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C1 and N5 derivatives of cerpegin: synthesis of a new series based on structure-activity relationships to optimize their inhibitory effect on 20S proteasome.

Abstract：

:Thirty-two new derivatives of cerpegin (1,1,5-trimethylfuro[3,4-c]pyridine-3,4-dione) were designed and synthesized in high yield by a new method, combining several C(1) and N(5) substituents. All compounds were tested for their inhibitory effect on the CT-L, T-L and PA proteolytic activities of a purified mammalian 20S proteasome. Only one molecule inhibited both CT-L and PA activities. Sixteen molecules specifically inhibited PA at the micromolar range, out of which fourteen had IC50 values around 5 μM and two had IC50 values closer to 2 μM. Except in one case, neither calpain I nor cathepsin B was inhibited. In silico docking suggests a unique mode of binding of the most efficient compounds to the β1 catalytic site (PA activity) in relation to the chemical nature of C(1) substituents.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Hovhannisyan A,Pham TH,Bouvier D,Qin L,Melikyan G,Reboud-Ravaux M,Bouvier-Durand M

doi

10.1016/j.bmcl.2013.02.079

subject

Has Abstract

pub_date

2013-05-01 00:00:00

pages

2696-703

issue

9

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(13)00264-3

journal_volume

23

pub_type

杂志文章

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