The semisynthetic landscape of aphidicolin: inspiration towards leishmanicidal compounds

Author(s):Show less -

Santos, Gabriela B. ^[1] ; Almeida, Marilia O. ^[1] ; Cardoso, Iara A. ^[1] ; Manfrim, Viviane ^[1] ; Chagas, Fernanda O. ^[1] ; Toledo, Juliano S. ^[2] ; Pinzan, Camila C. ^[2] ; de Araujo, Alexandre Suman ^[3] ; Cruz, Angela K. ^[2] ; Pupo, Monica T. ^[1] ; Emery, Flavio S. ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Ciencias Farmaceut, BR-14040903 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Biol Celular & Mol Bioagentes Patogen, BR-14040903 Ribeirao Preto, SP - Brazil

^[3] Univ Estadual Paulista, Inst Biociencias Letras & Ciencias Exatas Sao Jos, Dept Fis, BR-15054000 Sao Jose De Rio Preto, SP - Brazil

• Document type: Journal article
• Source: Journal of the Brazilian Chemical Society; v. 25, n. 10, p. 1885+, OCT 2014.
• Web of Science Citations: 2

Abstract

Recent studies have shown that aphidicolin, a secondary metabolite of the endophytic fungus Nigrospora sphaerica, has high activity against the protozoan Leishmania major. Despite its promising leishmanicidal potential, aphidicolin presents a therapeutically unsuitable physico-chemical and pharmacokinetic profile. In this sense, a review of the literature shows the limited types of modification for this terpene. In addition, it gives an idea about the molecular properties of the compounds produced and which were correlated to leishmanicidal derivatives. This analysis provided us a rationale for the development of an oxime derivative. We synthesized the oxime-aphidicolin and a series of derivatives for a preliminary evaluation of the structural requirements for the leishmanicidal activity of aphidicolin and its semisynthetic derivatives. Eight compounds have been synthesized and tested against different species of the Leishmania protozoa. The preliminary evaluation demonstrated high leishmanicidal activity for aphidicolin, while the oxime derivative shows moderate selectivity for the L. braziliensis species, which is commonly found in several South American countries. None of the compounds showed cytotoxicity against mammalian cells. (AU)

• FAPESP's process: 09/51812-0 - Development of a platform for the study of in vitro and in vivo metabolism of natural products, a need for pre-clinical testing system
• Grantee: Norberto Peporine Lopes
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants
• FAPESP's process: 09/14184-0 - Antiinfective compounds: bringing together medicinal chemistry and organic synthesis in search of lead antiparasitic compounds
• Grantee: Flavio da Silva Emery
• Support Opportunities: Regular Research Grants