Three‐Component Aminoalkylations Yielding Dihydronaphthoxazine‐Based Sirtuin Inhibitors: Scaffold Modification and Exploration of Space for Polar Side‐Chains

Abstract

Nonpolar derivatives of heterocyclic aromatic screening hits like the non-selective sirtuin inhibitor splitomicin tend to be poorly soluble in biological fluids. Unlike sp -rich natural products, flat aromatic compounds are prone to stacking and often difficult to optimize into leads with activity in cellular systems. The aim of this work was to identify anchor points for the introduction of sp -rich fragments with polar functional groups into the newly discovered active (IC = 5 μM) but nonpolar scaffold 1,2-dihydro-3H-naphth[1,2-e][1,3]oxazine-3-thione by a molecular modeling approach. Docking studies were conducted with structural data from crystallized human SIRT2 enzyme. Subsequent evaluation of the in silico hypotheses through synthesis and biological evaluation of the designed structures was accomplished with the aim to discover new SIRT2 inhibitors with improved aqueous solubility. Derivatives of 8-bromo-1,2-dihydro-3H-naphth[1,2-e][1,3]oxazine-3-thione N-alkylated with a hydrophilic morpholino-alkyl chain at the thiocarbamate group intended for binding in the acetyl-lysine pocket of the enzyme appeared to be promising. Both the sulfur of the thiocarbamate and the bromo substituent were assumed to result in favorable hydrophobic interactions and the basic morpholino-nitrogen was predicted to build a hydrogen bond with the backbone Ile196. While the brominated scaffold showed moderately improved activity (IC = 1.8 μM), none of the new compounds displayed submicromolar activity. Synthesis and characterization of the new compounds are reported and the possible reasons for the outcome are discussed.

Sirtuins in Alzheimer’s Disease: SIRT2-Related GenoPhenotypes and Implications for PharmacoEpiGenetics

“…New SIRT2 inhibitors with improved aqueous solubility have been discovered. Derivatives of 8-bromo-1,2-dihydro-3H-naphth[1,2-e][1,3]oxazine-3-thione N -alkylated with a hydrophilic morpholino-alkyl chain at the thiocarbamate group for binding in the acetyl-lysine pocket of the enzyme might become promising candidates as SIRT2 inhibitors [199].…”

Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors

“…Whereas most of the necessary amines were commercially available at reasonable cost, the secondary methylamine derivatives 17 r – t had to be synthesized by reductive amination by using suitable aromatic aldehyde derivatives and methylamine in methanolic solution (Figure ). Intermediate imines were reduced by addition of aqueous sodium borohydride solution …”

“…Intermediate imines were reduced by addition of aqueous sodium borohydride solution. [20] Synthesis of multipurposes creening compounds 16 a-t For amide coupling, am ultitude of reagents optimized for peptides ynthesis are available. The method of choice in our case provedt ob et he highly efficient [21] peptide-coupling reagent 1-bis(dimethylamino)methylene-1H-1,2,3-triazolo[4,5b]pyridinium 3-oxide hexafluorophosphate (HATU), affording amides 16 a-t in good yields.…”

Catalyzed ring transformation of cyclic N-aryl-azadiperoxides with participation of α,ω-dithiols

“…A probable pathway to the synthesis of 3-phenyl-1,5,3-dithiazepane 8 from 10-phenyl-7,8,12,13-tetraoxa-10-azaspiro[5.7]tridecane 1 includes 13 coordination of the peroxide oxygen atom to the central atom of the catalyst, nucleophilic addition of ethane-1,2-dithiol to the resulting carbocation, 14,15 and the subsequent ring closure giving heterocycle 8 ( Scheme 2 ).…”