ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Fatty Alcohols/pharmacology , Pyrans/pharmacology , RNA Splicing/drug effects , Antineoplastic Agents/chemical synthesis , Fatty Alcohols/chemical synthesis , HeLa Cells , Humans , Pyrans/chemical synthesis , Spliceosomes/drug effects , StereoisomerismABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemical synthesis , Cyclopropanes/chemical synthesis , Pyrans/chemical synthesis , Spiro Compounds/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cyclopropanes/chemistry , Cyclopropanes/pharmacology , HeLa Cells , Humans , Molecular Structure , Pyrans/chemistry , Pyrans/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , StereoisomerismABSTRACT
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.
