Direct Amidation to Access 3-Amido-1,8-Naphthalimides Including Fluorescent Scriptaid Analogues as HDAC Inhibitors.

Kyle N Hearn,Frederick M Pfeffer,Zikai Feng,Trent D Ashton,Nuri Gueven,Rameshwor Acharya

doi:10.3390/cells10061505

Abstract

Methodology to access fluorescent 3-amido-1,8-naphthalimides using direct Buchwald–Hartwig amidation is described. The protocol was successfully used to couple a number of substrates (including an alkylamide, an arylamide, a lactam and a carbamate) to 3-bromo-1,8-naphthalimide in good yield. To further exemplify the approach, a set of scriptaid analogues with amide substituents at the 3-position were prepared. The new compounds were more potent than scriptaid at a number of histone deacetylase (HDAC) isoforms including HDAC6. Activity was further confirmed in a whole cell tubulin deacetylation assay where the inhibitors were more active than the established HDAC6 selective inhibitor Tubastatin. The optical properties of these new, highly active, compounds make them amenable to cellular imaging studies and theranostic applications.

Highlights

Interest in functionalised 1,8-naphthalimides has primarily focussed on substitution at the 4-position to generate fluorophores suitable for sensing and imaging applications [1,2,3,4].Examples where sensors have been modified in the 3-position are less common, with notable examples including those reported by Zhang et al, Guo et al and Elmes et al.for the detection of CO2, ClO− and reductive stress, respectively [5,6,7]
We have recently demonstrated that in the synthesis of 4-amido-1,8-naphthalimides, the usual three-step approach can be avoided using a Buchwald–Hartwig cross-coupling protocol in which a range of amides as well as lactams, carbamates and urea can be introduced in a single step [11]
In the synthesis of KNH019 a solution of 3-bromo-1,8-naphthalimide 11, benzamide, Cs2CO3 and G3-xantphos in 1,4-dioxane were heated at 100 °C with the reaction progress being monitored using thin layer chromatography (TLC)

Summary

Introduction

Interest in functionalised 1,8-naphthalimides has primarily focussed on substitution at the 4-position to generate fluorophores suitable for sensing and imaging applications [1,2,3,4]. Nicotinamides were successfully coupled and the resultant probes shown to act as reversible indicators of the cellular redox state [12] This direct coupling approach has not yet been evaluated for introducing substituents at the 3-position. Cells 2021, 10, x generation of HDAC inhibitors have been developed to be selective for specific HDAC classes or isoforms [28,29,30] In this context, HDAC6 (Class IIb) has emerged as a valuable target as it has a clear role in the progression of a number of cancer types, and, unlike other. HDAC classes or isoforms [28,29,30] In this context, HDAC6 (Class IIb) has emerged as a valuable target as it has a clear role in the progression of a number of cancer types, and, unlike other isoforms, mouse models in which this isoform has been deleted are viable

Examples

Results andother

SO4 and provided the times desired brominatedtocompound

Synthesis

HDAC isoforms

Conclusions