Synthesis of novel oxadiazole derivatives and their cytotoxic activity against various cancer cell lines

Caffeic acid (CA), ferulic acid (FA) and caffeic acid phenethyl ester (CAPE) have a broad anticancer effect on various cell lines. In this study, nine ferulic and caffeic acid-based 1,2,4 and 1,3,4 oxadiazole molecular hybrids were synthesized and their cytotoxic activity was evaluated mainly against Glioblastoma (GBM) cell lines. Compounds 1 and 5 exhibited the highest inhibitory activity against three different GBM cell lines (LN229, T98G, and U87), without toxicity to healthy human mesenchymal stem cells (hMSC). In addition, their cytotoxicity was also evaluated against three additional cancer cell lines and more inhibitory results were found than GBM cell lines. The IC50 values of compound 5 in U87, T98G, LN229, SKOV3, MCF7, and A549 cells were determined as 35.1, 34.4, 37.9, 14.2, 30.9, and 18.3 µM. In the light of biological activity studies, the developed compounds have a high potential to lead studies for the development of new drug candidates for the treatment of cancer

Synthesis and antiproliferative evaluation of new 1,3,5-trisubstituted 1,2,4-triazole derivatives against glioblastoma cell lines

A series of novel 1,3,5-trisubstituted-1,2,4-triazole derivatives were successfully synthesized from the starting materials of caffeic acid (CA) and ferulic acid (FA) in moderate to good yields (45-71 %). All novel compounds were screened for antiproliferative activity against three glioblastoma (GB) cell lines. Several compounds exhibited improved cytotoxic activities compared to the caffeic acid phenethyl ester (CAPE). Among the novel derivatives, 4-(2-(1-benzyl-3-phenyl-1H-1,2,4-triazol-5-yl)vinyl)-2-methoxyphenol (4) exhibited the most potent activity against the U87G, T98G and LN229 cell lines. Western blot results showed significantly reduced poly(ADP-ribose) polymerase (PARP) and increased the Bcl-2-associated X (Bax) protein levels in T98G cells. Also, flow cytometry results using Annexin-V/Propidium Iodide (PI) staining indicated that apoptosis was induced in T98G cells. It was found to be a promising drug candidate with strong physicochemical and bioavailability properties as a result of SwissADME calculations. These results show that novel compounds containing a 1,2,4-triazole moiety have a good antiproliferative activity on GB cells

Effect of the direct renin Inhibitor aliskiren in the prevention of experimental contrast-induced nephropathy in the rat

Background: Renal vasoconstriction, activated by the reninangiotensin system, plays a pivotal role in the pathogenesis of contrast-induced nephropathy (CIN). The purpose of this study was to evaluate the effect of aliskiren, a direct renin inhibitor, for the prophylaxis of experimental CIN in the rat. Methods: Thirty-two Wistar albino rats were divided into four groups of 8 rats each, namely the control (C), aliskiren (A), contrast media (CM) and aliskiren plus contrast media (ACM) groups. Aliskiren was given orally at a dose of 50 mg/kg/day once daily for 5 consecutive days. CIN was induced by intravenous administration of indomethacin, N-nitro-L-arginine methyl ester and high-osmolar contrast medium meglumine amidotrizoate. Renal function parameters, kidney histology and tubular expression of vascular endothelial growth factor were determined. Results: Mean serum creatinine was significantly lower (p < 0.001) and mean creatinine clearance was higher (p < 0.001) in the ACM group compared with the CM group. However, there were no differences between the ACM and CM groups in terms of tubular necrosis, proteinaceous casts, medullary congestion and vascular endothelial growth factor expression. Conclusion: Our preliminary data seem to suggest a potential role of aliskiren for the prophylaxis of CIN in an experimental rat model.Department of Nephrology, Marmara University School of Medicine, Istanbul, Turke

Design and synthesis of novel caffeic acid phenethyl ester (CAPE) derivatives and their biological activity studies in glioblastoma multiforme (GBM) cancer cell lines

Glioblastoma Multiforme (GBM) is the most aggressive brain tumor and classified as one of the deadliest cancers. The current treatment plans for GBM remains to be ineffective because of its rapid progress and inability of the drugs used to cross the blood-brain barrier (BBB). Thus, developing more effective and potent medicines for GBM are needed. There have been several reports demonstrating that CAPE presents reasonably good anti-cancer activity in certain cancer cell lines and can penetrate the blood-brain barrier. Accordingly, in this study we synthesized several novel CAPE analogs with the addition of more druggable handles and solubilizing entities and subsequently evaluated their in vitro therapeutic efficacies in GBM cell lines (T98G and LN229). The most potent compound was then examined extensively and results showed that the 50 μM novel CAPE analog (compound 10) significantly decreases the viability of both T98G and LN229 GBM cells as compared to CAPE itself. Moreover, the compound 10 was not cytotoxic to healthy human cells (fibroblast-like mesenchymal stem cells) at the same concentration. Apoptotic (32.8%, and 44.6%) cell populations were detected in the compound 10 treated groups for LN229 and T98G, respectively. As an indication of apotosis, significantly increased PARP cleavage was detected in compound 10 versus CAPE treated LN229. In addition, we conducted molecular docking and molecular dynamics (MD) simulations studies on certain targets playing roles on GBM disease pathway such as NF-κB, EGFR, TNF-α, ERK2, PAPR1, hCA IX and hCA XII. Our findings demonstrated that designed CAPE analogs have anti-cancer activity on GBM cells and in silico studies also demonstrate the inhibitory ability of suggested compounds via interactions with critical residues in binding pockets of studied targets. Here, we suggest the novel CAPE analog to study further against GBM. Therefore, identification of the compound related molecular signature may provide more to understand the mechanism of action

Middle-term outcomes in renal transplant recipients with COVID-19: a national, multicenter, controlled study

Background In this study, we evaluated 3-month clinical outcomes of kidney transplant recipients (KTR) recovering from COVID-19 and compared them with a control group. Method The primary endpoint was death in the third month. Secondary endpoints were ongoing respiratory symptoms, need for home oxygen therapy, rehospitalization for any reason, lower respiratory tract infection, urinary tract infection, biopsy-proven acute rejection, venous/arterial thromboembolic event, cytomegalovirus (CMV) infection/disease and BK viruria/viremia at 3 months. Results A total of 944 KTR from 29 different centers were included in this study (523 patients in the COVID-19 group; 421 patients in the control group). The mean age was 46 +/- 12 years (interquartile range 37-55) and 532 (56.4%) of them were male. Total number of deaths was 8 [7 (1.3%) in COVID-19 group, 1 (0.2%) in control group; P = 0.082]. The proportion of patients with ongoing respiratory symptoms [43 (8.2%) versus 4 (1.0%); P Conclusion The prevalence of ongoing respiratory symptoms increased in the first 3 months post-COVID in KTRs who have recovered from COVID-19, but mortality was not significantly different