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

Biological evaluation of imidazopyridine derivatives as potential anticancer agents against breast cancer cells

Imidazo[1,2-a]pyridine cores have increasing importance in the pharmaceutical industry with their wide range pharmacological activities. In this study, two series of imidazopyridine derivatives were synthesized. It was planned to integrate the pyrimidine ring or N-acylhydrazone (NAH) to the carbon atom at the 3 position of the imidazo[1,2-a]pyridine scaffold. Pyrimidine-containing compounds (9-12) were obtained by palladium-catalyzed coupling reaction (Suzuki reaction), and NAH compounds (13-19) were obtained from the aldehyde intermediate synthesized as a result of the Vilsmeier-Haack reaction. All of the derivatives were evaluated in breast cancer cells for their antiproliferative potential. The pyrimidine-containing compounds did not show active results in both breast cancer cell lines, while the NAH derivatives showed significant results. Among the novel derivatives, compound 15 exhibited the most potent activity against the MCF7 and MDA-MB-231 cell lines with IC50 values of 1.6 and 22.4 mu M, respectively. The current study demonstrated that these compounds have anticancer activity and would be useful in developing more effective compounds for treating breast 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

Novel synthetic approaches for bisnaphthalimidopropyl (BNIP) derivatives as potential anti-parasitic agents for the treatment of leishmaniasis

Leishmaniasis is a neglected parasitic disease that is widely seen in more than 60 countries worldwide, including Turkey and its subcontinental region. There are several chemotherapy agents for the treatment of leishmaniasis, including pentavalent antimonials-i.e., sodium stibogluconate (Pentostan) and meglumine antimoniate (Glucantim), pentamidine, conventional amphotericin B deoxycholate, miltefosine, paramomycin (aminosidine), and liposomal amphotericin B. However, these therapies are usually unsatisfactory due to dose-limiting toxicity issues and limited efficacy. Furthermore, resistance gained by parasites endangers future success of these therapies. Addressing these issues, the development of novel drugs with high efficacy has a vital importance. Latest studies have shown that bisnaphthalimidopropyl (BNIP) derivatives display high activity against Leishmaniasis parasites by selectively targeting parasitic sirtuin proteins and interacting with DNA. Despite the promising anti-parasitic activity, the low solubility and toxicity on human macrophages are the limitations to overcome. This study describes the new synthesis strategies for existing-i.e., BNIPDaoct and BNIPDanon-and novel BNIP derivatives differing in respect of their alkyl linker chain lengths. The new synthesis approach provides certain advantages compared to its existing alternatives reported in the literature. The proposed methodology does not only decrease the number of synthesis steps and production time of BNIPDaoct and BNIPDanon, but also provides higher yields, thereby making the synthesis highly cost-effective

Synthesis of novel hybrid lonidamine-coumarin derivatives and their anticancer activities

In order to develop drugs against cancer, which is one of the deadliest diseases in the world, hybridizing structures with known anticancer activity can provide a dual activity for the treatment of cancer cases. For this purpose, a series of novel hybrid compounds combining lonidamine and 7-hydroxy-4-methylcoumarin via different linker modifications have been synthesized in this study. The chemical structures of the novel compound were elucidated with 1H and 13C NMR and mass spectrometry (HRMS) methods. All the synthesized compounds were screened for anticancer activity against MCF-7 and A549 cells. Among them, compound 2 appeared to be the most potent compound on MCF-7 lines; and IC50 dose was determined as 33.12 µM. IC50 of Compound 6 was determined as 139.6 µM for A549 cells. Considering anticancer activity studies, compounds 2 and 6 have potential to lead to the development of novel hybrid compounds for cancer therapy. Further studies to identify mechanistic explanations of the bioactivity of these molecules are ongoing and will be reported in due course

Synthesis of novel methyl jasmonate derivatives and evaluation of their biological activity in various cancer cell lines

