Tubitak projects targeting chronic inflammation
#108S210 "5-Lipoxygenase (5-LO) and FLAP Inhibitors as Leukotriene Modifiers"
#112S596 "Development Of 5-Lipoxygenase Activating Protein (FLAP) Inhibitors"
#218S555 "Studies on the Development of Novel Microsomal Prostaglandin E2
Synthase-1 (mPGES-1) Inhibitors"
Leukotrienes (LTs) and prostaglandin (PG)E2 are enzymatically produced from arachidonic acid (AA) and represent highly bioactive lipid mediators with pro-inflammatory functions. 5-Lipoxygenase-activating protein (FLAP) and microsomal prostaglandin E2 synthase-1 (mPGES-1) are important targets for new generation nonsteroidal anti-inflammatory drugs, and interfering with both targets in the AA pathway promises higher efficacy and better safety profile as opposed to single target drugs.
The three successive research projects (#108S210, #112S596, #218S555) are funded by The Scientific and Technological Research Council of Turkey (TUBITAK) on the development of novel FLAP and mPGES-1 inhibitors, and carried out in collaboration with our colleagues Prof. Oliver Werz (University of Jena) and Prof. Antonio Macchiarulo (University of Perugia). In summary, we discovered selective FLAP (BRP-7) and selective mPGES-1 (BRP-151) inhibitors as well as multi-target inhibitors that potently and dually interfere with FLAP and mPGES-1 in LT and PGE2 biosynthesis, namely BRP-187 and BRP-201. These compounds can be of value as pharmacological tools for researchers working in the same area, and are under further development in our laboratories.
New lead compounds as “selective FLAP” (BRP-7), selective mPGES-1 (BRP-151) and “dual mPGES-1 and FLAP” (BRP-201; BRP-187) inhibitors for further development
Tubitak project targeting cardiovascular diseases
"Studies on the synthesis, antiplatelet activity and structure-activity relationships of pyrazole derivatives"
Platelets play a pivotal role in the pathogenesis of cardiovascular thrombosis, and antiplatelet drugs are very important for prevention and treatment of recurrent acute coronary syndrome (ACS), MI and stroke. In this study, we developed potent inhibitors of platelet aggregation based on the 1,5-diarylpyrazol-3-carboxamide scaffold with IC50 values in low nanomolar range (5.7-83 nM). Based on their high potency in the cellular environment, these pyrazole derivatives may possess potential in the design of more potent compounds for intervention with cardiovascular diseases.
New lead compounds as inhibitors of AA-induced platelet aggregation for further development
Tubitak project targeting cancer
Mechanisms of Action of Novel Isoxazole Derivatives with Potential Anticancer Activity
Within the context of this project, novel isoxazole derivatives synthesized to establish a proper structure-activity relationship for obtaining more potent derivatives for liver and breast cancer cell lines. As a result, the most potent derivative 49d was selected for further studies, and found that it effectively reduces the proportion of liver cancer stem cells (CSCs) relative to sorafenib, a commonly used chemotherapeutic drug for hepatocellular carcinoma. To assess the characterization of 49d on liver cancer stem cells (LCSCs), we controlled cancer stem cells-associated characteristics in hepatocellular carcinoma (HCC) cells. LCSC surface markers, CD133 and EpCAM, lead to promote sphere formation, stemness gene expression, and tumorigenicity. The lead compound (below left) led to a significant drop in the percentage of CD133+/EpCAM+ cell population compared with controls. Besides, stemness-associated genes, NANOG and OCT4, regulateLCSCs by modulating self-renewal and embryonic stem cells’ pluripotency. Quantitative real-time polymerase chain reaction analysis and flow cytometry analysis showed that 49d could significantly decrease in the expression of NANOG and OCT4 stemness markers compared with the control group. An effective in vitro model to detect the self-renewal capacity of CSCs, sphere formation, is another stemness feature of LCSCs. 49d treated HCC cells had less relative sphere count and smaller average sphere size than the control group.This study demonstrates the ability of 49d with specific toxicity for epithelial CSCs.
Isoxazole-piperazine hybrids against liver and breast cancer with cancer stem cell inhibitory properties
Tubitak project targeting cancer
Vicinal diaryl heterocyclic compounds targeting PI3K/Akt Signaling Pathway for
Treatment of Breast and Liver Cancer
Compounds BRP-38 and BRP-91 showed potent cytotoxicity against a panel of liver and breast cell lines with IC50 values in the range of <0.1 to 5.8 μM. It was further demonstrated that the they caused apoptosis based on the cell cycle arrest at SubG1/G1 phase, inhibition of Akt protein phosphorylation and also by causing increased amounts of cleaved PARP in tested cell lines. In parallel to the in vitro results, in vivo efficacy of BRP-38 and -91 was demonstrated by its inhibition of tumor volume (20-50%) in xenografts established with Mahlavu and MDA-MB-231 cell lines.
Vicinal diaryl heterocycles against liver and breast cancer cells with in vivo efficacy