Total Syntheses, Fragmentation Studies, and Antitumor/Antiproliferative Activities of FR901464 and Its Low Picomolar Analogue

Abstract

FR901464 is a potent anticancer natural product that lowers the mRNA levels of oncogenes and tumor suppressor genes. In this article, we report a convergent enantioselective synthesis of FR901464, which was accomplished in 13 linear steps. Central to the synthetic approach was the diene-ene cross olefin metathesis reaction to generate the C6-C7 olefin without the use of protecting groups as the final step. Additional key reactions include a Zr/Ag-promoted alkynylation to set the C4 stereocenter, a mild and chemoselective Red-Al reduction, a reagent-controlled stereoselective Mislow-Evans-type [2,3]-sigmatropic rearrangement to install the C5 stereocenter, a Carreira asymmetric alkynylation to generate the C4′ stereocenter, and a highly efficient ring-closing metathesis-allylic oxidation sequence to form an unsaturated lactone. The decomposition pathways of FR901464's right fragment were studied under physiologically relevant conditions. Facile epoxide opening by -elimination gave two enones, one of which could undergo dehydration via its hemiketal to form a furan. To prevent this decomposition pathway, a right fragment was rationally designed and synthesized. This analogue was 12 times more stable than the right fragment of the natural product. Using this more stable right fragment analogue, an FR901464 analogue, meayamycin, was prepared in 13 linear steps. The inhibitions of human breast cancer MCF-7 cell proliferation by synthetic FR901464 and meayamycin were studied, and the GI 50 values for these compounds were determined to be 1.1 nM and 10 pM, respectively. Thus, meayamycin is among the most potent anticancer small molecules that do not bind to either DNA or microtubule.

Spliceostatin hemiketal biosynthesis in Burkholderia spp. is catalyzed by an iron/α-ketoglutarate–dependent dioxygenase

“…However, our experiments do not rule out that the observed R stereochemistry at C-1 of 12 and 13 may be defined posthydroxylation. The spliceostatin hemiketal core exists in equilibrium with its linear open-chain keto-alcohol (44,45). Conceivably, the isomerization of the hydroxyl group at C-1 of 8 and 9 (or of 12 and 13) could have occurred during this equilibration process.…”

SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes

“…Genomic sequencing was performed on coding regions for SF3B1 (exons [13][14][15][16]) SF3B14 (all exons), SF3B4 (all exons), and DYRK1A (all exons). Primer sequences and conditions used can be supplied on request.…”

“…Meayamycin was synthesized according to the literature 13 and purified on a C18 reverse-phase preparative HPLC. The fractions containing meayamycin were concentrated under vacuum to afford 16.3 mg of solid meayamycin.…”

mRNA Transcript Diversity Creates New Opportunities for Pharmacological Intervention

“…Targeting trans-acting splice proteins, however, lacks specificity, because these proteins direct alternative splicing of many genes and can lead to nonspecific effects. Natural compounds with antitumor activity have been discovered, and bind to components of the spliceosome, inhibiting pre-mRNA splicing (Albert et al, 2007;Kaida et al, 2007;Kotake et al, 2007;O'Brien et al, 2008). Although the development of new chemotherapeutics is promising, it is important to understand the implications of blocking splicing in general.…”