Strategic application of CuAAC click chemistry in the modification of natural products for anticancer activity

Natural products play a key role in the history of human drug discovery, and especially for the anticancer agents. Copper(I)-catalyzed alkyne-azide [3+2] cycloaddition (CuAAC) reaction is perhaps the most powerful method for the efficient modification of complex natural products, enabling the direct incorporation of various functional groups accompanied by the formation of the multifunctional 1,2,3-triazole motif, which could not only serve as an basic and hydrophilic connecting group but also as a bioisosteres of 5- or 6-membered heterocycles or an amide group, thus facilitating the improvement of anticancer activities and/or drug-like properties. This contribution extensively summarizes the state-of-the-art application of 1,2,3-triazole in the modification of natural products for anticancer activity. The aim is to gain a deep understanding of the fruitful achievements as well as limitations of CuAAC click chemistry in natural product modification for anticancer activity, and provide perspectives and directions regarding future studies in natural product medicinal chemistry

Mendelian randomization study of gastroesophageal reflux disease and major depression.

This study systematically investigated the causal relationship between gastroesophageal reflux disease (GERD) and major depression (MD). Single-nucleotide polymorphisms (SNPs) associated with disorders of interest were screened via the genome-wide association study (GWAS) enrolling individuals of European descent. Summary-level data for GERD and MD were extracted from the UK Biobank. The inverse-variance-weighted (IVW) method was utilized as the primary analysis. Sensitivity analyses were performed using the MR-Egger method, the Maximum likelihood method, the MR-pleiotropy residual sum outlier (MR-PRESSO) method, and MR-robust adjusted profile score (MR-RAPS) method. MR-Egger regression, heterogeneity tests, pleiotropy tests, and leave-one-out tests were also performed to analyze sensitivity. The MR Steiger test was used to verify the directionality of the exposure to the outcome. An available website tool (https://shiny.cnsgenomics.com/mRnd/) was used to calculate the statistical power of MR analysis. Meta-analysis was applied to test MD's average genetically predicted effect on GERD. Our MR study showed a bidirectional causal association between MD and GERD. Regarding MD to GERD, there was a positive association between them; the ORs were 1.500 (95% CI = 1.320-1.704; P = 4.91E-10) and 2.058 (95% CI = 1.868-2.267; P = 2.20E-48) in the IVW method, respectively. In addition, the meta-analysis also showed a strong positive causal association between MD and GERD. When exposure and outcome were reversed, genetic predisposition to GERD was significantly associated with the overall Risk of advanced MD (ieu-a-1187, OR = 1.982, 95% CI = 1.694-2.319, P = 1.41E-17; ieu-b-102, OR = 1.612, 95% CI = 1.530-2.700, P = 1.15E-70). Our study provides 100% power to detect the causal effect of MD on GERD and vice versa. Genetically predicted MD was positively associated with higher GERD risk, and vice versa. Our study reminds clinicians to pay attention to screening for GERD when diagnosing and treating MD and vice versa. Moreover, there may be positive feedback between MD and GERD when treating and preventing one disorder may benefit the treatment and prevention of the other

[18F]SuFEx Click Chemistry Enabled Ultrafast Late-stage Radiosynthesis

The lack of simple, efficient [18F]fluorination processes and new target-specific organofluorine probes remains the major challenge of fluorine-18-based positron emission tomography (PET). We report here a fast isotopic exchange method for the radiosynthesis of aryl [18F]fluorosulfate based PET agents enabled by the emerging sulfur fluoride exchange (SuFEx) click chemistry. The method has been applied to the fully-automated 18F-radiolabeling of twenty-five structurally diverse aryl fluorosulfates with excellent radiochemical yield (83–100%) and high molar activity (up to 281 GBq µmol–1) at room temperature in 30 seconds. The purification of radiotracers requires no time-consuming high-performance liquid chromatography (HPLC), but rather a simple cartridge filtration. The utility of aryl [18F]fluorosulfate is demonstrated by the in vivo tumor imaging by targeting poly(ADP-ribose) polymerase 1 (PARP1)

Forest plot to visualize causal effects of variation in GERD on MD.

Presented OR and CI correspond to the impact of GERD on MD. The results of MR analyses using different analysis methods (MR‒Egger, Maximum likelihood, MR-PRESSO, MR‒RAPS, IVW) are compared. Total SNP indicates the number of genetic variants used as instruments for MR analysis. MR, Mendelian randomization; MD, major depression; GERD, gastroesophageal reflux disease; SNP, single nucleotide polymorphisms; OR, odds ratio; confidence intervals (CI); IVW, inverse-variance-weighted; MR-PRESSO, MR-pleiotropy residual sum outlier; MR-RAPS, MR-robust adjusted profile score.</p