General and stereospecific route to 9-substituted, 8,9-disubstituted, and 9,10-disubstituted analogues of benzolactam-V8

Article abstract of DOI:10.1021/jo990605h

Nitration of the L-tyrosine derivative 9 provides the 3-nitro compound 13, which is converted into amide 15 by reduction and protection. Nitration of 15 either ortho or para to the acetamido group gives 16 and 17. After reduction of the nitro group, the anilines 21b and 29b are coupled with triflate 22a, and then cyclized to afford lactams 24 and 31, respectively. By means of a Pd-catalyzed coupling reaction, 8-acetamido-9-decynylbenzolactam- V8 (26) and 9-decynyl-10-acetamidobenzolactam-V8 (33) are obtained. The regioisomers 16 and 17 are transformed into a single isomer, 34, which is converted into 9-decynylbenzolactam-V8 (4). The K(i) values for 4, 26, and 33 to displace PDBU binding from recombinant PKCα (PKC = protein kinase C) are about 6, 173, and 46 nM. These results demonstrate that while the introduction of a substituent at either the 8- or 10-position of the 9- substituted benzolactam-V8s lowers their binding affinity, these newly generated analogues still retain reasonably good potency for PKC.