Warburg hypothesized that the energy consumption of cancer cells is different than the normal cells. When compared to normal conditions, cancer cells do not undergo tricarboxylic acid (TCA) cycle therefore resulting in more lactate in the cells. Glycolysis pathway is a way of cancer cells to provide energy. The first step in glycolysis is the phosphorylation of glucose to glucose-6-phosphate. This reaction is catalyzed by the hexokinase-II enzyme (HK-II) which is known to be overexpressed in tumor cells. The feeding of cancer cells can be prevented by inhibiting the hexokinase-II enzyme in the first step of aerobic glycolysis. In literature, Methyl Jasmonate (MJ) is known as a Hexokinase-II inhibitor since it disposes VDAC and HK-II interaction on mitochondrial membrane. In our study, we aimed to increase the activity by synthesizing the novel MJ analogues with appropriate modifications. Here we report Hexokinase-2 enzyme and cell viability study results in different cancer cells. Based on the three different cancer cell lines we investigated, our novel MJ analogues proved to be more potent than the original molecule. Thus this research may provide more efficacious/ novel HK-II inhibitors and may shed light to develop new anti-cancer agents.Türkiye Bilimsel ve Teknolojik Araştırma Kurumu (TÜBİTAK

Synthesis of New Tandospirone Analogues Carrying 1-(3-(Trifluoromethyl)phenyl)piperazine

<div><p></p><p>New tandospirone analogues containing a 1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP) moiety have been synthesized by hydroarylation reactions with Pd(OAc)₂. The perhydroisoindole derivatives were obtained by the reaction of reduced starting material with aryl-(heteroaryl) iodides under the same conditions. Spiro-1,3-indandionolylpyrrolidine derivatives having an array of stereocenters are reported.</p> </div

Potential of novel methyl jasmonate analogs as anticancer agents to metabolically target HK-2 activity in glioblastoma cells

Change in the energy metabolism of cancer cells, which display significant differences compared to normal cells, is a rising phenomenon in developing new therapeutic approaches against cancers. One of the metabolic enzymes, hexokinase-II (HK-II) is involved in glycolysis, and inhibiting the HK-II activity may be a potential metabolic target for cancer therapy as most of the drugs in clinical use act on DNA damage. Methyl jasmonate (MJ) is one of the compounds blocking HK-II activity in cancer cells. In a previous study, we showed that the novel MJ analogs inhibit HK-II activity through VDAC detachment from the mitochondria. In this study, to evaluate the potential of targeting HK-2 activity, through patient cohort analysis, we first determined HK-2 expression levels and prognostic significance in highly lethal glioblastoma (GBM) brain tumor. We then examined the in vitro therapeutic effects of the novel analogs in the GBM cells. Here, we report that, among all, compound-10 (C-10) showed significant in vitro therapeutic efficacy as compared to MJ which is in use for preclinical and clinical studies. Afterward, we analyzed cell death triggered by C-10 in two different GBM cell lines. We found that C-10 treatment increased the apoptotic/necrotic cells and autophagy in GBM cells. The newly developed analog, C-10, was found to be lethal against GBM by the activation of cell death authorities, mostly in a necrotic and autophagic fashion at the early stages of the treatment. Considering that possibly decreased intracellular ATP levels by C-10 mediated inhibition of HK-2 activity and disabled VDAC interaction, a more detailed analysis of HK-2 inhibition-mediated cell death can provide a deep understanding of the mechanism of action on the oncosis/necroptosis axis. These findings provide an option to design clinically relevant and effective novel HK-II inhibitors and suggest novel MJ analogs to further study them as potential anticancer agents against GBM.European Cooperation in Science and Technology (COST

Antileishmanial activity of BNIPdaoct- and BNIPdanon-loaded emulsomes on leishmania infantum parasites

