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Title: Sudemycin K: a synthetic anti-tumor splicing inhibitor variant with improved activity and versatile chemistry
Author: Makowski, Kamil
Vigevani, Luisa
Albericio Palomera, Fernando
Valcárcel, Juan
Álvarez Domingo, Mercedes
Keywords: Càncer
Inhibidors enzimàtics
Enzyme inhibitors
Issue Date: 24-Nov-2016
Publisher: American Chemical Society
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 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.
Note: Versió postprint del document publicat a:
It is part of: ACS Chemical Biology, 2016, vol. 12, num. 1, p. 163-173
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ISSN: 1554-8929
Appears in Collections:Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))
Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
Articles publicats en revistes (Química Inorgànica i Orgànica)

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