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.

[1]  S. Durdağı,et al.  Design and synthesis of novel caffeic acid phenethyl ester (CAPE) derivatives and their biological activity studies in glioblastoma multiforme (GBM) cancer cell lines. , 2022, Journal of molecular graphics & modelling.

[2]  G. Sethi,et al.  Caffeic acid and its derivatives as potential modulators of oncogenic molecular pathways: New hope in the fight against cancer. , 2021, Pharmacological research.

[3]  G. Alexiou,et al.  Haloperidol Induced Cell Cycle Arrest and Apoptosis in Glioblastoma Cells , 2020, Biomedicines.

[4]  Hsin-Yi Huang,et al.  Flunarizine, a drug approved for treating migraine and vertigo, exhibits cytotoxicity in GBM cells. , 2020, European journal of pharmacology.

[5]  L. Szoka,et al.  Capsaicin up-regulates pro-apoptotic activity of thiazolidinediones in glioblastoma cell line. , 2020, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[6]  Ji‐Hyun Lee,et al.  Combined effects of niclosamide and temozolomide against human glioblastoma tumorspheres , 2020, Journal of Cancer Research and Clinical Oncology.

[7]  B. Meyer,et al.  High expression of estrogen receptor alpha and aromatase in glial tumor cells is associated with gender-independent survival benefits in glioblastoma patients , 2020, Journal of Neuro-Oncology.

[8]  Piyoosh Sharma,et al.  Design, synthesis, and biological evaluation of ferulic acid based 1,3,4-oxadiazole hybrids as multifunctional therapeutics for the treatment of Alzheimer's disease. , 2019, Bioorganic chemistry.

[9]  T. Kálai,et al.  Synthesis and evaluation of paramagnetic caffeic acid phenethyl ester (CAPE) analogs , 2019, Monatshefte für Chemie - Chemical Monthly.

[10]  Y. Qin,et al.  Caffeic acid phenethyl ester suppressed growth and metastasis of nasopharyngeal carcinoma cells by inactivating the NF-κB pathway , 2019, Drug design, development and therapy.

[11]  A. Ikari,et al.  Caffeic acid phenethyl ester potentiates gastric cancer cell sensitivity to doxorubicin and cisplatin by decreasing proteasome function , 2019, Anti-cancer drugs.

[12]  A. Sculean,et al.  Caffeic acid phenethyl ester protects against oxidative stress and dampens inflammation via heme oxygenase 1 , 2019, International Journal of Oral Science.

[13]  S. Bajaj,et al.  Synthesis, thymidine phosphorylase inhibitory and computational study of novel 1, 3, 4-oxadiazole-2-thione derivatives as potential anticancer agents , 2018, Comput. Biol. Chem..

[14]  G. El Fakhri,et al.  Real‐Time Imaging of Brain Tumor for Image‐Guided Surgery , 2018, Advanced healthcare materials.

[15]  T. Massoud,et al.  Targeted nanoparticle delivery of therapeutic antisense microRNAs presensitizes glioblastoma cells to lower effective doses of temozolomide in vitro and in a mouse model , 2018, Oncotarget.

[16]  Hongyang Zhao,et al.  Inhibitor of Nicotinamide Phosphoribosyltransferase Sensitizes Glioblastoma Cells to Temozolomide via Activating ROS/JNK Signaling Pathway , 2016, BioMed research international.

[17]  X. Zhang,et al.  Ferulic acid exerts antitumor activity and inhibits metastasis in breast cancer cells by regulating epithelial to mesenchymal transition. , 2016, Oncology reports.

[18]  J. Prados,et al.  Temozolomide Resistance in Glioblastoma Cell Lines: Implication of MGMT, MMR, P-Glycoprotein and CD133 Expression , 2015, PloS one.

[19]  Y. Dodurga,et al.  Assessment of the anticancer mechanism of ferulic acid via cell cycle and apoptotic pathways in human prostate cancer cell lines , 2015, Tumor Biology.

[20]  P. Morin,et al.  Metabolic Effects of Known and Novel HDAC and SIRT Inhibitors in Glioblastomas Independently or Combined with Temozolomide , 2014, Metabolites.

[21]  P. Sharma,et al.  Synthesis and evaluation of substituted diphenyl-1,3,4-oxadiazole derivatives for central nervous system depressant activity , 2012, Organic and medicinal chemistry letters.

[22]  A. Plowright,et al.  Oxadiazoles in medicinal chemistry. , 2012, Journal of medicinal chemistry.

[23]  Fernanda Borges,et al.  Lipophilic caffeic and ferulic acid derivatives presenting cytotoxicity against human breast cancer cells. , 2011, Chemical research in toxicology.

[24]  S. Karthikeyan,et al.  Inhibitory effect of caffeic acid on cancer cell proliferation by oxidative mechanism in human HT-1080 fibrosarcoma cell line , 2011, Molecular and Cellular Biochemistry.

[25]  E. Laurini,et al.  Antimycobacterial activity of new 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-one derivatives. Molecular modeling investigations. , 2009, Bioorganic & medicinal chemistry.

[26]  A. Husain,et al.  Synthesis of novel 1,3,4-oxadiazole derivatives and their biological properties , 2009, Acta pharmaceutica.

[27]  Mohamed Ashraf Ali,et al.  Oxadiazole mannich bases: synthesis and antimycobacterial activity. , 2007, Bioorganic & medicinal chemistry letters.

[28]  R. D. Dyer,et al.  Synthesis, structure-activity relationships, and in vivo evaluations of substituted di-tert-butylphenols as a novel class of potent, selective, and orally active cyclooxygenase-2 inhibitors. 2. 1,3,4- and 1,2,4-thiadiazole series. , 1999, Journal of medicinal chemistry.