SYNTHESIS AND CHARACTERIZATION OF FORSKOLIN DERIVATIVES

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Forskolin interacts with a number of membrane proteins that appear to be structurally similar. By modifying forskolin at different sites of the molecule, intermediates were synthesized that are stable, easily derivatized, and have high affinities for different membrane proteins. For example, 7-(2-aminoethyl)aminocarbonyl-forskolin (7-AEC-Fsk), shows high affinity for the glucose transporter. In contrast, 6-(2- aminoethyl)carbonylforskolin, 6-AEC-Fsk, has high affinity for adenylyl cyclase and does not interact with the glucose transporter. Iodinated derivatives of these intermediates were prepared and used as ligands for assaying binding to adenylyl cyclase or the glucose transporter. Radiolabeled ligands were prepared from the two intermediates to develop ligand binding assays for adenylyl cyclase and the glucose transporter. Another intermediate was prepared from forskolin, 1-deoxy-1-(2 aminoethyl)aminoforskolin, 1-AEC-1-deoxyforskolin, to make a radiolabeled ligand to assay bacterial pentose transporters. The bromoacetyl and isothiocyanate alkylating derivatives of 6-AEC-Fsk and 7-AEC-Fsk were prepared. Both bromoacetyl derivatives exhibited irreversible binding to adenylyl cyclase and not to the glucose transporter. The isothiocyanates showed similar specificity though were less potent than the bromoacetyl derivatives at adenylyl cyclase. The aminoethylcarbamate derivative of the anticancer drug estramustane was synthesized. This was used to synthesize an iodinated photoaffinity label to study the interaction of extramustane with microtubule proteins.