Michael Leroy Phillips

Synthesis and structure-activity relationships of benzophenones as inhibitors of cathepsin D

Abstract Non peptide inhibitors of cathepsin D, an aspartyl protease that has been implicated in many disease states including Alzheimers disease, were prepared and evaluated. The most potent inhibitor of cathepsin D in this series was found to be (Z)-5-[[4-(4-benzoyl-3-hydroxy-2-propylphenoxy) methylphenyl]methylene]-2-thioxo-4-thiazolidinone ( 3f , IC 50 = 210 nM).

Reactions of TMSI with cephalosporin esters

Abstract The direct synthesis of 3-iodomethyl cephalosporin esters from 3-acetoxy- and 3-carbamoylmethyl analogues may be achieved using TMSI. The “one-pot” conversion of sodium cephalothin into a C-3 heterocycle-substituted cephalosporin may also be performed using TMSI-mediated chemistry.

The anti-inflammatory effects of LY178002 and LY256548

LY178002 (5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene-4-thiazolidinone) and its N-methyl analog, LY256548, inhibit the enzymatic activity of phospholipase A2, 5-lipoxygenase and fatty acid cycloxygenase. They also inhibit leukotriene B4 production from human polymorphonuclear leukocytes stimulated with the calcium ionophore A23187. Since products of the arachidonic acid cascade have been implicated as important mediators in a variety of inflammatory diseases including arthritis, LY178002 and LY256548 were studied in the Freunds Complete Adjuvant-Induced Arthritis (FCA) model in rats. The compounds were administered orally and inhibition of bone damage and paw swelling was assessed of both the injected and uninjected paws. At 50 mg/kg LY178002 inhibited soft tissue swelling in the uninjected paw by 81% while LY256548 exhibited 57% inhibition. Bone damage was also significantly inhibited by both compounds. A dose response was conducted. The minimum effective dose for LY178002 was 10 mg/kg p.o. In the established FCA model LY178002 at 50 mg/kg p.o. inhibited the uninjected paw swelling by 75% while LY256548 did not show this level of activity. These results suggest that LY178002 and LY256548 may be useful in the treatment of arthritis.

3-oxa-5-carba analogues of β-lactam antibiotics

Abstract The syntheses of some 3-oxa-l-azabicyclo[4.2.0]octan-8-one carboxylic acid salts is described using Hg+2-assisted intramolecular cyclization of an allyl-azetidinone alcohol.

SUBSTRATE SPECIFICITY OF THE KINETIC RESOLUTION OF SULFIDES BY ENANTIOSELECTIVE SULFOXIDE FORMATION

Abstract The kinetic resolution of tazofelone ( 1 ) has been reported. The resolution of this sulfide was accomplished via enantioselective sulfoxide formation with tert -Bu hydroperoxide in the presence of a chiral tartrate/titanium complex. The resolution was performed on analogues of compound 1 in order to explore the substrate specificity of the kinetic resolution. These experiments have shown that the success of the enantioselective oxidation of this sulfide by tert -Bu hydroperoxide is greatly influenced by the nature of the neighboring amide functionality.

Cyclic platelet-activating factor analogues derived from 2-deoxy-D-erythro-pentose

A method for the synthesis of chiral cyclic analogues of platelet-activating factor (PAF) is reported. Treatment of suitably substituted derivatives of 2-deoxy-D-erythro-pentose with phosphorus oxychloride, followed by choline p-toluenesulfonate generates cyclic phospholipids in good yield. Further chemical modification produces other compounds including optically active gamma-butyrolactones such as 2-deoxy-5-O-hexadecyl-3-O-phosphocholyl-D-erythro-pentono-1, 4-lactone and 2-deoxy-3-O-hexadecyl-5-O-phosphocholyl-D-erythro-pentono-1, 4-lactone. All phospholipids were poor antagonists of PAF-induced aggregation of human platelets, and two analogs were poor agonists. The chemistry presented should be useful for the syntheses of other conformationally restricted analogues of PAF.