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The conformations of the biologically active taxol analogs Taxotereo, 3R, 4R, and 4S, and the biologically inactive analog 3 S were evaluated in CDC13 and DMSO-water solution using 'H NMR coupling constant and NOESY data and molecular modeling. The solution structures of Taxoterem were very similar to those detected previously for taxol. The A-ring side chain conformations of analogs 3 and 4 could not be defined with the same precision as had been possible for taxol, but the conformational possibilities could be significantly limited by the data. Analogs 3R, 4R, and 4S (but not 3 s ) can mimic the dominant conforrnation of taxol in chloroform, but no logical relationship between biological activity and aqueous solution conformation could be detected. Chem. 72, 252 (1994).Faisant appel aux constantes de couplage en RMN du 'H obtenues pour des solutions de CDC13 ou aqueuses de DMSO, a des donnCes NEOSY et 3 de la modClisation molCculaire, on a CvaluC les conformations des analogues biologiquement actifs du taxol, les ~a x o t e r e @ 3 R , 4R et 4S, et de l'analogue biologiquement inactif 3 s . Les structures du ~a x o t e r e~ en solution sont trks semblables a celles dktectkes antkrieurement pour le taxol. Les conformations de la chaine laterale du cycle A des analogues 3 et 4 n'a pas CtC dkterminCe avec la prkcision qui avait CtC possible pour le taxol; toutefois, les possibilitCs conformationnelles ont pu Ctre skrieusement IimitCes par les donnCes. Les analogues 3R, 4R et 4S (mais pas le 3 s ) peuvent reproduire la conformation dominante du taxol dans le chloroforme; toutefois, on ne peut dCtecter aucune relation logique entre I'activitC biologique et la conformation en solution aqueuse.[Traduit par la rkdaction] Introduction The diterpenoid antineoplastic drug taxol (1, 2) is distinct from other anti-mitotic agents, such as the vinca alkaloids, in that it promotes the assembly and inhibits the disassembly of microtubules, both in vitro and in vivo (3). Whereas the structure-activity profile that is emerging3 hints at an intriguing interaction beiween taxol and its microtubular binding site(s).

A series of analogues of the protein kinase C (PKC) inhibitory natural product balanol which bear modified benzophenone subunits are described. The analogues were designed with the goal of uncovering structure-activity features that could be used in the development of PKC inhibitors with a reduced polar character compared to balanol itself. The results of these studies suggest that most of the benzophenone features found in the natural product are important for obtaining potent PKC inhibitory compounds. However, several modifications were found to lead to selective inhibitors of the related enzyme protein kinase A (PKA), and several specific modifications to the polar structural elements of the benzophenone were found to provide potent PKC inhibitors. In particular, it was found that replacement of the benzophenone carboxylate with bioisosteric equivalents could lead to potent analogues. Further, a tolerance for lipophilic substituents on the terminal benzophenone ring was uncovered. These results are discussed in light of recently available structural information for PKA.

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