel
A
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques; D003500:Cyclization; D003630:Daunorubicin / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D019450:Genes, MDR / Q000187:drug effects*; D006801:Humans; D007202:Indicators and Reagents; D007473:Ion Channels / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009865:Oocytes; D018408:Patch-Clamp Techniques; D051381:Rats; D011955:Receptors, Drug / Q000037:antagonists & inhibitors*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D014981:Xenopus
D000903:Antibiotics, Antineoplastic; D001381:Azepines; D007202:Indicators and Reagents; D007473:Ion Channels; D011955:Receptors, Drug; D003630:Daunorubicin