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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.

SUBMITTER: Duan D

PROVIDER: S-EPMC2574997 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Conformationally constrained analogues of diacylglycerol. 29. Cells sort diacylglycerol-lactone chemical zip codes to produce diverse and selective biological activities.

Duan Dehui D 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

Journal of medicinal chemistry 20080813 17

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 "chem ...[more]

PMID: 18698758

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Project description:Photosynthetic reaction centers convert excitation energy from absorbed sunlight into chemical potential energy in the form of a charge-separated state. The rates of the electron transfer reactions necessary to achieve long-lived, high-energy charge-separated states with high quantum yields are determined in part by precise control of the electronic coupling among the chromophores, donors, and acceptors and of the reaction energetics. Successful artificial photosynthetic reaction centers for solar energy conversion have similar requirements. Control of electronic coupling in particular necessitates chemical linkages between active component moieties that both mediate coupling and restrict conformational mobility so that only spatial arrangements that promote favorable coupling are populated. Toward this end, we report the synthesis, structure, and photochemical properties of an artificial reaction center containing two porphyrin electron donor moieties and a fullerene electron acceptor in a macrocyclic arrangement involving a ring of 42 atoms. The two porphyrins are closely spaced, in an arrangement reminiscent of that of the special pair in bacterial reaction centers. The molecule is produced by an unusual cyclization reaction that yields mainly a product with C(2) symmetry and trans-2 disubstitution at the fullerene. The macrocycle maintains a rigid, highly constrained structure that was determined by UV-vis spectroscopy, NMR, mass spectrometry, and molecular modeling at the semiempirical PM6 and DFT (B3LYP/6-31G**) levels. Transient absorption results for the macrocycle in 2-methyltetrahydrofuran reveal photoinduced electron transfer from the porphyrin first excited singlet state to the fullerene to form a P(•+)-C(60)(•-)-P charge separated state with a time constant of 1.1 ps. Photoinduced electron transfer to the fullerene excited singlet state to form the same charge-separated state has a time constant of 15 ps. The charge-separated state is formed with a quantum yield of essentially unity and has a lifetime of 2.7 ns. The ultrafast charge separation coupled with charge recombination that is over 2000 times slower is consistent with a very rigid molecular structure having a small reorganization energy for electron transfer, relative to related porphyrin-fullerene molecules.

Dataset Information

Conformationally constrained analogues of diacylglycerol. 29. Cells sort diacylglycerol-lactone chemical zip codes to produce diverse and selective biological activities.

Publications

Conformationally constrained analogues of diacylglycerol. 29. Cells sort diacylglycerol-lactone chemical zip codes to produce diverse and selective biological activities.

Similar Datasets

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