Several caspases have been implicated in the pathogenesis of Huntington’s disease (HD); however, existing caspase inhibitors lack the selectivity required to investigate the specific involvement of ...individual caspases in the neuronal cell death associated with HD. In order to explore the potential role played by caspase-2, the potent but non-selective canonical Ac-VDVAD-CHO caspase-2 inhibitor
1 was rationally modified at the P
2 residue in an attempt to decrease its activity against caspase-3. With the aid of structural information on the caspase-2, and -3 active sites and molecular modeling, a 3-(
S)-substituted-
l-proline along with four additional scaffold variants were selected as P
2 elements for their predicted ability to clash sterically with a residue of the caspase-3 S
2 pocket. These elements were then incorporated by solid-phase synthesis into pentapeptide aldehydes
33a–
v. Proline-based compound
33h bearing a bulky 3-(
S)-substituent displayed advantageous characteristics in biochemical and cellular assays with 20- to 60-fold increased selectivity for caspase-2 and ∼200-fold decreased caspase-3 potency compared to the reference inhibitor
1. Further optimization of this prototype compound may lead to the discovery of valuable pharmacological tools for the study of caspase-2 mediated cell death, particularly as it relates to HD.
Several caspases have been implicated in the pathogenesis of Huntington's disease (HD); however, existing caspase inhibitors lack the selectivity required to investigate the specific involvement of ...individual caspases in the neuronal cell death associated with HD. In order to explore the potential role played by caspase-2, the potent but non-selective canonical Ac-VDVAD-CHO caspase-2 inhibitor 1 was rationally modified at the P sub(2 residue in an attempt to decrease its activity against caspase-3. With the aid of structural information on the caspase-2, and -3 active sites and molecular modeling, a 3-(S)-substituted-l-proline along with four additional scaffold variants were selected as P) sub(2) elements for their predicted ability to clash sterically with a residue of the caspase-3 S sub(2 pocket. These elements were then incorporated by solid-phase synthesis into pentapeptide aldehydes 33a-v. Proline-based compound 33h bearing a bulky 3-(S)-substituent displayed advantageous characteristics in biochemical and cellular assays with 20- to 60-fold increased selectivity for caspase-2 and approx200-fold decreased caspase-3 potency compared to the reference inhibitor 1. Further optimization of this prototype compound may lead to the discovery of valuable pharmacological tools for the study of caspase-2 mediated cell death, particularly as it relates to HD.)
To examine the relationship between the maternal serum bisphenol A (BPA) concentration at the time of the missed menstrual cycle and miscarriage risk.
Retrospective cohort of prospectively collected ...serum samples.
Academic fertility center.
Women presenting for early pregnancy monitoring with singleton pregnancies.
Stored serum samples from 4 to 5 weeks' gestation analyzed for conjugated serum BPA concentrations.
Live birth, miscarriage, and chromosome content of miscarriage.
With the 115 women included in the study, there were 47 live births and 68 clinical miscarriages (46 aneuploid and 22 euploid). Median conjugated BPA concentrations were higher in the women who had miscarriages than in those who had live births (0.101 vs. 0.075 ng/mL). Women with the highest quartile of conjugated BPA had an increased relative risk of miscarriage (1.83; 95% CI, 1.14-2.96) compared with the women in the lowest quartile. We found a similar increase risk for both euploid and aneuploid miscarriages.
Maternal conjugated BPA was associated with a higher risk of aneuploid and euploid miscarriage in this cohort. The impact of reducing individual exposure on future pregnancy outcomes deserves further study.
An X‐ray crystal structure of Kelch‐like ECH‐associated protein (Keap1) co‐crystallised with ...(1S,2R)‐2‐(1S)‐1‐(1,3‐dioxo‐2,3‐dihydro‐1H‐isoindol‐2‐yl)methyl‐1,2,3,4‐tetrahydroisoquinolin‐2‐carbonylcyclohexane‐1‐carboxylic acid (compound (S,R,S)‐1 a) was obtained. This X‐ray crystal structure provides breakthrough experimental evidence for the true binding mode of the hit compound (S,R,S)‐1 a, as the ligand orientation was found to differ from that of the initial docking model, which was available at the start of the project. Crystallographic elucidation of this binding mode helped to focus and drive the drug design process more effectively and efficiently.
To dock or not to dock? Nrf2 has become an attractive neuroprotective target, as the Nrf2 pathway provides a natural cell defense mechanism against damage. Targeting its physiological negative modulator Keap1 with small molecules may allow Nrf2 to play its protective role. To this end, an X‐ray structure of Keap1 co‐crystallised with compound (S,R,S)‐1 a was obtained, elucidating its binding mode, which in turn helped to drive the drug design process.
The traceless cleavage of Rink amide resin to form thiazoles has been achieved using commercially available reagents. Conversion of Rink amide species to thioamides by use of Lawesson’s reagent ...prepares the resin bound substrates for traceless cleavage. Cleavage using limiting amounts of α-haloketones provides thiazole bearing compounds of high purity.
As part of a program of screening the Merck sample collection, N-ethyl-L-tryptophan benzyl ester was identified as a weak antagonist at the substance P (NK1) receptor. Structure-activity studies ...showed that the indole ring system could be replaced by 3,4-dichlorophenyl, alpha- or beta-naphthyl, or benzthiophene with retention or only small loss of affinity. It was found that acylation of the tryptophan nitrogen gave compounds with higher affinity than N-ethyl or other basic amines. Optimization of substitution on the benzyl ester led to the identification of the 3,5-bis-(trifluoromethyl)benzyl ester of N-acetyl-L-tryptophan 26 as a potent and selective substance P receptor antagonist. Compound 26 blocked substance P induced dermal extravasation in vivo and was the most potent compound from this structurally novel class of antagonists which further adds to the diversity of small molecules that bind to the (NK1) receptor.
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