Michael Hepperle

A Selective Small Molecule IκB Kinase β Inhibitor Blocks Nuclear Factor κB-Mediated Inflammatory Responses in Human Fibroblast-Like Synoviocytes, Chondrocytes, and Mast Cells

IκB kinase (IKK) β is essential for inflammatory cytokine-induced activation of nuclear factor κB (NF-κB). NF-κB plays a pivotal role in the function of major cell types that contribute to the pathophysiological process of rheumatoid arthritis (RA). Here, we report the mechanism and the effect of the IKKβ inhibitor N-(6-chloro-7-methoxy-9H-β-carbolin-8-yl)-2-methylnicotinamide (ML120B), a β-carboline derivative, on NF-κB signaling and gene activation in RA-relevant cell systems. ML120B is a potent, selective, reversible, and ATP-competitive inhibitor of IKKβ with an IC50 of 60 nM when evaluated in an IκBα kinase complex assay. ML120B does not inhibit other IKK isoforms or a panel of other kinases. ML120B concentration-dependently inhibits tumor necrosis factor α (TNFα)-stimulated NF-κB signaling via inhibition of IκBα phosphorylation, degradation, and NF-κB translocation into the nucleus. For the first time, we have demonstrated that in human fibroblast-like synoviocytes, TNFα- or interleukin (IL)-1β-induced monocyte chemoattractant protein-1 regulated on activation, normal T cell expressed and secreted and production is IKKβ-dependent. In addition, for the first time, we have demonstrated that lipopolysaccharide- or peptidoglycan-induced cytokine production in human cord blood-derived mast cells is IKKβ-dependent. In addition, in human chondrocytes, ML120B inhibited IL-1β-induced matrix metalloproteinase production with an IC50 of approximately 1 μM. ML120B also blocked IL-1β-induced prostaglandin E2 production. In summary, ML120B blocked numerous NF-κB-regulated cell responses that are involved in inflammation and destructive processes in the RA joint. Our findings support the evaluation of IKKβ inhibitors as anti-inflammatory agents for the treatment of RA.

Schotten-Baumann acylation of N-debenzoyltaxol; an efficient route to N-acyl taxol analogues and their biological evaluation

Abstract An efficient route to N-acyl taxol analogues is described utilizing N-debenzoyltaxol ( 11 ). Acylation of 11 with various acid chlorides under Schotten-Baumann conditions led to a facile one step synthesis of several N-acyl taxol analogues from a common intermediate.

An efficient semisynthesis of taxol from (3R,4S)-N-Benzoyl-3-[(t-butyldimethylsilyl)oxy]-4-phenyl-2-azetidinone and 7-(Triethylsilyl)baccatin III

Abstract An investigation of the ester enolate-imine cyclocondensation demonstrated that (−)-10-dicyclohexylsulfamoyl-D-isoborneol is an excellent chiral auxiliary for the formation of (3R,4S)-3-[(t-butyldimethylsilyl)oxy]-4-phenyl-2-azetidinone in high enantiomeric purity. Coupling between (3R,4S)-N-benzoyl-3-[(t-butyldimethylsilyl)oxy]-4-phenyl-2-azetidinone and 7-(triethylsilyl)baccatin III in the presence of sodium hydride as the base provided an efficient taxol semisynthesis.

The oxetane conformational lock of paclitaxel: Structural analysis of D-secopaclitaxel

Analysis of the 1H NMR data of paclitaxel in comparison with its oxetane ring-opened analogue D-secopaclitaxel suggests that the oxetane moiety (D-ring) of paclitaxel serves as a conformational lock for the diterpene moiety and the C13 side chain.

Heteroaromatic taxol analogues: The chemistry and biological activities of 3'-furyl and 3'-pyridyl substituted taxanes

Abstract A series of novel heterocyclic taxol analogues has been synthesized utilizing 2-azetidinones derived from the ester enolate-imine cyclocondensation. 2-Azetidinones possessing stereochemistry complementary to that of taxols phenylisoserine side chain were synthesized in fair to high enantiomeric purity utilizing the chiral glycolate derived from Oppolzers chiral auxiliary and the appropriate N-trimethylsilylaldimines. These novel analogues were evaluated in the microtubule assembly assay as well as tested for cytotoxicity against B16 melanoma cells. The 2-furyl analoug e 29 proved to be more active than the parent, taxol.

Synthesis and antiviral activity of HCV NS3/4A peptidomimetic boronic acid inhibitors.

A new series of NS3/4A protease boronic acid inhibitors is described. The compounds show good biochemical potency and cellular activity. The peptidomimetic inhibitors were evaluated against proteases from different HCV genotypes and clinically relevant NS3/4A mutants. Compound 28 displayed subnanomolar to single digit nanomolar potencies in the enzymatic assays and an EC50 of 25 nM in the replicon cell-based assay.

Synthesis of 2-O-heteroaroyl taxanes: evaluation of microtubule assembly promotion and cytotoxicity

Abstract A series of heterocyclic taxanes were synthesized and evaluated to investigate structure activity relationships at the 2-position of paclitaxel. The compounds were prepared through a regioselective deacylation, reacylation sequence of suitably protected paclitaxel. The heterocyclic substituted diterpenes were synthesized from paclitaxel in four steps in high overall yields. Evaluation of these analogues in a microtubule assembly assay and for their cytotoxicity against B16 melanoma cells illustrated that these compounds had diminished activity compared to paclitaxel.

Topliss approach to the synthesis of biologically active substituted N-benzoyl taxol analogues

Abstract A series of compounds, directed by the Topliss Operational Scheme, were synthesized and evaluated to investigate structure activity relationships of the N -benzoyl moiety of taxol. Evaluation of the newly prepared derivatives in the microtubule assembly assay and for cytotoxicity revealed that they possessed biological properties similar to taxol. Nine novel substituted N -benzoyl analogues of taxol were prepared, using the Topliss approach to drug design. The taxanes were prepared from N -acyl-3-hydroxy-4-phenyl-2-azetidinones and baccatin III or by acylation of N -debenzoyltaxol. In vitro biological evaluation revealed that these analogues had activity similar to taxol.

Synthesis and biology of substituted 3′-phenyl taxol analogues

Abstract A series of substituted 3′-phenyl taxol analogues, directed by the Topliss Operational Scheme, were synthesized and evaluated for their biological activity. The novel analogues were prepared from baccatin III and N-acyl β-lactams. Evaluation in the microtubule assembly assay and for cytotoxicity against B16 melanoma cells illustrated a modest influence of aromatic substitution on bioactivity.