We found that DAG-lactone libraries generated by a solid-phase approach produced a multitude 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 non-kinase target proteins containing diacylglycerol-responsive, membrane-interacting C1 domains, the resulting complexes are directed to diverse intracellular sites where different substrates are accessed. Multiple cellular bioassays show that DAG-lactones, which bind to PKC-alpha, expand their biological repertoire into a larger domain, eliciting distinct cellular responses (J. Med. Chem. 2008, 51, 5198-5220). Expanding on these findings and using the same diacylglycerol-lactone (DAG-lactone) template we discovered a series of novel DAG-lactones containing heterocyclic moieties (pyridines, quinolines and indoles) as alpha-arylidene fragments that show selective binding to RasGRP3 as compared to PKC-alpha by more than two orders of magnitude and with subnanomolar binding affinities (J. Med. Chem. 2008, 51, 5371-5386). Two compounds have been selected for submission to the JDC committee of the Molecular Targets Faculty for possible pre-clinical and clinical investigations. A study on the biophysical properties of some DAG-lactones carrying rigid oligo(p-phenyleneethynylene) acyl units exploring the thermodynamics and structural features of these compounds and their lipid interactions at the air/water interface suggest that the DAG-lactones are predominantly incorporated within fluid phospholipids phases rather than in condensed phases formed, for example, by cholesterol (Langmuir 2008, in press).
| Kang, Ji-Hye; Garg, Himanshu; Sigano, Dina M et al. (2009) Ceramides: branched alkyl chains in the sphingolipid siblings of diacylglycerol improve biological potency. Bioorg Med Chem 17:1498-505 |
| Comin, Maria J; Czifra, Gabriella; Kedei, Noemi et al. (2009) Conformationally constrained analogues of diacylglycerol (DAG). 31. Modulation of the biological properties of diacylgycerol lactones (DAG-lactones) containing rigid-rod acyl groups separated from the core lactone by spacer units of different lengths. J Med Chem 52:3274-83 |
