Organocatalytic synthesis and antitumor activity of novel 1,2,3-triazoles derived from fatty β-ketoesters

Background: Developing methods to synthesize highly functionalized and complex 1,2,3-triazoles from various combinations of substrates remains a significant challenge in organic synthesis. Thus, to the best of our knowledge, an organocatalytic approach to synthesize 1,2,3-triazoles derived from fatty acids has not been explored. Objective: In this sense, we describe here the organocatalyzed synthesis and preliminary results of antitumor and cytotoxic activity of a range of 1,2,3-triazoles derived from fatty esters. Methods: To synthesize 1,2,3-triazoles 3 derived from fatty β-ketoesters, we performed the reaction of appropriate aryl azides 2a-j with β-ketoesters 1a-c in the presence of 5 mol% of DBU using DMSO as a solvent at 70 °C for 24 h. The viability of 5637 cells was determined by measuring the reduction of soluble MTT to water-insoluble formazan. The IC50 concentration that inhibits 50% of cell growth and the results were obtained by at least three independent experiments in triplicate for each test. Results: Through enolate-mediated organocatalysis, 1,2,3-triazoles 3 derived from fatty β-ketoesters were synthesized in moderate to excellent yields by reacting fatty esters 1 with aryl azides 2 in the presence of a catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (5 mol%). All compounds derived from palmitic acetoacetate 1a were evaluated regarding induced cytotoxicity in vitro in a human bladder cancer cell line, and compounds 3a, 3d, 3e, and 3g were shown to be promising alternatives for bladder cancer treatment and presented the lowest inhibitory concentration of IC50. Conclusion: We described a synthetic procedure to prepare 1,2,3-triazoles derived from fatty β-ketoesters by DBU-catalyzed 1,3-dipolar cycloaddition reactions of fatty esters with different aryl azides. Compounds derived from palmitic acetoacetate were screened for antitumor and cytotoxic activity in vitro in human bladder cancer cell lines, and compounds 3a, 3d, 3e, and 3g showed potential to treat bladder cancer.

Lepidium graminifolium L.: Glucosinolate Profile and Antiproliferative Potential of Volatile Isolates

Glucosinolates (GSLs) from Lepidium graminifolium L. were analyzed qualitatively and quantitatively by their desulfo-counterparts using UHPLC-DAD-MS/MS technique and by their volatile breakdown products-isothiocyanates (ITCs) using GC-MS analysis. Thirteen GSLs were identified with arylaliphatic as the major ones in the following order: 3-hydroxybenzyl GSL (glucolepigramin, 7), benzyl GSL (glucotropaeolin, 9), 3,4,5-trimethoxybenzyl GSL (11), 3-methoxybenzyl GSL (glucolimnanthin, 12), 4-hydroxy-3,5-dimethoxybenzyl GSL (3,5-dimethoxysinalbin, 8), 4-hydroxybenzyl GSL (glucosinalbin, 6), 3,4-dimethoxybenzyl GSL (10) and 2-phenylethyl GSL (gluconasturtiin, 13). GSL breakdown products obtained by hydrodistillation (HD) and CH2Cl2 extraction after hydrolysis by myrosinase for 24 h (EXT) as well as benzyl ITC were tested for their cytotoxic activity using MTT assay. Generally, EXT showed noticeable antiproliferative activity against human bladder cancer cell line UM-UC-3 and human glioblastoma cell line LN229, and can be considered as moderately active, while IC50 of benzyl ITC was 12.3 μg/mL, which can be considered as highly active.

Transcriptome analysis of low-risk and high-risk non-muscular invasive bladder cancer patients to reveal disease progression related genes.

483 Background: According to the EAU prognostic risk classes, non-muscle invasive bladder cancer (NMIBC) is divided into low, medium, and high risk. Patients with high-risk NMIBC (T1/Tis, with high grade/G3, or CIS) represent a challenging group as they are at greater risk of recurrence and progression.Our specific aim was to investigate the biomarkers associated with progression and recurrence in NMIBC. Methods: Tumor tissue were collected from 70 patients with bladder cancer, including high-risk NMIBC (n = 44),low-risk NMIBC (n = 10) and (n = 16) MIBC. mRNA sequenced using the ABclonal Whole RNA-seq Lib Prep kit.The differentially expressed genes were identified using DESeq2 and the analysis of the association between genes expression and patient survival with NMIBC cohorts data(Jakob et al., 2016). RNAseq data of human bladder cancer cell lines were achieved from the Cell Model Passports website (https://cellmodelpassports.sanger.ac.uk/). Results:A total of 456 genes are significantly high expressed in high-risk NMIBC group compared with the low-risk NMIBC group. Combined with MIBC expression data,we found 16 genes with consistently increasing expression from the low-risk NMIBC group to high-risk NMIBC group and MIBC group using a fold change of at least 2, and a false discovery rate (FDR) of 0.05.Among these genes,14 genes were also highly expressed in human bladder cancer cell lines. Survival analysis by Kaplan-Meier,we finally identified 13 high-expressed genes, including KRT6A、SPHK1、S100A9、SLC16A1、CDC25B、NELL2、PREX1、C15orf48、AKR1B10、CERCAM、PKMYT1、UCHL1、SLC16A1, were significantly associated with poor progression-free survival(p<0.05). Conclusions: We identified a set of 13 genes that may predict the progression of NMIBC and may serve as molecular targets for NMIBC therapy. these study results need to be confirmed in larger research studies.