Efficient synthesis of ether phosphonates using trichloroacetimidate and acetate coupling methods

A series of ether phosphonates have been prepared by trichloroacetimidate and acetate coupling methods. Trichloroacetimidates or acetates were treated with primary and secondary alcohols as O-nucleophiles in the presence of catalytic TMSOTf to afford 21 examples of diethyl alkyloxy(substitutedphenyl)methyl phosphonates via C–O bond formation in 55–90% yields and short reaction time.

An efficient method for the synthesis of various ether phosphonates by trichloroacetimidate and acetate coupling methods is described.     

Assessment of Low LDL Cholesterol in Patients Treated by PCSK9 Inhibition: Comparison of Martin/Hopkins and Friedewald Estimations

Purpose

Recent guidelines recommend further reduction of low-density lipoprotein cholesterol (LDL-C) in high-risk populations. The use of proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i) enables many patients to achieve profound reduction in LDL-C. However, in patients with low cholesterol, the commonly used Friedewald equation tends to underestimate LDL-C, which may result in undertreatment. We aimed to compare Friedewald LDL-C estimation with the more novel Martin/Hopkins method in PCSK9i-treated patients achieving low LDL-C.

Methods

We investigated high-risk patients treated by PCSK9i in whom Friedewald LDL-C levels were <?70 mg/dL and triglycerides ≤?300 mg/dL. LDL-C was additionally assessed by the Martin/Hopkins method. The compatibility between estimations was evaluated using methods of concordance and reclassification between LDL-C categories (<?25, 25–40, 40–55, 55–70 mg/dL) and according to triglyceride strata.

Results

Mean age was 65?±?10 years. The correlation coefficient between LDL-C estimations was r?=?0.898. Martin/Hopkins reclassified 269 of the 608 patients (44%) to a higher LDL-C category, with 14% of the patients reaching LDL-C >?70 mg/dL. Of the 390 patients achieving Friedewald LDL-C <?55 mg/dL, 113 (29%) were estimated to have LDL-C ≥?55 mg/dL by the Martin/Hopkins equation. The magnitude of discordance between LDL-C estimates was more pronounced in hypertriglyceridemic patients in whom LDL-C reclassification from <?55 to ≥?55 mg/dL was observed in 48%.

Conclusions

In real-world practice of high-risk patients achieving low LDL-C under PCSK9i, Martin/Hopkins algorithm displayed significant proportion of LDL-C upward discordance compared to the Friedewald equation, particularly observed in patients with elevated triglycerides, identifying patients that may need treatment intensification.

     

Design,synthesis, antimicrobial,and DNA gyrase inhibitory properties of fluoroquinolone–dichloroacetic acid hybrids

A series of new fluoroquinolone conjugates 8a–g and 9a–f were synthesized via benzotriazole‐mediated synthetic approach with good yield and purity. Some of the synthesized analogs exhibited significant antibacterial properties against Escherichia coli and Staphylococcus aureus with potency higher than that of the parent drugs through in vitro standard bioassay procedure (conjugates 8c and 8d reveal antimicrobial properties with potency 1.9, 61.9, 20.7 and 2.4, 37.1, 8.3 folds relative to the parent antibiotic 6 against E. coli, S. aureus, and Enterococcus faecalis, respectively). The observed experimental data were supported by enzymatic DNA gyrase inhibitory property. Developed BMLR‐QSAR model validates the observed experimental data and recognizes the parameters responsible for the enhanced antibacterial properties.     

HLA-DO increases bacterial superantigen binding to human MHC molecules by inhibiting dissociation of class II-associated invariant chain peptides

HLA-DO (H2-O in mice) is an intracellular non-classical MHC class II molecule (MHCII). It forms a stable complex with HLA-DM (H2-M in mice) and shapes the MHC class II-associated peptide repertoire. Here, we tested the impact of HLA-DO and H2-O on the binding of superantigens (SAgs), which has been shown previously to be sensitive to the structural nature of the class II-bound peptides. We found that the binding of staphylococcal enterotoxin (SE) A and B, as well as toxic shock syndrome toxin 1 (TSST-1), was similar on the HLA-DO⁺ human B cell lines 721.45 and its HLA-DO⁻ counterpart. However, overexpressing HLA-DO in MHC class II⁺ HeLa cells (HeLa-CIITA-DO) improved binding of SEA and TSST-1. Accordingly, knocking down HLA-DO expression using specific siRNAs decreased SEA and TSST-1 binding. We tested directly the impact of the class II-associated invariant chain peptide (CLIP), which dissociation from MHC class II molecules is inhibited by overexpressed HLA-DO. Loading of synthetic CLIP on HLA-DR⁺ cells increased SEA and TSST-1 binding. Accordingly, knocking down HLA-DM had a similar effect. In mice, H2-O deficiency had no impact on SAgs binding to isolated splenocytes. Altogether, our results demonstrate that the sensitivity of SAgs to the MHCII–associated peptide has physiological basis and that the effect of HLA-DO on SEA and TSST-1 is mediated through the inhibition of CLIP release.