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Sudemycin K: A Synthetic Antitumor Splicing Inhibitor Variant with Improved Activity and Versatile Chemistry
Version 2 2016-12-05, 19:19
Version 1 2016-12-01, 16:49
journal contribution
posted on 2016-11-08, 00:00 authored by Kamil Makowski, Luisa Vigevani, Fernando Albericio, Juan Valcárcel, Mercedes ÁlvarezImportant
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.