Synthesis and biological activity of fostriecina analogues

Author(s)

Ilton Barros Daltro de Castro

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Química
• Defense date: 2010-12-21

Examining board members

Ronaldo Aloise Pilli; Alcindo Aparecido dos Santos; Antonio Carlos Bender Burtoloso; Antonio Claudio Herrera Braga; Paulo Mitsuo Imamura

• Advisor: Ronaldo Aloise Pilli

Abstract

Fostriecin (10) is a natural cytotoxic organic phosphate isolated from Streptomyces pulveraceus which exhibits potent antitumor activity against leukemic cells (IC50=0,46 mM), among others. The cytotoxic properties of this compound are presumably linked to the selective inhibition of the phosphatase protein 2A (IC50=3,2 mM). Although fostriecin has advanced to clinical studies, these were suspended due to its chemical instability, which was assigned to the trienic moiety of the structure. Therefore it was decided to prepare fostriecin analogues (105a and 105b), which should present chemical stability and potent biological activity.The synthetic strategy proposed towards the achievement of analogues 105a and 105b was guided by a main idea that aimed to preserve the integrity of the dihydropyran ring and to properly control the geometry of the double bonds, as well as the absolute stereochemistry of the stereogenic centers, without compromising the efficiency of the synthetic route. The key steps in the preparation of the fostriecin analogues were: a Yamamoto catalytic and asymmetric allylation reaction to install the stereogenic center in C5; a Sharpless asymmetric dihydroxilation reaction to access the stereogenic center in C8; and an aldol reaction to form the bond between C10-C11. The target products, as well as advanced synthetic intermediates were submitted to three biological assays: antiproliferative activity in vitro against 10 cancer cell lines; LMWPTP isolated enzyme inhibition; and cell viability within cell lines that overexpress the LMWPTP. Three of those compounds showed promising results, exhibiting higher inhibition than the positive controls and with low cytotoxicity to healthy cells. These results suggest that these compounds induct apoptosis via disruption of the LMWPTP enzyme signaling pathways (AU)

• FAPESP's process: 05/03002-8 - Synthesis and biological activity of fostriecin analogues
• Grantee: Ilton Barros Daltro de Castro
• Support Opportunities: Scholarships in Brazil - Doctorate