2026-04-17T14:28:56Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/1081862025-12-05T14:23:41Zcom_2072_1057col_2072_478816col_2072_478908col_2072_478917col_2072_478933

00925njm 22002777a 4500 dc Makowski, Kamil author Vigevani, Luisa author Albericio Palomera, Fernando author Valcárcel, Juan author Álvarez Domingo, Mercedes author 2017-03-09T15:07:47Z 2017-11-24T23:01:22Z 2016-11-24 2017-03-09T15:07:47Z 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 function- ally probe key functional 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. Càncer Medicaments Inhibidors enzimàtics Cancer Drugs Enzyme inhibitors Sudemycin K: a synthetic anti-tumor splicing inhibitor variant with improved activity and versatile chemistry