233277-99-1

Basic information

• Product Name: N-(4-Methylpiperazin-1-ylcarbonyl)-L-phenylalanine 1(S)-(2-phenylethyl)-3-(phenylsulfonyl) -2(E)-propenyl amide
• Synonyms: K-777; CRA-3316; APC-3316; K-11777
• CAS NO: 233277-99-1
• Molecular Formula: C₃₂H₃₈N₄O₄S
• Molecular Weight: 574.74806
• Mol File: 233277-99-1.mol

Chemical Properties

• Boiling Point: 861.0±65.0 °C(Predicted)
• Density: 1.217±0.06 g/cm3(Predicted)
• PKA: 12.48±0.20(Predicted)
• CAS DataBase Reference: N-(4-Methylpiperazin-1-ylcarbonyl)-L-phenylalanine 1(S)-(2-phenylethyl)-3-(phenylsulfonyl) -2(E)-propenyl amide(CAS DataBase Reference)
• NIST Chemistry Reference: N-(4-Methylpiperazin-1-ylcarbonyl)-L-phenylalanine 1(S)-(2-phenylethyl)-3-(phenylsulfonyl) -2(E)-propenyl amide(233277-99-1)
• EPA Substance Registry System: N-(4-Methylpiperazin-1-ylcarbonyl)-L-phenylalanine 1(S)-(2-phenylethyl)-3-(phenylsulfonyl) -2(E)-propenyl amide(233277-99-1)

Safety Data

• Hazardous Substances Data: 233277-99-1(Hazardous Substances Data)

Upstream product

• 170111-43-0 (1E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-amine hydrochloride 
• 115766-11-5 N-[(4-methyl-1-piperazinyl)carbonyl]-L-phenylalanine 
• 109-01-3 1-methyl-piperazine 
• 38066-16-9 diethyl [(phenylthio)methyl]phosphonate 
• 56069-39-7 diethyl phenylsulfonylmethylphosphonate 
• 82732-07-8 Boc-L-homophenylalanine 
• 2462-32-0 L-phenylalanine benzyl ester hydrochloride 
• 108-98-5 thiophenol 
• 119624-66-7 benzyl (2S)-2-isocyanato-3-phenylpropanoate 
• 170112-07-9 (S)-tert-butyl (1-oxo-4-phenylbutan-2-yl)carbamate 
• 183444-03-3 tert-butyl (S)-(1-(methoxy(methyl)amino)-1-oxo-4-phenylbutan-2-yl)-carbamate 
• 170111-73-6 (3S)-N-(1-benzenesulfonyl-5-phenyl-pent-1-en-3-yl)carbamic acid tert-butyl ester 
• 55112-42-0 4-methylpiperazine-1-carbonyl chloride monohydrochloride 
• 119601-52-4 benzyl (S)-2-[(4-methylpiperazine-1-carbonyl)amino]-3-phenylpropionate 

Relevant articles and documents

Photoredox Alkenylation of Carboxylic Acids and Peptides: Synthesis of Covalent Enzyme Inhibitors

The synthesis of vinyl sulfones and (α,β-unsaturated) nitriles from carboxylic acids was realized through oxidative decarboxylation with 1,4-dicyanoanthracene as an organic photoredox catalyst. Various types of C-radicals are generated and used to construct three different classes of potential covalent protease inhibitors. The procedure is functional group tolerant and applicable to natural products and druglike scaffolds. It may serve for the rapid construction of screening candidates as demonstrated by a three-step synthesis of the known protease inhibitor K11777.

INHIBITORS OF SARS COV-2 INFECTION AND USES THEREOF

Provided herein are pharmaceutical compositions including compounds having Formula I (I) in an effective amount to inhibit non-viral cysteine protease (e.g., mammalian cysteine protease, such as human cathepsin L), as well as methods of using thereof.

Asymmetric Synthesis of γ-Amino-Functionalised Vinyl Sulfones: De Novo Preparation of Cysteine Protease Inhibitors

The enantioselective azo-based -amination of an aldehyde followed by a Horner Wadsworth Emmons-based vinyl sulfone formation is reported. The thus obtained optically active N,N'-diprotected trans-(phenylsulfonyl)vinyl hydrazine products were then converted into the corresponding N-functionalised trans-(phenylsulfonyl)vinyl amines. Specifically, reaction of 4-phenylbutanal with di-tert-butyl azodicarboxylate (DBAD) in the presence of L- or D-proline, followed by addition of diethyl [(phenylsulfonyl)methyl]phosphonate, gave either enantiomer of di-tert-butyl trans-1-[5-phenyl-1-(phenylsulfonyl)pent-1-en-3-yl]hydrazine-1,2-dicarboxylate. The enantiomeric excesses of the (+)- and (-)-enantiomers prepared in this manner were in the range 86 89%. The conversion of these -hydrazino vinyl sulfones into the corresponding -amino-substituted compounds was achieved following a Boc deprotection, Zn reduction, N-functionalisation sequence. This three-step sequence was reasonably efficient (approx. 50%) and no erosion of enantiopurity was found to have taken place. The compounds accessed via this process include both enantiomers of tert-butyl trans-[5-phenyl-1-(phenylsulfonyl)pent-1-en-3-yl]carbamate and epimeric dipeptide mimetics including 4-methyl-N-{(S)-1-oxo-3-phenyl-1-[((S,E)-5-phenyl-1-(phenylsulfonyl)pent-1-en-3-yl)amino]propan-2-yl}piperazine-1-carboxamide (also known as K777).

