96658-25-2

Upstream product

• 15260-10-3 N-Boc-O-benzyl-L-threonine 

Downstream Products

• 1609286-22-7 (2S,3R)-N,N'-(3-benzyloxybutane-1,2-diyl)bis(2-chloroacetamide) 
• 1609286-26-1 (S)-2-((R)-1-(benzyloxy)ethyl)-1,4-diaza-bicyclo[2.2.2]octane 
• 1609286-29-4 (S)-2-((R)-1-(benzyloxy)ethyl)-1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octane chloride 
• 1609286-36-3 (S)-2-((R)-1-(benzyloxy)ethyl)-1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octane trifluoromethanesulfonate 
• 135791-91-2 tert-butyl ((S)-1-(((2S,3R)-1-amino-3-(benzyloxy)-1-oxobutan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate 
• 138093-22-8 <β-(benzylthio)-β,β-pentamethylenepropionyl>-Tyr(Me)-Phe-Gln-Asn-Cys(Bzl)-Pro-Arg(Tos)-Thr(Bzl)-NH2 

Relevant academic research and scientific papers

Design, synthesis and stepwise optimization of nitrile-based inhibitors of cathepsins B and L

Human cathepsin B (CatB) is an important biological target in cancer therapy. In this work, we performed a knowledge-based design approach and the synthesis of a new set of 19 peptide-like nitrile-based cathepsin inhibitors. Reported compounds were assayed against a panel of human cysteine proteases: CatB, CatL, CatK, and CatS. Three compounds (7h, 7i, and 7j) displayed nanomolar inhibition of CatB and selectivity over CatK and CatL. The selectivity was achieved by using the combination of a para biphenyl ring at P3, halogenated phenylalanine in P2 and Thr-O-Bz group at P1. Likewise, compounds 7i and 7j showed selective CatB inhibition among the panel of enzymes studied. We have also described a successful example of bioisosteric replacement of the amide bond for a sulfonamide one [7e → 6b], where we observed an increase in affinity and selectivity for CatB while lowering the compound lipophilicity (ilogP). Our knowledge-based design approach and the respective structure–activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cathepsins.

Mapping the s1 and s1’ subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents

The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. A series of 26 new compounds were designed, synthesized, and tested against the recombinant cruzain (Cz) to map its S1/S1′ subsites. The same series was evaluated on a panel of four human cysteine proteases (CatB, CatK, CatL, CatS) and Leishmania mexicana CPB, which is a potential target for the treatment of cutaneous leishmaniasis. The synthesized compounds are dipeptidyl nitriles designed based on the most promising combinations of different moieties in P1 (ten), P2 (six), and P3 (four different building blocks). Eight compounds exhibited a Ki smaller than 20.0 nM for Cz, whereas three compounds met these criteria for LmCPB. Three inhibitors had an EC50 value of ca. 4.0 μM, thus being equipotent to benznidazole according to the antitrypanosomal effects. Our mapping approach and the respective structure-activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cysteine proteases.

CHIRAL FLUORINATING REAGENTS

This invention relates to fluorinating agents and, more particularly, to chiral non-racemic fluorinating agents useful for enantioselective fluorination, as well as to their synthesis and use and other subject matter. The fluorinating agents are based on a substituted 1,4-diazabicyclo[2.2.2]octane (DABCO) skeleton and provide electrophillic fluorine enantioselectively.