(3Z)-2-Acetylamino-3-octadecen-1-ol as a potent apoptotic agent against HL-60 cells.
(2R,3Z)-, (2R,3E)-, (2S,3Z) and (2S,3E)-2-Acetylamino-3-octadecen-1-ol, and (2R)- and (2S)-2-acetylamino-octadecan-1-ol were prepared using the Wittig olefination of Garner's aldehyde (N-Boc-N,O-isopropylidene-L- or D-serinal) from L- or D-serine. The apoptotic activities of these saturated and unsaturated 2-acetylaminoalcohols were examined in human leukemia HL-60 cells using MTT assay. Among the newly synthesized compounds, the cis-isomers were the most potent. Despite their simple structures, (2R,3Z)- and (2S,3Z)-2-acetylamino-3-octadecen-1-ol showed high and comparable apoptotic activities compared with N-acetyl-D-erythro-sphingosine (D-e-C2-Cer, a well-known inducer of apoptosis). Their apoptotic activities were in the order D-e-C2-Cer approximately L-e-C2-Cer approximately (2R,3Z)- approximately (2S,3Z)->>(2R,3E)- approximately (2S,3E)- approximately (2R)- approximately (2S)-derivative. Qualitative analysis of DNA fragmentation caused by these compounds was conducted using agarose gel electrophoresis, and typical DNA fragmentation was found in the cases of (2R,3Z)- and (2S,3Z)-isomers such as C2-Cer, but not trans and saturated isomers. The morphological features of the cells, the proteolytic processing of pro-caspase-3, and the cleavage of PARP as a result of exogenous treatment with (2R,3Z)- and (2S,3Z)-isomers indicated that cell death induced by these compounds was apoptosis. These observations suggest that these newly synthesized compounds, (3Z)-2-Acetylamino-3-octadecen-1-ol, have similar characteristics and apoptosis-inducing activities against HL-60 cells with C2-Cer.
Niiro
Hayato
H
Department of Applied & Bioapplied Chemistry, Graduate School of Engineering, Osaka City University, Sugimoto 3-3-138, Sumiyoshi-ku, 558-8585, Osaka, Japan.
Azuma
Hideki
H
Tanago
Shinsuke
S
Matsumura
Kiyohiro
K
Shikata
Keiji
K
Tachibana
Taro
T
Ogino
Kenji
K
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D018922:HL-60 Cells; D006801:Humans; D009829:Oleic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism
D000970:Antineoplastic Agents; C064769:N-acetylsphingosine; D009829:Oleic Acids; D013110:Sphingosine