Marbostat-100 Defines a New Class of Potent and Selective Antiinflammatory and Antirheumatic Histone Deacetylase 6 Inhibitors

Abstract

Epigenetic modifiers of the histone deacetylase (HDAC) family contribute to autoimmunity, cancer, HIV infection, inflammation, and neurodegeneration. Hence, histone deacetylase inhibitors (HDACi), which alter protein acetylation, gene expression patterns, and cell fate decisions, represent promising new drugs for the therapy of these diseases. Whereas pan-HDACi inhibit all 11 Zn-dependent histone deacetylases (HDACs) and cause a broad spectrum of side effects, specific inhibitors of histone deacetylase 6 (HDAC6i) are supposed to have less side effects. We present the synthesis and biological evaluation of Marbostats, novel HDAC6i that contain the hydroxamic acid moiety linked to tetrahydro-β-carboline derivatives. Our lead compound Marbostat-100 is a more potent and more selective HDAC6i than previously established well-characterized compounds in vitro as well as in cells. Moreover, Marbostat-100 is well tolerated by mice and effective against collagen type II induced arthritis. Thus, Marbostat-100 represents a most selective known HDAC6i and the possibility for clinical evaluation of a HDAC isoform-specific drug.

Enantioselective synthesis and biological investigation of tetrahydro‐β‐carboline‐based HDAC6 inhibitors with improved solubility

“…To get the desired specific HDAC6 inhibitors bearing the morpholineethoxy substituent, the phenolic intermediate was synthesized as described by Sellmer et al…”

“…To achieve the enantiomers R ‐ 16 / S ‐ 16 we started the stereoselective synthesis with 5‐benzyloxyindole ( 6 ) by using a chiral catalysis . According to the synthesis of ( R )‐ and ( S )‐Marbostat‐100 aminoindanolthiocarbamate organocatalysts were used for the enantioselective addition of 6 to 7 to get R ‐ 9 / S ‐ 9 . The absolute stereochemistry at the CH‐acidic position of the ethyl 2‐(5‐benzyloxy)‐1 H ‐indole‐3yl)‐3‐nitropropanoate R ‐ 9 / S ‐ 9 was ( S ), when (1 S ,2 R )‐amino‐2,3‐dihydro‐1 H ‐inden‐2‐ol, and ( R ) when (1 R ,2 S )‐amino‐2,3‐dihydro‐1 H ‐inden‐2‐ol was used.…”

“…As mentioned by Sellmer et al, the racemic 8‐(morpholineethoxy) derivative 21 shows similar in vitro selectivity and potency to Marbostat‐100. They could also observe significant effects regarding the clinical arthritis score and relative bone surface BS/BV for the compound 21 in the CIA (collagen‐induced arthritis) mouse model.…”

Combined Ligand and Fragment‐based Drug Design of Selective Histone Deacetylase – 6 Inhibitors

“…Initial drug discovery protocols signified bulkiness of the CAP group as important chemical motif for HDAC6 selectivity . The latest structure based drug design studies identified several HDAC6 selective inhibitors with significant changes in linker chemistry, such as design of aromatic linkers instead of aliphatic linkers) ,…”

“…[23][24][25][26] The latest structure based drug design studies identified several HDAC6 selective inhibitors with significant changes in linker chemistry, such as design of aromatic linkers instead of aliphatic linkers). [27,28] The ligand-based (LB) drug design approaches are widely used modelling techniques for fast and accurate activity prediction of newly designed or synthesized com-pounds. [29] One of the most studied LB-approaches is threedimensional Quantitative Structure-Activity Relationship (3D-QSAR) study.…”