Polymer-assisted solution-phase synthesis and neurite-outgrowth-promoting activity of 15-deoxy-delta(12,14)-PGJ2 derivatives.
An efficient solution-phase synthesis of rac-15-deoxy-delta(12,14)-PGJ2 (15dPGJ2) derivatives that contain variable alpha and omega chains based on a polymer-assisted strategy and their neurite-outgrowth-promoting activity are described. The strategy for the synthesis of PGJ2 derivatives involves the use of a vinyl iodide bearing cyclopentenone as a key intermediate, which undergoes Suzuki-Miyaura coupling and subsequent Lewis acid catalyzed aldol condensation for incorporation of the omega and alpha chains, respectively. For easy access to the PGJ2 derivatives, a polymer-supported catalyst and scavengers were adapted for use in these four diverse steps, in which workup and purification can be performed by simple filtration of the solid-supported reagents. By using this methodology, we succeeded in the synthesis of 16 PGJ2 derivatives with four alkyl boranes and four aldehydes. The neurite-outgrowth-promoting activity of the 16 synthetic compounds in PC12 cells revealed that the side-chains play a major role in modulating their biological activity. The carboxylic acid on the alpha chain improved the biological activity, although it was not absolutely required. Furthermore, a PGJ2 derivative with a phenyl moiety on the omega chain was found to exhibit an activity comparable to that of natural 15dPGJ2.
Tanaka
Hiroshi
H
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro, Tokyo 152-8552, Japan.
Hasegawa
Tsuyoshi
T
Kita
Narumi
N
Nakahara
Hiroko
H
Shibata
Takahiro
T
Oe
Sho
S
Ojika
Makoto
M
Uchida
Koji
K
Takahashi
Takashi
T
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D008858:Microscopy, Phase-Contrast; D015394:Molecular Structure; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D016716:PC12 Cells; D011108:Polymers / Q000737:chemistry*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012996:Solutions; D013329:Structure-Activity Relationship
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D011108:Polymers; D012996:Solutions; D015230:Prostaglandin D2