A CHALLENGING GUANIDINE-BASED MOLECULE – THE SYNTHESIS AND ITS ACTION

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Aminal Guanidine-Based Molecules: Synthesis and Application

Publication . Rippel, Rafael Alves; Branco, Paula; Ferreira, Luísa

Cernumidine is a natural alkaloid found in Solanum cernuum Vell leaves in Brazil. Its unique structure includes an unprecedented hybrid aminal system and a guanidine functionality, giving it a unique 2- aminopyrrolidine-1-carboxamidine core with four consecutive C-N bonds. Attempts to synthesize cernumidine used a proposed biosynthetic pathway involving L-arginine and L-Proline decarboxylation. However, L-Arg coupling failed, and only (±)-Cernumidine (22%) and analogues were achieved using the L-Pro approach. An enantioselective approach from L-proline using the Curtius rearrangement to forge the aminal core was envisioned. However, racemization was observed after isocyanate trapping by diverse organometallic reagents, and computational studies were carried out to unveil the racemization pathway. The reaction enantioselectivity may be controlled by coordination with the N-Boc protecting group and product stability. The ferulic moiety of cernumidine was installed using a Heck reaction. Similarly to the Grignard addition, changes relative to the starting material were observed. Which may result from the two new stereogenic centers that were formed during the migratory insertion step. A possible formation of heteroenergetic diastereomers and Pd-coordination groups at the phenyl ring may contribute to the observed ee changes. N-Boc removal was challenging due to aminal instability under acidic conditions, but researchers overcame this by conducting the reaction in the presence of AlMe3. Guanylation then prepared Cernumidine (1) in a 12% yield over seven steps with 70% ee, along with eight other analogues (11-55%). The resulting compounds showed anti-inflammatory properties in lipopolysaccharide-stimulated human THP1 cells, with good activity observed in those with a guanidine core and electron-donating groups. These compounds may be promising candidates for further development as anti-inflammatory agents.

2023Tese de doutoramento

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Exploring the synthesis of aminal guanidine-based molecules

Publication . Rippel, Rafael; Leitão, Flávia; Georgieva, Miglena K.; Mamede, Rafael; Gomes, Clara S. B.; Roma-Rodrigues, Catarina; Fernandes, Alexandra R.; Lourenço, Ana; Ferreira, Luísa M.; Branco, Paula S.; DQ - Departamento de Química; LAQV@REQUIMTE; UCIBIO - Applied Molecular Biosciences Unit; DCV - Departamento de Ciências da Vida; RSC - Royal Society of Chemistry

A novel approach has been developed for the efficient synthesis of the unsymmetrical (2-aminopyrrolidin-1-yl)carboxamidine alkaloidal core found in cernumidine (1) and its analogs (20a, 20c, 20f, 20i-o). The key transformation in this process involves the utilization of the Curtius rearrangement, which plays a pivotal role in constructing the aminal moiety. One of the major challenges encountered during this synthesis was the instability of the free aminal core intermediate. Furthermore, a noteworthy observation during the synthesis was the racemization process that occurred during the isocyanate trapping by organometallic reagents. Detailed DFT calculations shed light on this phenomenon, revealing a neighboring coordination-induced mechanism. The resulting compounds were subjected to evaluation for their anti-inflammatory properties using lipopolysaccharide-stimulated human THP1 cells. Notably, compounds featuring the guanidine moiety and electron-donating groups exhibited significant anti-inflammatory activity. These findings suggest that these compounds hold promise as potential candidates for further development as anti-inflammatory agents.

2024-03-18Artigo científico

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Entidade financiadora

Fundação para a Ciência e a Tecnologia

Número da atribuição

SFRH/BD/136692/2018