Synthesis of Sulfonamido‐Pseudopeptides: New Chiral Unnatural Oligomers

Gennari, Cesare; Salom, Barbara; Potenza, Donatella; Williams, Anthony

doi:10.1002/anie.199420671

Cited by 144 publications

(84 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…3 by using the general sequence reported by Gennari et al (13) with appropriate modifications. Vinyl sulfonamides were synthesized by a Horner-WadsworthEmmons reaction of N-BOC-homophenylalanal (Fig.…”

Section: Methodsmentioning

confidence: 99%

Structure-Activity Relationships for Inhibition of Cysteine Protease Activity and Development of Plasmodium falciparum by Peptidyl Vinyl Sulfones

Shenai

Lee

Álvarez‐Hernández

et al. 2003

Antimicrob Agents Chemother

160

148

View full text Add to dashboard Cite

The Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3 appear to be required for hemoglobin hydrolysis by intraerythrocytic malaria parasites. Previous studies showed that peptidyl vinyl sulfone inhibitors of falcipain-2 blocked the development of P. falciparum in culture and exerted antimalarial effects in vivo. We now report the structure-activity relationships for inhibition of falcipain-2, falcipain-3, and parasite development by 39 new vinyl sulfone, vinyl sulfonate ester, and vinyl sulfonamide cysteine protease inhibitors. Levels of inhibition of falcipain-2 and falcipain-3 were generally similar, and many potent compounds were identified. Optimal antimalarial compounds, which inhibited P. falciparum development at low nanomolar concentrations, were phenyl vinyl sulfones, vinyl sulfonate esters, and vinyl sulfonamides with P 2 leucine moieties. Our results identify independent structural correlates of falcipain inhibition and antiparasitic activity and suggest that peptidyl vinyl sulfones have promise as antimalarial agents.Malaria is one of the most important infectious diseases in the world. Plasmodium falciparum, the most virulent human malaria parasite, is estimated to cause over 300 million new cases and 1 million deaths annually (33). Further complicating this grim scenario is the emergence of the widespread resistance of P. falciparum to available antimalarial drugs (25). New drugs to combat malaria are urgently needed.Among potential new targets for antimalarial chemotherapy are enzymes that mediate hemoglobin hydrolysis. Intraerythrocytic P. falciparum trophozoites derive amino acids for protein synthesis from the hydrolysis of host cell hemoglobin in an acidic food vacuole (12,20,27). Proteases that hydrolyze hemoglobin in the food vacuole include members of the aspartic protease (1), cysteine protease (38, 39), and metalloprotease (9) families. Cysteine protease inhibitors arrested the erythrocytic life cycle of P. falciparum (26). Examination of inhibitortreated parasites revealed abnormally swollen food vacuoles filled with undigested hemoglobin, indicating that the block in parasite development was due to the inhibition of hemoglobin hydrolysis (26).P. falciparum contains three fairly typical papain family cysteine proteases, known as falcipains (28,38,39). Falcipain-2 and falcipain-3 appear to be the principal cysteine protease hemoglobinases (38, 39). Both of these proteases localize to vacuolar parasite fractions and readily hydrolyze hemoglobin under physiological reducing conditions at acidic pHs (37). Falcipain-2 is considerably more active against small peptide substrates, but the specificities of the two proteases are similar; both enzymes display a strong preference for leucine at the P 2 position (38, 39). The role of falcipain-1 in hemoglobin hydrolysis is unknown.In earlier studies, peptidyl vinyl sulfones inhibited falcipain-2 activity and parasite development at nanomolar concentrations and were active in vivo against murine malaria (22,29,30). We have now init...

show abstract

Section: Methodsmentioning

confidence: 99%

Structure-Activity Relationships for Inhibition of Cysteine Protease Activity and Development of Plasmodium falciparum by Peptidyl Vinyl Sulfones

Shenai

Lee

Álvarez‐Hernández

et al. 2003

Antimicrob Agents Chemother

160

148

View full text Add to dashboard Cite

show abstract

“…[13] Briefly, Cbzprotected leucinol (2) was converted into the corresponding amino aldehyde (3) by a Swern oxidation. A Wittig-Horner reaction with ethyl diethylphosphoryl methanesulfonate afforded vinylsulfonate ester 6, which was cleaved by Bu4NI.…”

Section: Chemistrymentioning

confidence: 99%

Proteasome inhibition by new dual warhead containing peptido vinyl sulfonyl fluorides

Brouwer

Álvarez

Ciaffoni

et al. 2016

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

“…80b, 91,92 The ability to efficiently assemble large synthetic oligomers provides an opportunity to generate unnatural polymers with defined secondary and tertiary structures. To designate these type of compounds, Borman and Gellman 93 introduced the concept of the foldamer.…”

Section: Michael Addition Of Nitrogen Derivatives To Vinyl Sulfonatesmentioning

confidence: 99%

Asymmetric Synthesis of α-Substituted-β-Amino Phosphonates and Phosphinates and β-Amino Sulfur Analogs

Palacios¹,

Alonso²,

Santos³

2005

Enantioselective Synthesis of Β-Amino Acids

View full text Add to dashboard Cite

Synthesis of Sulfonamido‐Pseudopeptides: New Chiral Unnatural Oligomers

Cited by 144 publications

References 46 publications

Structure-Activity Relationships for Inhibition of Cysteine Protease Activity and Development of Plasmodium falciparum by Peptidyl Vinyl Sulfones

Structure-Activity Relationships for Inhibition of Cysteine Protease Activity and Development of Plasmodium falciparum by Peptidyl Vinyl Sulfones

Proteasome inhibition by new dual warhead containing peptido vinyl sulfonyl fluorides

Asymmetric Synthesis of α-Substituted-β-Amino Phosphonates and Phosphinates and β-Amino Sulfur Analogs

Contact Info

Product

Resources

About