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

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Direct Amidation to Access 3-Amido-1,8-Naphthalimides Including Fluorescent Scriptaid Analogues As HDAC Inhibitors cells Article Direct Amidation to Access 3-Amido-1,8-Naphthalimides Including Fluorescent Scriptaid Analogues as HDAC Inhibitors Kyle N. Hearn 1,2, Trent D. Ashton 1,3,4 , Rameshwor Acharya 5, Zikai Feng 5 , Nuri Gueven 5 and Frederick M. Pfeffer 1,* 1 School of Life and Environmental Sciences, Deakin University, Waurn Ponds, VIC 3216, Australia 2 STEM College, RMIT University, Melbourne, VIC 3000, Australia; [email protected] 3 Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; [email protected] 4 Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia 5 School of Pharmacy and Pharmacology, College of Health and Medicine, University of Tasmania, Hobart, TAS 7001, Australia; [email protected] (R.A.); [email protected] (Z.F.); [email protected] (N.G.) * Correspondence: [email protected] 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 Citation: Hearn, K.N.; Ashton, T.D.; HDAC6 selective inhibitor Tubastatin. The optical properties of these new, highly active, compounds Acharya, R.; Feng, Z.; Gueven, N.; make them amenable to cellular imaging studies and theranostic applications. Pfeffer, F.M. Direct Amidation to Access 3-Amido-1,8-Naphthalimides Keywords: Buchwald–Hartwig; scriptaid; histone deacetylase; HDAC; 1,8-naphthalimide; fluores- Including Fluorescent Scriptaid cence; imaging; tubulin deacetylase Analogues as HDAC Inhibitors. Cells 2021, 10, 1505. https://doi.org/ 10.3390/cells10061505 Academic Editors: Doug Brooks, 1. Introduction Alexandra Sorvina and Shane Hickey Interest in functionalised 1,8-naphthalimides has primarily focussed on substitution at the 4-position to generate fluorophores suitable for sensing and imaging applications [1–4]. Received: 11 May 2021 Examples where sensors have been modified in the 3-position are less common, with Accepted: 7 June 2021 notable examples including those reported by Zhang et al., Guo et al. and Elmes et al. Published: 15 June 2021 − for the detection of CO2, ClO and reductive stress, respectively [5–7]. Examples that incorporate a 3-amido substituent are particularly rare [5,8–10], likely due to the multistep Publisher’s Note: MDPI stays neutral nature of the synthetic protocols required to access them. We have recently demonstrated with regard to jurisdictional claims in that in the synthesis of 4-amido-1,8-naphthalimides, the usual three-step approach can be published maps and institutional affil- avoided using a Buchwald–Hartwig cross-coupling protocol in which a range of amides as iations. well as lactams, carbamates and urea can be introduced in a single step [11]. Nicotinamides were also 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. Copyright: © 2021 by the authors. The 1,8-naphthalimide core has also been employed in medicinal chemistry [13,14]. Licensee MDPI, Basel, Switzerland. Relevant examples (Figure1) include (i) scriptaid [ 15] (an inhibitor of histone deacetylases This article is an open access article (HDAC)) and amonafide [16–19] (a DNA intercalator and topoisomerase II inhibitor). distributed under the terms and Amonafide is converted in vivo into the bioactive N-acetyl-amonafide. conditions of the Creative Commons The HDAC family has become well-studied due to their roles in a number of disease Attribution (CC BY) license (https:// states [20–22]. Indeed, a number of HDAC inhibitors are FDA-approved for clinical use as creativecommons.org/licenses/by/ treatments for T-cell lymphoma or myeloma [23–27]. In an effort to mitigate side effects, the 4.0/). Cells 2021, 10, 1505. https://doi.org/10.3390/cells10061505 https://www.mdpi.com/journal/cells Cells 2021, 10, x 2 of 11 Cells 2021, 10, 1505 2 of 10 next generation of HDAC inhibitors have been developed to be selective for specific HDAC classes or isoforms [28–30]. In this context, HDAC6 (Class IIb) has emerged as a valuable Cells 2021, 10, x 2 of 11 target as it has a clear role in the progression of a number of cancer types, and, unlike other Figure 1. Examples of 1,8-naphthalimides in medicinal chemistry. isoforms, mouse models in which this isoform has been deleted are viable [31,32]. The HDAC family has become well-studied due to their roles in a number of disease states [20–22]. Indeed, a number of HDAC inhibitors are FDA-approved for clinical use as treatments for T-cell lymphoma or myeloma [23–27]. In an effort to mitigate side effects, the next generation of HDAC inhibitors have been developed to be selective for specific HDAC classes or isoforms [28–30]. 