title: Sudemycin K: A Synthetic Antitumor Splicing Inhibitor Variant with Improved Activity and Versatile Chemistry.
abstract: Important links exist between the process of pre-mRNA splicing and cancer, as illustrated by the frequent mutation of splicing factors in tumors and the emergence of various families of antitumor drugs that target components of the splicing machinery, notably SF3B1, a protein subunit of spliceosomal U2 small nuclear ribonucleoprotein particle (snRNP). Sudemycins are synthetic compounds that harbor a pharmacophore common to various classes of splicing inhibitors. Here, we describe the synthesis and functional characterization of novel sudemycin analogues that functionally probe key chemical groups within this pharmacophore. Our results confirm the importance of a conjugated diene group and in addition reveal significant spatial flexibility in this region of the molecule. Sudemycin K, a derivative that replaces the pharmacophore's oxycarbonyl by an amide group, displays improved potency as an inhibitor of cancer cell proliferation, as a regulator of alternative splicing in cultured cells and as an inhibitor of in vitro spliceosome assembly. Sudemycin K displays higher stability, likely related to the replacement of the oxycarbonyl group, which can be a substrate of esterases, by an amide group. The activity and special reactivity of sudemycin K can pave the way to the synthesis and evaluation of a variety of novel sudemycin derivatives.
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology , Dr. Aiguader 88, 08003 Barcelona, Spain.|Institute for Research in Biomedicine (IRB-Barcelona) , Baldiri i Reixac 10, 08028, Barcelona, Spain.
authors.forename: Kamil
authors.initials: K
authors.lastname: Makowski
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology , Dr. Aiguader 88, 08003 Barcelona, Spain.|Universitat Pompeu Fabra (UPF) , Dr. Aiguader 88, 08003 Barcelona, Spain.
authors.forename: Luisa
authors.identifier: 0000-0002-2590-8141
authors.initials: L
authors.lastname: Vigevani
authors.affiliation: Institute for Research in Biomedicine (IRB-Barcelona) , Baldiri i Reixac 10, 08028, Barcelona, Spain.|Department of Organic Chemistry, Faculty of Chemistry, University of Barcelona , Martí Franqués 1, 08028 Barcelona, Spain.|CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine , Barcelona, Spain.
authors.forename: Fernando
authors.identifier: 0000-0002-8946-0462
authors.initials: F
authors.lastname: Albericio
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology , Dr. Aiguader 88, 08003 Barcelona, Spain.|Universitat Pompeu Fabra (UPF) , Dr. Aiguader 88, 08003 Barcelona, Spain.|ICREA , Pg. Lluís Companys 23, 08010 Barcelona, Spain.
authors.forename: Juan
authors.identifier: 0000-0001-5398-3571
authors.initials: J
authors.lastname: Valcárcel
authors.affiliation: Institute for Research in Biomedicine (IRB-Barcelona) , Baldiri i Reixac 10, 08028, Barcelona, Spain.|CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine , Barcelona, Spain.|Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona , Joan XXIII s/n, 08028 Barcelona, Spain.
authors.forename: Mercedes
authors.identifier: 0000-0002-2025-9111
authors.initials: M
authors.lastname: Álvarez
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D004146:Dioxanes / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D012322:RNA Precursors / Q000235:genetics; D012326:RNA Splicing / Q000187:drug effects*; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology*; D017381:Spliceosomes / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004146:Dioxanes; D010879:Piperazines; D012322:RNA Precursors; D013141:Spiro Compounds; C000614304:sudemycin K; D000077489:Piperazine