Studies of sulfurated compounds and epoxidation of MDH adducts. New inhibitors of cysteine proteases.

Abstract

A. L. Martínez presents a PhD thesis on syntheses design and testing of new protease inhibitors targeting proteasome and cysteine proteases, e.g. cathepsins. With the various chapters his thesis covers fields from organic chemistry and medicinal chemistry, it includes detailed mechanistic studies on reaction mech- anisms and stereochemical output of the reactions.

In chapter 1 A. L. Martínez presents his work on syntheses of unsaturated compounds from sulfinyl esters by elimination reaction. His detailed and very systematic studies resulted in a proposal for a complete reaction pathway which explains the formation of all by-products. He could also demonstrate by trapping reactions and mass spectrometric studies that the elimination of 2-arylsulfinyl esters proceeds via an intermolecular radical process.

Chapter 2 describes the results on stereoisomerization studies of ¿-hydroxy-ß-sulfenyl-¿,ß-naphthoquinones. This isomerization is a consequence of sulfur-oxygen (S-O)-interactions which is proven by a systematic work including the X-ray structure of a representative compound, analyses of the isomerization with different bases and studies with model compounds which contain oxygen instead of sulfur. With this part he could demonstrate that the S-O-interaction is the driving reason for the stereochemical outcome of the isomerization reaction of the naphthoquinones.

Chapter 3 also deals with stereoselectivity of an organic reaction, namely the epoxidation of 3-hydroxy-2-methylene esters. A. L. Martínez performed an extensive synthetic work for the optimization of the synthesis of differently substituted unsaturated esters by Morita-Baylis-Hillman (MBH) reaction and the optimization of their epoxidation. He confirmed the stereoselectivity and relative configuration by transformation of epoxides into the respective cyclic carbonates and their analyses by NOE mesurements.

Chapter 4 covers a medicinal chemistry topic, the development of inhibitors of proteasome and cysteine proteases. The main goal of this part was the evaluation of new electrophilic warheads for peptidic or peptidomimetic inhibitors, i.e. warheads which covalently block the active site residues of the proteases. A. L. Martínez synthesized nitroalkenes which should covalently but reversibly inhibit the proteases. From these inhibitors also epoxides, cyclopropanes and aziridines should be derived. Furthermore, epoxy sulfones related to the well-known vinyl sulfone K11777 should be synthesized, as well as chloroketone sulfones, chlorovinyl sulfones, and finally carbonyl acetylenic inhibitors. A. L. Martínez not only succeeded in syntheses of all desired compounds (except the aziridines which only could be obtained as crude mixtures), but he also could improve the synthetic route for epoxy esters, and could confirm the stereochemistry of the epoxy sulfones by converting them into oxazolidinones and by NOE measurements. The biological testing proved the new warheads as suitable traps for proteases.