Quantum Chemical-Based Protocol for the Rational Design of Covalent Inhibitors

We propose a structure-based protocol for the development of customized covalent inhibitors. Starting from a known inhibitor, in the first and second steps appropriate substituents of the warhead are selected on the basis of quantum mechanical (QM) computations and hybrid approaches combining QM with molecular mechanics (QM/MM). In the third step the recognition unit is optimized using docking approaches for the noncovalent complex. These predictions are finally verified by QM/MM or molecular dynamic simulations. The applicability of our approach is successfully demonstrated by the design of reversible covalent vinylsulfone-based inhibitors for rhodesain. The examples show that our approach is sufficiently accurate to identify compounds with the desired properties but also to exclude nonpromising ones.

Total Synthesis of K777: Successful Application of Transition-Metal-Catalyzed Alkyne Hydrothiolation toward the Modular Synthesis of a Potent Cysteine Protease Inhibitor

We report the total synthesis of K777 and a series of analogues via alkyne hydrothiolation catalyzed by Wilkinson's complex (ClRh(PPh3)3). The alkyne hydrothiolation reactions proceeded with excellent regio- and diastereoselectivity

Optimization of peptidyl allyl sulfones as clan CA cysteine protease inhibitors

This research investigates the synthesis and inhibitory potency of a series of novel dipeptidyl allyl sulfones as clan CA cysteine protease inhibitors. The structure of the inhibitors consists of a R1-Phe-R2-AS-Ph scaffold (AS = allyl sulfone). R1 was varied with benzyloxycarbonyl, morpholinocarbonyl, or N-methylpiperazinocarbonyl substituents. R2 was varied with either Phe of Hfe residues. Synthesis involved preparation of vinyl sulfone analogues followed by isomerization to allyl sulfones using n-butyl lithium and t-butyl hydroperoxide. Sterics, temperature and base strength were all factors that affected the formation and stereochemistry of the allyl sulfone moiety. The inhibitors were assayed with three clan CA cysteine proteases (cruzain, cathepsin B and calpain I) as well as one serine protease (trypsin). The most potent inhibitor, (E)-Mu-Phe-Hfe-AS-Ph, displayed at least 10-fold selectivity for cruzain over clan CA cysteine proteases cathepsin B and calpain I with a kobs/[I] of 6080 ± 1390 M-1s-1.

Optimization of peptidyl allyl sulfones as clan CA cysteine protease inhibitors

This research investigates the synthesis and inhibitory potency of a series of novel dipeptidyl allyl sulfones as clan CA cysteine protease inhibitors. The structure of the inhibitors consists of a R1-Phe-R2-AS-Ph scaffold (AS=allyl sulfone). R1 was varied with benzyloxycarbonyl, morpholinocarbonyl, or N-methylpiperazinocarbonyl substituents. R2 was varied with either Phe of Hfe residues. Synthesis involved preparation of vinyl sulfone analogues followed by isomerization to allyl sulfones using n-butyl lithium and t-butyl hydroperoxide. Sterics, temperature and base strength were all factors that affected the formation and stereochemistry of the allyl sulfone moiety. The inhibitors were assayed with three clan CA cysteine proteases (cruzain, cathepsin B and calpain I) as well as one serine protease (trypsin). The most potent inhibitor, (E)-Mu-Phe-Hfe-AS-Ph, displayed at least 10-fold selectivity for cruzain over clan CA cysteine proteases cathepsin B and calpain I with a kobs/[I] of 6080±1390M-1s-1.

Proteomic profiling and potential cellular target identification of K11777, a clinical cysteine protease inhibitor, in Trypanosoma brucei

We report herein the design, synthesis and application of K11777-derived activity-based probes (ABPs) allowing in situ profiling and identification of potential cellular targets of K11777 in Trypanosoma brucei.

Potency and selectivity of P2/P3-modified inhibitors of cysteine proteases from trypanosomes

A systematic study of P2 and P3 substitution in a series of vinyl sulfone cysteine protease inhibitors is described. The introduction of a methyl substituent in the P2 phenylalanine aryl ring had a favorable effect on protease inhibition and conferred modest selectivity for rhodesain over cruzain. Rhodesain selectivity could be enhanced further by combining these P2 modifications with certain P3 amide substituents.