Chemical Modifications on Filifolinol. New Derivatives Potentially Suitable for Oral Administration

Chemical Modifications on Filifolinol. New Derivatives Potentially Suitable for Oral Administration

Larghi, Enrique L.; Operto, María A.; Coscia, Andrea V.; Torres, René; Kaufman, Teodoro S.

Abstract:

The Complement system is a phylogenetically conserved element which emerged about 600-700 million years ago, preceding antibody development, and evolved as a sophisticated, distinct and important part of the innate immune system, reflecting its relevance in protection against non-self. Several diseases involve improper activation of the Complement system (Alzheimer’s disease; rheumatoid arthritis; multiple sclerosis, etc.). Hyperacute rejection of transplants, isquemia reperfusion and others pathologies also take place with an unregulated response of this system. Unfortunately, only few drugs are available to treat disorders based on Complement system, and none of them can be administrated orally. Synthesis is one of the most relevant methodologies to opitmize the pharmacological profile of an active molecule. In this context, we have been able to produce new derivatives of filifolinol (1), a natural product structurally reminiscent of the well established Complement inhibitor K-76 (2, isolated form Stachybotrys complementii) and its acid derivative (3). We have synthesized (Figure 1) filifolinol derivatives modified on C3’ and C7 with improved bioactivity (4-6).

The Complement system is a phylogenetically conserved element which emerged about 600-700 million years ago, preceding antibody development, and evolved as a sophisticated, distinct and important part of the innate immune system, reflecting its relevance in protection against non-self. Several diseases involve improper activation of the Complement system (Alzheimer’s disease; rheumatoid arthritis; multiple sclerosis, etc.). Hyperacute rejection of transplants, isquemia reperfusion and others pathologies also take place with an unregulated response of this system. Unfortunately, only few drugs are available to treat disorders based on Complement system, and none of them can be administrated orally. Synthesis is one of the most relevant methodologies to opitmize the pharmacological profile of an active molecule. In this context, we have been able to produce new derivatives of filifolinol (1), a natural product structurally reminiscent of the well established Complement inhibitor K-76 (2, isolated form Stachybotrys complementii) and its acid derivative (3). We have synthesized (Figure 1) filifolinol derivatives modified on C3’ and C7 with improved bioactivity (4-6).

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DOI: 10.5151/chempro-14bmos-R0386-2

Referências bibliográficas

• [1] 1Larghi, E. L.; Kaufman, T. S. Arkivoc 2011, vii, 49 (and references therein).
• [2] 2Larghi, E. L.; Operto, M. A.; Torres, R.; Kaufman, T. S. Bioorg. Med. Chem. Lett. 2009, 19, 6172.

Como citar:

Larghi, Enrique L.; Operto, María A.; Coscia, Andrea V.; Torres, René; Kaufman, Teodoro S.; "Chemical Modifications on Filifolinol. New Derivatives Potentially Suitable for Oral Administration", p-386-386. In: In Blucher Chemistry Proceedings, São Paulo, v. 1, n. 1, Setembro.2013. São Paulo: Blucher, 2013.
ISSN 23184043, DOI 10.5151/chempro-14bmos-R0386-2