Stereoselective synthesis and structure-activity relationship of novel ceramide trafficking inhibitors. (1R,3R)-N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide and its analogues.
New ceramide trafficking inhibitors, (1R,3R)-N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide (HPA-12) and a series of its analogues, were synthesized in diastereomerically and enantiomerically pure forms, and the structure-activity relationship was investigated. These analogues were stereoselectively synthesized via catalytic enantioselective Mannich-type reactions using a Cu(II)-chiral diamine 4 complex. Analysis of HPA-12 analogues having various lengths of the amide side chain showed that the optimal chain length for the inhibition of sphingomyelin biosynthesis is 13 with an IC(50) of approximately 50 nM. Masking of the hydroxy group at the 2'- or 3-position of HPA-12 was carried out by methylation, and it was revealed that these hydroxy groups were essential for the activity. Installation of another hydroxy group onto HPA-12 at the same position as that in the natural ceramide was also conducted, but no enhancement of the activity was observed.
Nakamura
Yoshitaka
Y
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyou-ku, Tokyo 113-0033, Japan.
Matsubara
Ryosuke
R
Kitagawa
Hidetoshi
H
Kobayashi
Shū
S
Kumagai
Keigo
K
Yasuda
Satoshi
S
Hanada
Kentaro
K
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D016466:CHO Cells; D002518:Ceramides / Q000378:metabolism*; D006224:Cricetinae; D013109:Sphingomyelins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D002518:Ceramides; C441643:N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide; D013109:Sphingomyelins