An improved synthesis of aziridine-2,3-dicarboxylates via azido alcohols—epimerization studies

Breuning, Alexander; Vičík, Radim; Schirmeister, Tanja

doi:10.1016/j.tetasy.2003.09.015

Cited by 44 publications

(46 citation statements)

References 42 publications

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“…The latter two compounds were prepared stereoselectively as published recently. [15] Dipeptides for fragment coupling were synthesized by using standard peptide coupling procedures (Scheme 1: a). [16] These dipeptides were coupled with the aziridine building block with the EEDQ procedure to give aziridinyl tripeptides (Scheme 1: c).…”

Section: Synthesesmentioning

confidence: 99%

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Aziridide‐Based Inhibitors of Cathepsin L: Synthesis, Inhibition Activity, and Docking Studies

et al. 2006

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A comprehensive screening of N-acylated aziridine (aziridide) based cysteine protease inhibitors containing either Boc-Leu-Caa (Caa=cyclic amino acid), Boc-Gly-Caa, or Boc-Phe-Ala attached to the aziridine nitrogen atom revealed Boc-(S)-Leu-(S)-Azy-(S,S)-Azi(OBn)(2) (18 a) as a highly potent cathepsin L (CL) inhibitor (K(i)=13 nM) (Azy=aziridine-2-carboxylate, Azi=aziridine-2,3-dicarboxylate). Docking studies, which also accounted for the unusual bonding situations (the flexibility and hybridization of the aziridides) predict that the inhibitor adopts a Y shape and spans across the entire active site cleft, binding into both the nonprimed and primed sites of CL.

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Section: Synthesesmentioning

confidence: 99%

“…[15] Dipeptides (Boc-Phe-Ala, Boc-Leu- Caa, Boc-Gly-Caa) were synthesized and deprotected prior to coupling with the aziridine according to standard peptide-coupling procedures (for details, see Scheme 1). [16] All 1 H NMR assignments were supported by 2D COSY experiments.…”

Section: Abbreviationsmentioning

confidence: 99%

Aziridide‐Based Inhibitors of Cathepsin L: Synthesis, Inhibition Activity, and Docking Studies

et al. 2006

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“…Diethyl and dibenzyl aziridine-2,3-dicarboxylates in either the (S,S) or (R,R) configuration were prepared stereoselectively as described before (28). In the same manner, (2S,3S)-bis(4-bromobenzyl) aziridine-2,3-dicarboxylate was synthesized as a building block for s38, using (4-bromophenyl)methanol and L-(ϩ)-tartaric acid as the starting materials.…”

Section: Methodsmentioning

confidence: 99%

Development of a New Antileishmanial Aziridine-2,3-Dicarboxylate-Based Inhibitor with High Selectivity for Parasite Cysteine Proteases

Schad

Baum²,

Frank³

et al. 2016

Antimicrob Agents Chemother

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L eishmaniasis is one of the 17 neglected tropical diseases (NTDs) assigned by the World Health Organization (WHO). NTDs affect 1 billion people worldwide (1). The primary occurrences are in low-income countries in sub-Saharan Africa, Asia, and Latin America, but the Mediterranean countries of Europe are also concerned (2). Among the NTDs is the group of "most neglected diseases," affecting the poorest, mainly rural areas, including leishmaniases, sleeping sickness (African trypanosomiasis), and Chagas' disease (3). These three NTDs have the highest rates of death. However, the NTD drug discovery pipeline is almost empty, thus leading to a lack of efficient and safe drugs (2, 4). Because of climate warming and tourism, the occurrence of leishmaniasis is also reported in states around the Mediterranean Sea (1).Leishmaniasis is caused by more than 20 species of protozoan parasites belonging to the genus Leishmania. The parasite life cycle is characterized by two morphological stages: extracellular flagellated promastigotes, occurring in the insect vector, and intracellular aflagellated amastigotes, occurring in the mammalian host. The promastigotes are transmitted by an insect bite into the skin of the host, where they are internalized by macrophages, dendritic cells, neutrophils, and fibroblasts and differentiate into amastigotes residing and replicating in parasitophorous vacuoles of these phagocytes. The parasites disseminate through the lymphatic and vascular systems. During the blood meal of an (uninfected) sand fly, amastigotes are transmitted back from the infected mammalian host to the insect vector and differentiate again into promastigotes (5, 6).The clinical outcome of leishmaniasis depends on the complex interactions between the virulence characteristics of the infecting species and the type of immune response of the host. There are three clinical forms: cutaneous, mucocutaneous, and visceral leishmaniases (6).Concerning the treatment of leishmaniasis, it is obvious that new drugs must circumvent the limitations of currently established chemotherapies, i.e., toxicity, long courses of treatment, the frequent need for parenteral administration, high costs in countries where the disease is endemic, and the emergence of resistance. Therefore, it is important not only to test and apply combinations of existing drugs to avoid resistance but also to develop new potential leishmanicidal compounds with alternative mechanisms, as well as vaccination strategies (7,8).Cysteine proteases (CPs) of parasites such as Plasmodium, Trypanosoma, and worms are druggable targets for developing a new promising strategy for chemotherapy based on protease inhi-

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“…1) which has recently been used as electrophilic "warhead" for a cell-permeable affinity labeling protease probe [21]. This trans-configured aziridine is either synthesized as a racemate [22] or stereoselectively with trans-S,S, trans-R,R or cis-R,S configuration [23]. While cis and trans products can be easily separated via column chromatography on silica gel, the discrimination of the trans-configured enantiomers of 5 has only been carried out by means of polarimetry until now [23].…”

Section: Introductionmentioning

confidence: 99%

Comparison of the separation of aziridine isomers applyingheptakis(2,3-di-O-methyl-6-sulfato)β-CD andheptakis(2,3-di-O-acetyl-6-sulfato)β-CD in aqueous and nonaqueous systems

Bitar¹,

Degel²,

Schirmeister³

et al. 2005

Electrophoresis

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Aziridines are attracting interest as protease inhibitors, which might be used, e.g., for treatment of parasitic diseases. Within the framework of greater projects dealing with the search of new selective protease inhibitors, a huge number of aziridines with two stereogenic centers will be synthesized. Thus, a fast and reliable screening method for the evaluation of the isomeric composition is needed. Robust baseline separations were obtained using heptakis(2,3-di-O-acetyl-6-sulfato)beta-CD (HDAS) in acidic methanol and sulfated beta-CD in acidic phosphate buffer. With HDAS the resolutions were higher and migration times shorter. Thus, the method will be used as a screening method for further isomeric mixtures of aziridines.

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An improved synthesis of aziridine-2,3-dicarboxylates via azido alcohols—epimerization studies

Cited by 44 publications

References 42 publications

Aziridide‐Based Inhibitors of Cathepsin L: Synthesis, Inhibition Activity, and Docking Studies

Aziridide‐Based Inhibitors of Cathepsin L: Synthesis, Inhibition Activity, and Docking Studies

Development of a New Antileishmanial Aziridine-2,3-Dicarboxylate-Based Inhibitor with High Selectivity for Parasite Cysteine Proteases

Comparison of the separation of aziridine isomers applyingheptakis(2,3-di-O-methyl-6-sulfato)β-CD andheptakis(2,3-di-O-acetyl-6-sulfato)β-CD in aqueous and nonaqueous systems

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