Objectives: Tumours remain a serious threat to human life. Following rapid progress in oncology research, tyrosine kinase inhibitors have been used to treat multiple tumour types. Given the great influence of kidneys on pharmacokinetics, renal toxicities associated with TKIs have attracted attention. However, the TKIs with the lowest risks of renal impairment are unclear. In this study, we conducted a Bayesian network meta-analysis to compare the incidence of renal impairment among different TKIs in patients with tumours.Methods and analysis: Six databases (PubMed, EMBASE, The Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang Data, and China Biomedical Literature Database) were electronically searched from inception to 1 November 2021 to identify randomized controlled trials on the incidence of renal impairment for different TKIs in patients with tumours. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias of the included studies. Then, a pairwise meta-analysis was conducted using Stata version 13, and network meta-analysis within the Bayesian framework was conducted using R software version 3.5.3 with the package “gemtc 0.8–2” recalling JAGS (version 4.3.0).Results: Overall, 34 randomized controlled trials were included in this study. Although renal toxicity was common among patients receiving TKIs, the incidence and severity greatly differed among the drugs and studies. Elevated creatinine and protein levels were the most common nephrotoxic events, whereas haematuria was relatively rare. Among TKIs, nintedanib and ripretinib carried the lowest risks of renal impairment.Conclusion: TKIs displayed different profiles of renal toxicity because of their different targets and underlying mechanisms. Clinicians should be aware of the risks of renal impairment to select the optimal treatment and improve patient adherence to treatment.Systematic Review Registration: [www.crd.york.ac.uk/prospero/], identifier [CRD42022295853].
A nitrene/alkyne
cascade reaction terminating in C–H bond
insertion to form functionalized bridged azacycles from carbonazidates
is presented. Due to an initial Huisgen cyclization, all carbonazidates
reacted with the alkyne in an exo mode in contrast to the use of sulfamate
esters, which react predominately in an endo mode. Substrates with
different ring sizes as well as different aryl and heteroaryl groups
were also explored. Variation of the nitrene tether showed that 7-membered
rings were the maximum ring size to be formed by nitrene attack on
the alkyne. Examples incorporating stereocenters on the carbonazidate’s
tether induced diasteroselectivity in the formation of the bridged
ring and two new stereocenters. Additionally, propellanes containing
aminals, hemiaminals, and thioaminals formed from the bridged azacycles
in the same reaction via an acid-promoted rearrangement.
Unusual
intermolecular trapping of esters by carbenes generated
via a Huisgen cyclization/retroelectrocyclization/dediazotization
cascade reaction is presented. β-Oxo-N-vinylimidates
could be obtained in one step from propargyl carbonazidates. Mechanistic
control experiments suggested reversible dipole formation by ester
addition to the carbene, and nitrogen attack to the ester carbonyl
was irreversibly followed by stereoselective decarboxylative elimination
to give the Z-vinyl imidate. The cross-conjugated
enone, imidate, and enamine functional groups in the β-oxo-N-vinylimidates offer novel syntheses of functionalized
oxazoles.
In anoxic environments, microbial activation of alkanes for subsequent metabolism occurs most commonly through the addition of fumarate to a subterminal carbon, producing an alkylsuccinate. Alkylsuccinate synthases are complex, multi‐subunit enzymes that utilize a catalytic glycyl radical and require a partner, activating enzyme for hydrogen abstraction. While many genes encoding putative alkylsuccinate synthases have been identified, primarily from nitrate‐ and sulfate‐reducing bacteria, few have been characterized and none have been reported to be functionally expressed in a heterologous host. Here, we describe the functional expression of the (1‐methylalkyl)succinate synthase (Mas) system from Azoarcus sp. strain HxN1 in recombinant Escherichia coli. Mass spectrometry confirms anaerobic biosynthesis of the expected products of fumarate addition to hexane, butane, and propane. Maximum production of (1‐methylpentyl)succinate is observed when masC, masD, masE, masB, and masG are all present on the expression plasmid; omitting masC reduces production by 66% while omitting any other gene eliminates production. Meanwhile, deleting iscR (encoding the repressor of the E. coli iron–sulfur cluster operon) improves product titer, as does performing the biotransformation at reduced temperature (18°C), both suggesting alkylsuccinate biosynthesis is largely limited by functional expression of this enzyme system.
A variety of Huisgen cyclization or nitrene/carbene alkyne cascade reactions with different types of termination were investigated. Accessible nitrene precursors were assessed, and carbonazidates were found to be the only effective initiators. Solvents, terminal alkynyl substituents, and catalysts can all impact the reaction outcome. Study of the mechanism both computationally (by density functional theory) and experimentally revealed relevant intermediates and plausible reaction pathways. Article pubs.acs.org/joc
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