Among bisnaphthalimidopropyl (BNIP) derivatives, BNIPDaoct and BNIPDanon recently came forward with antileishmanial activities beyond the standard, commercialized antileishmanial therapies. However, high-level toxicity on macrophages plus poor aqueous solubility and poor bioavailability of the compounds limit their application in therapies. Addressing these limitations, the present study introduces BNIPDaoct- and BNIPDanon-loaded emulsomes as lipid-based nanocarrier systems. Accordingly, emulsome formulations were prepared with the presence of BNIP compounds. The average diameters of BNIPDaoct- and BNIPDanon-loaded emulsomes were found as 363.1 and 337.4 nm, respectively; while empty emulsomes differed with a smaller average particle diameter, i.e., 239.1 nm. All formulations exhibited a negative zeta potential value. The formulations achieved the encapsulation of BNIPDaoct and BNIPDanon at approximately 0.31 mg/ml (501 µM) and 0.24 mg/ml (387 µM), respectively. The delivery of BNIP within the emulsomes improved the antileishmanial activity of the compounds. BNIPDaoct-loaded emulsome with 50% inhibitory concentration (IC50) value of 0.59 ± 0.08 µM was in particular effective against Leishmania infantum promastigotes compared to free BNIPDaoct (0.84 ± 0.09 µM), free BNIPDanon (1.85 ± 0.01 µM), and BNIPDanon-loaded emulsome (1.73 ± 0.02 µM). Indicated by at least ≥ 2-fold higher 50% cytotoxic concentration (CC50) values, the incorporation of BNIP into emulsomes significantly reduced the toxicity of BNIPs against macrophages, corresponding to up to 16-fold improvement in selectivity index (CC50/IC50) for L. infantum promastigotes. The infection rates of macrophages were determined using dual-fluorescent flow cytometry as 68.6%. Both BNIP formulations at concentration of 1.87 µM reduced the parasitic load nearly to 40%, whereas BNIPDaoct-loaded emulosmes could further decrease the parasitic load below 20% at 7.5 µM and above. In conclusion, the incorporation of BNIPDaoct and BNIPDanon into emulsomes results in water-soluble dispersed emulsome formulations that do not only successfully facilitate the delivery of BNIP compounds into the parasites and the Leishmania-infected macrophages in vitro but also enhance antileishmanial efficacy as proven by the decline in IC50 values. The selectivity of the formulation for L. infantum parasites further contributes to the challenging safety profile of the compounds. The promising in vitro antileishmanial efficacy of BNIP-loaded emulsomes highlights the potential of the system for the future in vivo studies

Development of light and pH-dual responsive self-quenching theranostic SPION to make EGFR overexpressing micro tumors glow and destroy

Drug resistant and undetectable tumors easily escape treatment leading metastases and/or recurrence of the lethal disease. Therefore, it is vital to diagnose and destroy micro tumors using simple yet novel approaches. Here, we present fluorescence-based detection and light-based destruction of cancer cells that are known to be resistant to standard therapies. We developed a superparamagnetic iron oxide nanoparticle (SPION)-based theranostic agent that is composed of self-quenching light activated photosensitizer (BPD) and EGFR targeting ligand (Anti-EGFR ScFv or GE11 peptide). Photosensitizer (BPD) was immobilized to PEG-PEI modified SPION with acid-labile linker. Prior to stimulation of the theranostic system by light its accumulation within cancer cells is vital since BPD phototoxicity and fluorescence is activated by lysosomal proteolysis. As BPD is cleaved, the system switches from off to on position which triggers imaging and therapy. Targeting, therapeutic and diagnostic features of the theranostic system were evaluated in high and moderate level EGFR expressing pancreatic cancer cell lines. Our results indicate that the system distinguishes high and moderate EGFR expression levels and yields up to 4.3-fold increase in intracellular fluorescence intensity. Amplification of fluorescence signal was as low as 1.3-fold in the moderate or no EGFR expressing cell lines. Anti-EGFR ScFv targeted SPION caused nearly 2-fold higher cell death via apoptosis in high EGFR expressing Panc-1 cell line. The developed system, possessing advanced targeting, enhanced imaging and effective therapeutic features, is a promising candidate for multi-mode detection and destruction of residual drug-resistant cancer cells