Novel guanidinylating reagents and heterocyclic structures for peptidomimetic drug design.

摘要

In our program to develop resin-bound reagents, we synthesized resin-bound N-Boc-N′-triflyl guanidine. This structure was immobilized on the solid support via a urethane linker resembling the known di-urethane protected triflyl guanidines. The reagent has been shown to act as a guanidinylating reagent. Secondary amines, which are extremely difficult to guanidinylate with previously developed guanidinylating reagents, can now be readily transformed into guanidines. A series of primary and secondary amines have been subjected to the resin-bound guanidinylating reagent to form immobilized guanidines. The target molecules were formed under mild conditions, over reasonable reaction times and in modest to high yields. Utilizing the Wang linker, we were able to cleave these N-alkyl and N,N-dialkyl guanidines from the linker in a traceless manner. In addition, the development of solid-phase guanidinylating reagents yielded new guanidine and heterocyclic structures for the design and synthesis of drug candidate molecules.; Inspired by the resin-bound guanidines, we synthesized novel heterocyclic compounds incorporating the guanidine group. For this purpose an amine immobilized on a solid-support was acylated with protected amino acids. Following the deprotection, the liberated amines were guanidinylated utilizing a new reagent, N,N′-bis(allyloxy-carbonyl)-N ′′-triflyl guanidine, which has not been reported in the literature. This reagent was synthesized in multi-gram quantities from guanidine hydrochloride. The deprotected guanidines were subsequently regioselectively cyclized with β-keto esters producing heterocyclic compounds in high purities. Following the synthesis of several target structures, the synthesis of a library by combinatorial methodology was carried out utilizing different amino acids and β-keto esters which produced novel heterocycles.; An ongoing project in our laboratories involves the peptide hormone somatostatin. Non-peptidic analogs of somatostatin have been prepared previously and shown to bind selectively to somatostatin receptor subtype 2. We designed novel heterocyclic scaffolds incorporating substituents which are required for biological activity. Starting from optically active tryptophan, we prepared somatostatin analogs in a multi-step synthesis featuring an intramolecular Fukuiyama-Mitsunobu reaction. The target structures are based on substituted pyrazino[1,2- b]isoquinolin-4-one and pyrrolo[1,2-a]pyrazine-4-one scaffolds. These scaffolds contain asymmetric centers over which we have full control. The biological properties of the target molecules are currently under investigation.