Conformationally constrained analogues of diacylglycerol. 29. Cells sort diacylglycerol-lactone chemical zip codes to produce diverse and selective biological activities.
Diacylglycerol-lactone (DAG-lactone) libraries generated by a solid-phase approach using IRORI technology produced a variety of unique biological activities. Subtle differences in chemical diversity in two areas of the molecule, the combination of which generates what we have termed "chemical zip codes", are able to transform a relatively small chemical space into a larger universe of biological activities, as membrane-containing organelles within the cell appear to be able to decode these "chemical zip codes". It is postulated that after binding to protein kinase C (PKC) isozymes or other nonkinase target proteins that contain diacylglycerol responsive, membrane interacting domains (C1 domains), the resulting complexes are directed to diverse intracellular sites where different sets of substrates are accessed. Multiple cellular bioassays show that DAG-lactones, which bind in vitro to PKCalpha to varying degrees, expand their biological repertoire into a larger domain, eliciting distinct cellular responses.
Duan
Dehui
D
Laboratory of Medicinal Chemistry, National Cancer Institute at Frederick, National Institutes of Health, 376 Boyles Street, Frederick, Maryland 21702, USA.
Sigano
Dina M
DM
Kelley
James A
JA
Lai
Christopher C
CC
Lewin
Nancy E
NE
Kedei
Noemi
N
Peach
Megan L
ML
Lee
Jeewoo
J
Abeyweera
Thushara P
TP
Rotenberg
Susan A
SA
Kim
Hee
H
Kim
Young Ho
YH
El Kazzouli
Saïd
S
Chung
Jae-Uk
JU
Young
Howard A
HA
Young
Matthew R
MR
Baker
Alyson
A
Colburn
Nancy H
NH
Haimovitz-Friedman
Adriana
A
Truman
Jean-Philip
JP
Parrish
Damon A
DA
Deschamps
Jeffrey R
JR
Perry
Nicholas A
NA
Surawski
Robert J
RJ
Blumberg
Peter M
PM
Marquez
Victor E
VE
D001665:Binding Sites; D055598:Chemical Phenomena; D002621:Chemistry; D020650:Combinatorial Chemistry Techniques; D004075:Diglycerides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007783:Lactones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008968:Molecular Conformation; D011485:Protein Binding; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
C011439:1,2-diacylglycerol; D004075:Diglycerides; D007783:Lactones; D054852:Small Molecule Libraries; D051571:Protein Kinase C-alpha