title: Conformationally constrained analogues of diacylglycerol. 29. Cells sort diacylglycerol-lactone chemical zip codes to produce diverse and selective biological activities.
abstract: 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.
authors.affiliation: Laboratory of Medicinal Chemistry, National Cancer Institute at Frederick, National Institutes of Health, 376 Boyles Street, Frederick, Maryland 21702, USA.
authors.forename: Dehui
authors.initials: D
authors.lastname: Duan
authors.forename: Dina M
authors.initials: DM
authors.lastname: Sigano
authors.forename: James A
authors.initials: JA
authors.lastname: Kelley
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Lai
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lewin
authors.forename: Noemi
authors.initials: N
authors.lastname: Kedei
authors.forename: Megan L
authors.initials: ML
authors.lastname: Peach
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
authors.forename: Thushara P
authors.initials: TP
authors.lastname: Abeyweera
authors.forename: Susan A
authors.initials: SA
authors.lastname: Rotenberg
authors.forename: Hee
authors.initials: H
authors.lastname: Kim
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Kim
authors.forename: Saïd
authors.initials: S
authors.lastname: El Kazzouli
authors.forename: Jae-Uk
authors.initials: JU
authors.lastname: Chung
authors.forename: Howard A
authors.initials: HA
authors.lastname: Young
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Young
authors.forename: Alyson
authors.initials: A
authors.lastname: Baker
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Colburn
authors.forename: Adriana
authors.initials: A
authors.lastname: Haimovitz-Friedman
authors.forename: Jean-Philip
authors.initials: JP
authors.lastname: Truman
authors.forename: Damon A
authors.initials: DA
authors.lastname: Parrish
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Perry
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Surawski
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
mesh_terms: 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
chemical_list: C011439:1,2-diacylglycerol; D004075:Diglycerides; D007783:Lactones; D054852:Small Molecule Libraries; D051571:Protein Kinase C-alpha