7 research outputs found
Recommended from our members
Arynes and Cyclic Alkynes as Synthetic Building Blocks for Stereodefined Quaternary Centers
We report a facile method to synthesize
stereodefined quaternary
centers from reactions of arynes and related strained intermediates
using β-ketoester-derived substrates. The conversion of β-ketoesters
to chiral enamines is followed by reaction with in situ generated
strained arynes or cyclic alkynes. Hydrolytic workup provides the
arylated or alkenylated products in enantiomeric excesses as high
as 96%. We also describe the one-pot conversion of a β-ketoester
substrate to the corresponding enantioenriched α-arylated product.
Computations show how chirality is transferred from the <i>N</i>-bound chiral auxiliary to the final products. These are the first
theoretical studies of aryne trapping by chiral nucleophiles to set
new stereocenters. Our approach provides a solution to the challenging
problem of stereoselective β-ketoester arylation/alkenylation,
with formation of a quaternary center
2<i>H</i>‑1,2,3-Triazole-Based Dipeptidyl Nitriles: Potent, Selective, and Trypanocidal Rhodesain Inhibitors by Structure-Based Design
Macrocyclic
inhibitors of rhodesain (RD), a parasitic cysteine
protease and drug target for the treatment of human African trypanosomiasis,
have shown low metabolic stability at the macrocyclic ether bridge.
A series of acyclic dipeptidyl nitriles was developed using structure-based
design (PDB ID: 6EX8). The selectivity against the closely related cysteine protease
human cathepsin L (hCatL) was substantially improved, up to 507-fold.
In the S2 pocket, 3,4-dichlorophenylalanine residues provided high
trypanocidal activities. In the S3 pocket, aromatic residues provided
enhanced selectivity against hCatL. RD inhibition (<i>K</i><sub>i</sub> values) and <i>in vitro</i> cell-growth of <i>Trypanosoma brucei rhodesiense</i> (IC<sub>50</sub> values)
were measured in the nanomolar range. Triazole-based ligands, obtained
by a safe, gram-scale flow production of ethyl 1<i>H</i>-1,2,3-triazole-4-carboxylate, showed excellent metabolic stability
in human liver microsomes and <i>in vivo</i> half-lives
of up to 1.53 h in mice. When orally administered to infected mice,
parasitaemia was reduced but without complete removal of the parasites
2<i>H</i>‑1,2,3-Triazole-Based Dipeptidyl Nitriles: Potent, Selective, and Trypanocidal Rhodesain Inhibitors by Structure-Based Design
Macrocyclic
inhibitors of rhodesain (RD), a parasitic cysteine
protease and drug target for the treatment of human African trypanosomiasis,
have shown low metabolic stability at the macrocyclic ether bridge.
A series of acyclic dipeptidyl nitriles was developed using structure-based
design (PDB ID: 6EX8). The selectivity against the closely related cysteine protease
human cathepsin L (hCatL) was substantially improved, up to 507-fold.
In the S2 pocket, 3,4-dichlorophenylalanine residues provided high
trypanocidal activities. In the S3 pocket, aromatic residues provided
enhanced selectivity against hCatL. RD inhibition (<i>K</i><sub>i</sub> values) and <i>in vitro</i> cell-growth of <i>Trypanosoma brucei rhodesiense</i> (IC<sub>50</sub> values)
were measured in the nanomolar range. Triazole-based ligands, obtained
by a safe, gram-scale flow production of ethyl 1<i>H</i>-1,2,3-triazole-4-carboxylate, showed excellent metabolic stability
in human liver microsomes and <i>in vivo</i> half-lives
of up to 1.53 h in mice. When orally administered to infected mice,
parasitaemia was reduced but without complete removal of the parasites
Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors
Improving the binding affinity of
a chemical series by systematically
probing one of its exit vectors is a medicinal chemistry activity
that can benefit from molecular modeling input. Herein, we compare
the effectiveness of four approaches in prioritizing building blocks
with better potency: selection by a medicinal chemist, manual modeling,
docking followed by manual filtering, and free energy calculations
(FEP). Our study focused on identifying novel substituents for the
apolar S2 pocket of cathepsin L and was conducted entirely in a prospective
manner with synthesis and activity determination of 36 novel compounds.
We found that FEP selected compounds with improved affinity for 8
out of 10 picks compared to 1 out of 10 for the other approaches.
From this result and other additional analyses, we conclude that FEP
can be a useful approach to guide this type of medicinal chemistry
optimization once it has been validated for the system under consideration
Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors
Improving the binding affinity of
a chemical series by systematically
probing one of its exit vectors is a medicinal chemistry activity
that can benefit from molecular modeling input. Herein, we compare
the effectiveness of four approaches in prioritizing building blocks
with better potency: selection by a medicinal chemist, manual modeling,
docking followed by manual filtering, and free energy calculations
(FEP). Our study focused on identifying novel substituents for the
apolar S2 pocket of cathepsin L and was conducted entirely in a prospective
manner with synthesis and activity determination of 36 novel compounds.
We found that FEP selected compounds with improved affinity for 8
out of 10 picks compared to 1 out of 10 for the other approaches.
From this result and other additional analyses, we conclude that FEP
can be a useful approach to guide this type of medicinal chemistry
optimization once it has been validated for the system under consideration
Structural Characterization of the Highly Cyclized Lantibiotic Paenicidin A via a Partial Desulfurization/Reduction Strategy
Lantibiotics
are ribosomally synthesized antimicrobial peptides
produced by bacteria that are increasingly of interest for food preservation
and possible therapeutic uses. These peptides are extensively post-translationally
modified, and are characterized by lanthionine and methyllanthionine
thioether cross-links. <i>Paenibacillus polymyxa</i> NRRL
B-30509 was found to produce polymyxins and tridecaptins, in addition
to a novel lantibiotic termed paenicidin A. A bacteriocin termed SRCAM
602 previously reported to be produced by this organism and claimed
to be responsible for inhibition of <i>Campylobacter jejuni</i> could not be detected either directly or by genomic analysis. The
connectivities of the thioether cross-links of paenicidin A were solved
using a novel partial desulfurization/reduction strategy in combination
with tandem mass spectrometry. This approach overcame the limitations
of NMR-based structural characterization that proved mostly unsuccessful
for this peptide. Paenicidin A is a highly cyclized lantibiotic, containing
six lanthionine and methyllanthionine rings, three of which are interlocking
Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors
Rhodesain
(RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease
produced by Trypanosoma brucei (<i>T</i>. <i>b</i>.) species and a potential drug target
for the treatment of human African trypanosomiasis (HAT). A library
of hCatL inhibitors was screened, and macrocyclic lactams were identified
as potent RD inhibitors (<i>K</i><sub>i</sub> < 10 nM),
preventing the cell-growth of Trypanosoma brucei rhodesiense (IC<sub>50</sub> < 400 nM). SARs addressing the S2 and S3 pockets
of RD were established. Three cocrystal structures with RD revealed
a noncovalent binding mode of this ligand class due to oxidation of
the catalytic Cys25 to a sulfenic acid (Cys–SOH) during crystallization.
The P-glycoprotein efflux ratio was measured and the in vivo brain
penetration in rats determined. When tested in vivo in acute HAT model,
the compounds permitted up to 16.25 (vs 13.0 for untreated controls)
mean days of survival