title: Novel amide- and sulfonamide-based aromatic ethanolamines: effects of various substituents on the inhibition of acid and neutral ceramidases.
abstract: In the present study we describe the design and synthesis of a series of amide- and sulfonamide-based compounds as inhibitor of recombinant acid and neutral ceramidases. Inhibition of ceramidases has been shown to induce apoptosis and to increase the efficacy of conventional chemotherapy in several cancer models. B-13, lead in vitro inhibitor of acid ceramidase has been recently shown to be virtually inactive towards lysosomal acid ceramidase in living cells at lower concentrations and for a shorter time of treatment, suggesting the development of more potent inhibitors. In this study, a detailed SAR investigation has been performed to understand the effect of different substituents on the phenyl ring of amide- and sulfonamide-based compounds that partially resemble the structure of well-known inhibitors such as B-13, D-e-MAPP as well as NOE. Our results suggest that the electronic effects of the substituents on phenyl ring in B-13 and D-e-MAPP analogues have negligible effects either in enhancing the inhibition potencies or for selectivity towards aCDase over nCDase. However, the hydrophobicity and the steric effects of longer alkyl chains (n-Pr, n-Bu or t-Bu groups) at the phenyl ring were found to be important for an enhanced selectivity towards aCDase over nCDase.
authors.affiliation: Humboldt Universität zu Berlin, Institute for Chemistry, Brook-Taylor-Str. 2, 12489 Berlin, Germany.
authors.forename: Krishna P
authors.initials: KP
authors.lastname: Bhabak
authors.forename: Christoph
authors.initials: C
authors.lastname: Arenz
mesh_terms: D055573:Acid Ceramidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000577:Amides / Q000737:chemistry*; D004983:Ethanolamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D055576:Neutral Ceramidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*
chemical_list: D000577:Amides; D004983:Ethanolamines; D011994:Recombinant Proteins; D013449:Sulfonamides; D055573:Acid Ceramidase; D055576:Neutral Ceramidase