Structure-activity analysis of 2'-modified cinnamaldehyde analogues as potential anticancer agents.
The natural product 2'-hydroxycinnamaldehyde (HCA) and its analogue, 2'-benzoyloxycinnamaldehyde (BCA), have been previously shown to have antiproliferative and proapoptotic effects in vitro and inhibit tumor growth in vivo. In this study, we use structure-activity analysis to define structural features that are important for the activity of cinnamaldehyde analogues. Our results emphasize an important role for both the propenal group as well as the modification at the 2'-position. Further studies were aimed to characterize the mechanism of action of BCA. Exposure to BCA induced cell death via caspase-dependent and -independent pathways. Cell death was not due to autophagy or necrosis as a result of energy depletion or induction of reactive oxygen species. Our findings have important implications for future drug design and highlight the importance of defining molecular drug targets for this promising class of potential anticancer agents.
Gan
Fei Fei
FF
Department of Biochemistry, National University of Singapore, Singapore.
Chua
Yee Shin
YS
Scarmagnani
Silvia
S
Palaniappan
Puvithira
P
Franks
Mark
M
Poobalasingam
Thurka
T
Bradshaw
Tracey D
TD
Westwell
Andrew D
AD
Hagen
Thilo
T
D000171:Acrolein / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy; D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
C484327:2'-benzoyloxycinnamaldehyde; D000972:Antineoplastic Agents, Phytogenic; D001565:Benzoates; D002934:Cinnamates; C117045:p-hydroxycinnamaldehyde; D000171:Acrolein; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C012843:cinnamaldehyde