Mustafa Guzel

On the origins of enantioselectivity in oxazaborolidine mediated carbonyl reductions

Abstract A series of tricyclic oxazaborolidine catalysts have been prepared from readily available ( S )-indoline-2-carboxylic acid. In each case, an arene chromium(0) carbonyl group was introduced on one face of the catalyst. Results obtained in the borane mediated reduction of ketones highlight the stereodirective importance of the α,α-appendages in the catalyst architecture.

Refined enantioselective methylation catalysts: improved routes to bifunctional C5 synthons

Abstract Catalytic enantioselective routes to bifunctional C5 synthons, including those of the macrolide ( S )-(−)-zearalenone have been achieved. Stereochemistry was introduced using a mixed ligand arene chromium tricarbonyl catalyst to mediate the enantioselective addition of dimethyl zinc to a functionalized aldehyde. Comparison with alternate reduction strategies is presented.

Enantioselective cycloadditions catalyzed by face resolved arene chromium carbonyl complexes

Abstract A new class of readily accessible enantioselective catalysts has been developed, and examined in the Diels–Alder cycloaddition of methacrolein. Analysis of potential transition state influences provides an insight for future modification and refinement.

Induction of Heme Oxygenase I (HMOX1) by HPP-4382: A Novel Modulator of Bach1 Activity

Oxidative stress is generated by reactive oxygen species (ROS) produced in response to metabolic activity and environmental factors. Increased oxidative stress is associated with the pathophysiology of a broad spectrum of inflammatory diseases. Cellular response to excess ROS involves the induction of antioxidant response element (ARE) genes under control of the transcriptional activator Nrf2 and the transcriptional repressor Bach1. The development of synthetic small molecules that activate the protective anti-oxidant response network is of major therapeutic interest. Traditional small molecules targeting ARE-regulated gene activation (e.g., bardoxolone, dimethyl fumarate) function by alkylating numerous proteins including Keap1, the controlling protein of Nrf2. An alternative is to target the repressor Bach1. Bach1 has an endogenous ligand, heme, that inhibits Bach1 binding to ARE, thus allowing Nrf2-mediated gene expression including that of heme-oxygenase-1 (HMOX1), a well described target of Bach1 repression. In this report, normal human lung fibroblasts were used to screen a collection of synthetic small molecules for their ability to induce HMOX1. A class of HMOX1-inducing compounds, represented by HPP-4382, was discovered. These compounds are not reactive electrophiles, are not suppressed by N-acetyl cysteine, and do not perturb either ROS or cellular glutathione. Using RNAi, we further demonstrate that HPP-4382 induces HMOX1 in an Nrf2-dependent manner. Chromatin immunoprecipitation verified that HPP-4382 treatment of NHLF cells reciprocally coordinated a decrease in binding of Bach1 and an increase of Nrf2 binding to the HMOX1 E2 enhancer. Finally we show that HPP-4382 can inhibit Bach1 activity in a reporter assay that measures transcription driven by the human HMOX1 E2 enhancer. Our results suggest that HPP-4382 is a novel activator of the antioxidant response through the modulation of Bach1 binding to the ARE binding site of target genes.