Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
Angew Chem Int Ed Engl ; 62(39): e202309295, 2023 Sep 25.
Article in English | MEDLINE | ID: mdl-37535392

ABSTRACT

The borylation of Csp3 -H bonds is a challenging transformation that is typically restricted to transition metal catalysis. Herein, we report the site-selective metal-free Csp3 -H borylation of saturated cyclic amines. It is possible to selectively borylate piperidine derivatives at the α or ß positions according to the reaction conditions. The mechanism was supported by NMR spectroscopy, calorimetry experiments and density functional theory (DFT) computations. It suggests that the piperidine is dehydrogenated by complexation with BBr3 to produce an enamine intermediate, which is in turn borylated at either the α or ß position according to the reaction conditions.

2.
Virology ; 561: 47-57, 2021 09.
Article in English | MEDLINE | ID: mdl-34146963

ABSTRACT

Thymidylate synthase (TS) is a key enzyme in nucleotide biosynthesis. A study performed by our group on human monocyte-derived macrophages (MDMs) infected with HIV-1 showed that many enzymes related to the folate cycle pathway, such as TS, are upregulated in productively infected cells. Here, we suggest that TS is essential for an effective HIV-1 infection in MDMs. Indeed, a TS specific small interfering RNA (siRNA) as well as the TS specific inhibitor Raltitrexed (RTX) caused a reduction in productively infected cells. Quantitative PCR analysis showed that this treatment decreased the efficacy of the early steps of the viral cycle. The RTX inhibitory effect was counteracted by dNTP addition. These results suggest that TS is essential for the early stages of HIV-1 infection by providing optimal dNTP concentrations in MDMs. TS and its related pathway may thus be considered as a potential therapeutic target for HIV-1 treatment.


Subject(s)
HIV-1/physiology , Macrophages/enzymology , Macrophages/virology , Thymidylate Synthase/metabolism , Virus Replication , Cells, Cultured , Enzyme Inhibitors , Humans , Quinazolines/pharmacology , RNA Interference , RNA, Small Interfering , SAM Domain and HD Domain-Containing Protein 1/metabolism , Thiophenes/pharmacology , Thymidylate Synthase/antagonists & inhibitors , Thymidylate Synthase/genetics , Thymine Nucleotides/metabolism , Virus Replication/drug effects
3.
J Am Chem Soc ; 141(31): 12305-12311, 2019 08 07.
Article in English | MEDLINE | ID: mdl-31283206

ABSTRACT

The potential advantages of using arylboronic esters as boron sources in C-H borylation are discussed. The concept is showcased using commercially available 2-mercaptopyridine as a metal-free catalyst for the transfer borylation of heteroarenes using arylboronates as borylation agents. The catalysis shows a unique functional group tolerance among C-H borylation reactions, tolerating notably terminal alkene and alkyne functional groups. The mechanistic investigation is also described.

4.
J Virol ; 93(7)2019 04 01.
Article in English | MEDLINE | ID: mdl-30674627

ABSTRACT

The molecular basis for HIV-1 susceptibility in primary human monocyte-derived macrophages (MDMs) was previously evaluated by comparing the transcriptome of infected and bystander populations. Careful analysis of the data suggested that the ubiquitin ligase MDM2 acted as a positive regulator of HIV-1 replication in MDMs. In this study, MDM2 silencing through transcript-specific small interfering RNAs in MDMs induced a reduction in HIV-1 reverse transcription and integration along with an increase in the expression of p53-induced genes, including CDKN1A Experiments with Nutlin-3, a pharmacological inhibitor of MDM2 p53-binding activity, showed a similar effect on HIV-1 infection, suggesting that the observed restriction in HIV-1 production results from the release/activation of p53 and not the absence of MDM2 per se Knockdown and inhibition of MDM2 also both correlate with a decrease in the Thr592-phosphorylated inactive form of SAMHD1. The expression level of MDM2 and the p53 activation status are therefore important factors in the overall susceptibility of macrophages to HIV-1 infection, bringing a new understanding of signaling events controlling the process of virus replication in this cell type.IMPORTANCE Macrophages, with their long life span in vivo and their resistance to HIV-1-mediated cytopathic effect, might serve as viral reservoirs, contributing to virus persistence in an infected individual. Identification of host factors that increase the overall susceptibility of macrophages to HIV-1 might provide new therapeutic targets for the efficient control of viral replication in these cells and limit the formation of reservoirs in exposed individuals. In this study, we demonstrate the importance of p53 regulation by MDM2, which creates a cellular environment more favorable to the early steps of HIV-1 replication. Moreover, we show that p53 stabilization reduces virus infection in human macrophages, highlighting the important role of p53 in antiviral immunity.


Subject(s)
HIV Infections/genetics , HIV-1/pathogenicity , Macrophages/metabolism , Macrophages/virology , Proto-Oncogene Proteins c-mdm2/genetics , Tumor Suppressor Protein p53/genetics , HEK293 Cells , HIV Infections/metabolism , HIV Infections/virology , Humans , Phosphorylation/genetics , Proto-Oncogene Proteins c-mdm2/metabolism , Reverse Transcription/genetics , Tumor Suppressor Protein p53/metabolism , Virus Replication/genetics
5.
Chem Sci ; 9(22): 5057-5063, 2018 Jun 14.
Article in English | MEDLINE | ID: mdl-29938036

ABSTRACT

While the dearomatization of indoles by carbon-boron bond forming reactions is new and quite promising, they are so far mainly metal-catalyzed. Here, we establish the use of metal-free catalysts in promoting such reactions in an atom-efficient way. The in situ generated ambiphilic aminoborane catalyst (1-Pip-2-BH2-C6H4)2 (Pip = piperidyl) promotes borylative dearomatization of various 1-arylsulfonyl indoles with pinacolborane in a syn addition fashion, with H and Bpin groups added respectively to the 2 and 3 positions of indoles. Catalysis proceeds with good to excellent conversion and essentially with complete regio- and diastereoselectivity. From mechanistic insights and DFT computations, we realized and established that prototypical boranes can also catalyze this borylative dearomatization.

SELECTION OF CITATIONS
SEARCH DETAIL
...