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 Figure 1. Examples of 1,8-naphthalimides in medicinal chemistry. [31,32].Figure 1. Examples of 1,8-naphthalimides in medicinal chemistry. TheThe entranceentrance toto thethe HDAC6HDAC6 activeactive sitesite isis slightlyslightly largerlarger [[33,34]33,34] thanthan thatthat ofof thethe otherother isoforms,isoforms,The HDAC andand thereforetherefore family has aa successfulsuccessful become well-studied strategystrategy forfor enhancingenhancingdue to their selectivityselectivity roles in a fornumberfor thisthis isoform isoformof disease isis thethestates modificationmodification [20–22]. Indeed, ofof thethe a pharmacophoricpharmacophoric number of HDAC cappingcapping inhibitors group.group. are AmidesFDA-approvedAmides offeroffer notnot for justjust clinical aa meansmeans use totoas introduceintroducetreatments additionaladditional for T-cell size;lymphomasize; theythey presentpresent or myeloma bothboth anan [23–2 H-bondH-bond7]. In donordonoran effort andand to acceptoracceptor mitigate toto side maximisemaximise effects, potentialpotentialthe next generationinteractionsinteractions of withwith HDAC residuesresidues inhibitors atat thethe have activeactive been sitesite developed peripheryperiphery [[35–37].35to –be37 ].selective for specific HDACThereThere classes areare currently currentlyor isoforms only only [28–30]. three three published publishedIn this context, examples examples HDAC6 of of scriptaid scriptaid (Class analoguesIIb) analogues has emerged with with substi- sub-as a valuable target as it has a clear role in the progression of a number of cancer types, and, tutionstitution at theat the 3-position, 3-position, and and only only compound compound3 has3 has full full HDAC HDAC IC IC5050activity activity datadata recordedrecorded (Figure(Figureunlike 2other 2))[ [38–40].38 –isoforms,40]. ThereThere mouse areare nono models scriptaidscriptaid in analogueswhichanalogues this with withisoform 3-amido3-amido has been substituentssubstituents deleted describedaredescribed viable inin[31,32]. thethe literature.literature. AsAs such,such, thethe generationgeneration ofof aa smallsmall setset ofof 3-amido-substituted3-amido-substituted scriptaidscriptaid analoguesanaloguesThe entrance presentspresents to thethe the opportunityopportunity HDAC6 active to (i) site testtest is theslightly Buchwald–HartwigBuchwald–Hartwig larger [33,34] than amidation that of the method- other ologyologyisoforms, beyondbeyond and thethetherefore 4-position4-position a successful andand toto (ii)(ii) strategy furtherfurthe rfor exploreexplore enhancing thethe structure-activitystructure-activity selectivity for this relationshiprelationship isoform is ofofthe functionalisedfunctionalised modification of scriptaidscriptaid the pharmacophoric analogues.analogues. Our capping own recent group. work Amides (CF010 offer and not CF011 just a,, FigureFiguremeans2 2)to) hashasintroduce identifiedidentified additional that,that, forfor size; the 4-position,they present relativelyrelative both anly smallH-bond substituents donor and can acceptor dramatically to maximise influ-influ- enceencepotential isoformisoform interactions selectivityselectivity with andand residues fluorescencefluorescence at the propertiesprop activeerties site [ [41].41periphery]. WhileWhile [35–37]. ourour effortsefforts havehave focussedfocussed onon modifyingThere are scriptaid scriptaidcurrently to toonly develop develop three highly published highly fluo fluorescentrescent examples anticancer anticancer of scriptaid agents, agents, analogues related related recentwith recent sub- ex- examplesamplesstitution exist at exist the for 3-position, for identifying identifying and biofilms biofilmsonly compound and and detecting detecting 3 has influenza full influenza HDAC [42,43]. [IC4250,43 activity ]. data recorded (Figure 2) [38–40]. There are no scriptaid analogues with 3-amido substituents described in the literature. As such, the generation of a small set of 3-amido-substituted scriptaid
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