Synthesis and biological evaluation of potential inhibitors of COX-2, from Morita-Baylis-Hillman adducts

Author(s)

Luis Gustavo de Souza Filho

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Química
• Defense date: 2014-03-28

Examining board members

Fernando Antonio Santos Coelho; Letícia Veras Costa Lotufo; Marco Edilson Freire de Lima; Sisi Marcondes; Luciana Gonzaga de Oliveira

• Advisor: Fernando Antonio Santos Coelho

Abstract

This paper describes a new approach for the synthesis of substituted cyclopentenones with potential anti-inflammatory activity. The cyclopentenones play diverse biological activities, namely: anti-inflammatory, anticancer and antiviral. Due to their biological importance synthesize various cyclopentenones using Morita-Baylis-Hillman as substrate. The sequence was based on the use of a 1,4 addition reaction catalyzed by rhodium, with Morita-Baylis-Hillman, leading to the formation of alpha-substituted cinnamates with high stereoselectivity E. From the latter, a sequence of steps allowed the preparation of 4 different cyclopentenones in 7 steps with overall yields ranging from 10 to 30%. The cyclopentenones synthesized had their anti-inflammatory profile assessed in experimental models of non-allergic inflammation, paw edema and peritonitis ¿ in vivo and test platelet aggregation - in vitro. Demonstrated through such experiments , these cyclopentenones inhibit the inflammatory process, ie , reduce paw edema and cell migration into the abdominal cavity, as well as a possible indication of the mechanism of action of these molecules on the isoenzyme cyclooxygenase type 2 (COX-2). The platelet aggregation assays allowed us to propose that the mechanism of action may be through inhibition of COX - 2, since these trials have shown that these molecules do not inhibit COX-1 enzyme. This is the first paper describing the synthesis of substituted cyclopentenones from Morita-Baylis-Hillman adducts (AU)

• FAPESP's process: 08/09230-0 - Synthesis of potential COX-2 selective inhibitors
• Grantee: Luis Gustavo de Souza Filho
• Support Opportunities: Scholarships in Brazil - Doctorate