RESUMEN
Herboxidiene is a potent antitumor agent that targets the SF3B subunit of the spliceosome. Herboxidiene possesses a complex structural architecture with nine stereocenters and design of potent less complex structures would be of interest as a drug lead as well as a tool for studying SF3B1 function in splicing. We investigated a number of C-6 modified herboxidiene derivatives in an effort to eliminate this stereocenter and, also to understand the importance of this functionality. The syntheses of structural variants involved a Suzuki-Miyaura cross-coupling reaction as the key step. The functionalized tetrahydrofuran core has been constructed from commercially available optically active tri-O-acetyl-d-glucal. We investigated the effect of these derivatives on splicing chemistry. The C-6 alkene derivative showed very potent splicing inhibitory activity similar to herboxidiene. Furthermore, the C-6 gem-dimethyl derivative also exhibited very potent in vitro splicing inhibitory activity comparable to herboxidiene.
Asunto(s)
Antineoplásicos/farmacología , Alcoholes Grasos/farmacología , Piranos/farmacología , Empalme del ARN/efectos de los fármacos , Antineoplásicos/síntesis química , Alcoholes Grasos/síntesis química , Células HeLa , Humanos , Piranos/síntesis química , Empalmosomas/efectos de los fármacos , EstereoisomerismoRESUMEN
Spliceostatin A is a potent inhibitor of spliceosomes and exhibits excellent anticancer activity against multiple human cancer cell lines. We describe here the design and synthesis of a stable cyclopropane derivative of spliceostatin A. The synthesis involved a cross-metathesis or a Suzuki cross-coupling reaction as the key step. The functionalized epoxy alcohol ring was constructed from commercially available optically active tri- O-acetyl-d-glucal. The biological properties of the cyclopropyl derivative revealed that it is active in human cells and inhibits splicing in vitro comparable to spliceostatin A.
Asunto(s)
Antineoplásicos/síntesis química , Ciclopropanos/síntesis química , Piranos/síntesis química , Compuestos de Espiro/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Ciclopropanos/química , Ciclopropanos/farmacología , Células HeLa , Humanos , Estructura Molecular , Piranos/química , Piranos/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , EstereoisomerismoRESUMEN
An enantioselective total synthesis of spliceostatin G has been accomplished. The synthesis involved a Suzuki cross-coupling reaction as a key step. The functionalized tetrahydropyran ring was constructed from commercially available optically active tri-O-acetyl-d-glucal. Other key reactions include a highly stereoselective Claisen rearrangement, a Cu(I)-mediated 1,4 addition of MeLi to install the C8 methyl group, and a reductive amination to incorporate the C10 amine functionality of spliceostatin G. Biological evaluation of synthetic spliceostatin G and its methyl ester revealed that it does not inhibit splicing in vitro.