Trivella Daniela B B, Pereira Alban R, Stein Martin L, Kasai Yusuke, Byrum Tara, Valeriote Frederick A, Tantillo Dean J, Groll Michael, Gerwick William H, Moore Bradley S
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093-0212, USA; Institute of Chemistry, University of Campinas, Campinas SP 13083-970, Brazil; Brazilian Biosciences National Laboratory, National Center for Research in Energy and Materials, Campinas SP 13083-970, Brazil.
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093-0212, USA.
Chem Biol. 2014 Jun 19;21(6):782-91. doi: 10.1016/j.chembiol.2014.04.010. Epub 2014 Jun 12.
Hydroamination reactions involving the addition of an amine to an inactivated alkene are entropically prohibited and require strong chemical catalysts. While this synthetic process is efficient at generating substituted amines, there is no equivalent in small molecule-mediated enzyme inhibition. We report an unusual mechanism of proteasome inhibition that involves a hydroamination reaction of alkene derivatives of the epoxyketone natural product carmaphycin. We show that the carmaphycin enone first forms a hemiketal intermediate with the catalytic Thr1 residue of the proteasome before cyclization by an unanticipated intramolecular alkene hydroamination reaction, resulting in a stable six-membered morpholine ring. The carmaphycin enone electrophile, which does not undergo a 1,4-Michael addition as previously observed with vinyl sulfone and α,β-unsaturated amide-based inhibitors, is partially reversible and gives insight into the design of proteasome inhibitors for cancer chemotherapy.
涉及将胺加成到钝化烯烃上的氢胺化反应在熵上是被禁止的，并且需要强化学催化剂。虽然这种合成过程在生成取代胺方面很有效，但在小分子介导的酶抑制中却没有类似的情况。我们报道了一种不寻常的蛋白酶体抑制机制，该机制涉及环氧酮天然产物卡马霉素的烯烃衍生物的氢胺化反应。我们表明，卡马霉素烯酮首先与蛋白酶体的催化性苏氨酸1残基形成半缩酮中间体，然后通过意外的分子内烯烃氢胺化反应环化，形成稳定的六元吗啉环。卡马霉素烯酮亲电试剂不像之前观察到的乙烯基砜和基于α,β-不饱和酰胺的抑制剂那样发生1,4-迈克尔加成，它是部分可逆的，这为癌症化疗用蛋白酶体抑制剂的设计提供了思路。
