Basic hydrolysis was found to be appropriate for the removal of the N-protecting group. The spirocyclic compounds 6c– 13c were obtained by standard acid-catalyzed reaction with the corresponding diols for the formation of acetals 6c– 12c and propanedithiol for 13c, starting from N-acetyl-4-piperidone. The acetals 8a and 9a formed as mixtures of diastereomers, whereas compound 10a was enantiomerically and diastereomerically pure. All the new compounds, shown in Scheme 1, were obtained in enantiomerically pure form, with the stereogenic carbinol center adopting ( R) configuration.
#Bruker apex iii ii series
Therefore, an initial series of 4-aminopiperidines 2a– 4a and, in a second approach, new spirocyclic acetals 5a– 12a as well as the thioacetal 13a were synthesized. Thus, we replaced the piperazine motif in 1 by a piperidine ring carrying either nitrogen or oxygen as a hetero substituent(s) in the 4-position. Whereas biochemical studies with the novel compounds will be disclosed separately, we present in this article the synthesis, in detail, of twelve new compounds that may provide reversal of multidrug-resistant activity.Īs extended studies on modifications of zosuquidar ( 1a) had revealed both the 5-oxyquinoline and the hydroxypropane spacer as being crucial for inhibitory activity on P-glycoprotein, our strategy was based on modification or replacement of the dibenzosuberyl and the piperazine moieties, whereas the above-mentioned “southern part” of zosuquidar ( 1a) was planned to be maintained, including the absolute configuration of the stereogenic carbinol center. Thus, we synthesized, guided by the lead structure zosuquidar ( 1a), a series of compounds that were evaluated as potential inhibitors of LmrCD and Pdr5. Therefore, we were interested in developing inhibitors of efflux pumps from bacterial and fungal organisms, namely LmrCD from Lactococcus lactis and Pdr5 from Saccharomyces cerevisiae. Īpart from their role in multidrug resistance of tumor cells, ABC-type efflux pumps are also involved in multidrug resistance of pathogenic Gram-positive bacteria and fungi for which inhibitors have only rarely been studied. The drug zosuquidar ( 1a) emerged as the most promising among them however, so far it has not made its way into routine clinical application. These efforts were pursued for a longer period leading to a variety of small-molecular compounds with different structures that act as P-glycoprotein inhibitors. As P-glycoprotein is considered to be a major player in multidrug resistance and has been found to be over expressed in tumor cells, considerable attempts have been made to develop inhibitors of P-glycoprotein in order to reverse multidrug resistance. Among these multidrug-resistance ABC transporters, the P-glycoprotein has been investigated most intensively. Various transporters of the ATP-binding cassette family, so called ABC transporters, have been shown to be responsible for multidrug resistance. The treatment of cancer is often severely hampered by efflux pumps, which are responsible for the extrusion of various chemotherapeutics from the tumor cell, an effect termed “multidrug resistance”.
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