Donald T. Witiak

Design, combinatorial chemical synthesis and in vitro characterization of novel urea based gelatinase inhibitors.

A novel series of hydroxamate/urea-based inhibitors of gelatinases has been discovered via solid-phase combinatorial chemistry. SAR of P1, P2, and P3 has been exploited and structures different from traditional succinate-based MMP inhibitors have been found.

Potent inhibitory activities of hydrophobic aci-reductones (2-hydroxytetronic acid analogs) against membrane and human low-density lipoprotein oxidation.

The effects of selected aci-reductones, which are hydrophobic ascorbate-related analogs including 4-chlorophenyl-2-hydroxytetronic acid (Cpd A), 4-(1,1-biphenyl)-2-hydroxytetronic acid (Cpd B), and 4-(4-chloro-1,1-biphenyl)-2-hydroxytetronic acid (Cpd C), on membrane and low density lipoprotein (LDL) oxidation were assessed. Hepatic microsomal lipid peroxidation was induced by the ascorbate + Fe(II) chemical system. All three agents inhibited membrane lipid peroxidation in a concentration-dependent manner with the order of potency: Trolox (vitamin E) < or = Cpd A << Cpd B < Cpd C; based on the EC50 values, Cpd B and Cpd C were 11- and 19-fold, respectively, more potent than Trolox. In contrast to ascorbic acid, all three agents did not display any membrane prooxidative effect in the presence of iron. When human LDL was incubated with 10 microM of Cu(II), LDL oxidation, determined by the formation of thiobarbituric acid reactive substances, followed a typical sigmoidal curve with an initial lag phase. Preincubation of the LDL samples with low micromolar concentrations (1 and 3 microM) of each agents for 30 min before the addition of copper resulted in significant delays of the lag time of LDL oxidation, and the effectiveness of Cpd B and Cpd C was more prominent than that mediated by either Trolox or probucol. Since clinical evidence strongly supports the hypothesis that atherogenesis is initiated by LDL oxidation, the results suggest that these aryl tetronic acid analogs may serve as promising candidates for future therapeutic use as anti-atherogenic agents.

Synthesis of All Distinct α-Methyl-Substituted Isomers of Amino Bis(2,2′-Ethanoic Acid) Diethyl Ester and Ethylene Diamine Tetraacetic Acid Tetraethyl Ester Scaffolds

Abstract The syntheses of three dialkylated and six tetraalkylated ethylene diamine tetraacetic acid tetraesters is described. The dialkylated derivatives were synthesized by a convergent non-racemizing route to yield three enantiomerically and diastereomerically pure tetraesters ( SS )- 3a , ( RR )- 3b and ( R ∗ S ∗ )- 3c in 55–57% yields from alanine ethyl ester 1 . Enantiomerically and diastereomerically pure tetraalkylated derivatives ( SSSS )- 8a , ( RRRR )- 8b , (2 R ∗ ,2′ S ∗ ,2″ R ∗ ,2‴ S ∗ )- 8c , (2 R ∗ ,2′ R ∗ ,2″ S ∗ ,2‴ S ∗ )- 8d , (2 R ,2′ R ,2″ R ,2‴ S )- 8e and (2 S ,2′ S ,2″ S ,2‴ R )- 8f were synthesized in two to five steps and 22–49% overall yields from alanine ethyl ester 1 .

Inhibition of topoisomerase II by ICRF-193, the meso isomer of 2,3-bis(2,6-dioxopiperazin-4-yl)butane: Critical dependence on 2,3-butanediyl linker absolute configuration

The bis(2,6-dioxopiperazine)s are a structurally and mechanistically unique class of topoisomerase II inhibitors that do not bind DNA and that do not stabilize topoisomerase II-DNA strand passing intermediates (cleavable complexes). The most effective topoisomerase II inhibitor in the bis(2,6-dioxopiperazine) series is ICRF-193 (meso or S*, R* isomer), with a meso 2,3-butanediyl linker connecting the dioxopiperazine rings. The two enantiomeric diastereomers, (R,R) and (S,S), of ICRF-193 possessing the two optically active 2,3-butanediyl linkers have been prepared from their respective optically pure 2,4-diaminobutanes via 2,3-diaminobutane-N,N,N,N-tetraacetic acid, esterification, and imide formation. Both in vivo and in vitro assays for catalytic inhibition of topoisomerase II were employed to show that the (S,S)- and (R,R)-isomers are almost inactive as topoisomerase II inhibitors. The data indicate that the meso stereochemistry of the alkanediyl linker is crucial for activity and provides additional evidence that the cytotoxicity of the bis(2,6-dioxopiperazine)s is due to their ability to inhibit topoisomerase II.

aci-Reductones: Drug design, enantioselective syntheses and biological activities within lipid membranes

Atherosclerosis is a chronic inflammatory disease which correlates with both elevated levels of lipids and depleted levels of endogenous antioxidants, a measure of oxidative stress. Oxidatively modified LDL (LDL-ox), monocytes, macrophages, smooth muscle cells, adhesion cell molecules, cytokines, foam cells and reactive oxygen species (ROS) are intrinsically linked to the inflammatory response element, nuclear factor-κB (NF-κB), in a biochemical cascade that leads to arterial plaque formation and progression.1 Dual lipophilic chain breaking antioxidant/arachidonic acid (AA) metabolic inhibitors are expected to retard atherosclerotic plaque formation through simultaneous blockade of multiple mechanisms of atherogenesis, protect against ROS induced tissue damage and restore natural antioxidant defenses. Several series of racemic and enantiomerically pure 4-substituted 2-hydroxytetronic acids, which represent both substrates and inhibitors of cyclooxygenase have been prepared and screened in a multitude of in vitro biological assays. These aci-reductones inhibit NF-κB activation (50% @ 30nM), protect against Cu++ catalyzed LDL oxidation in vitro and prevent monocyte/HUVEC binding significantly better than the antilipidemic drug probucol, and enantioselectively inhibit AA induced platelet aggregation (AAIPA) of human platelet rich plasma (PRP). This data indicates that some of these experimental antioxidants may be particularly useful for the treatment of atherosclerosis and associated vascular diseases.