Anti-GBM potential of Rosmarinic acid and its synthetic derivatives via targeting IL17A mediated angiogenesis pathway

Md Shamsuddin Sultan Khan ^A,C,E, Mohammad Adnan Iqbal ^B, Muhammad Asif ^A, Tabinda Azam ^B, Majed Al-Mansoub ^A, Rosenani S. M. A. Haque ^B, Mohammed Khadeer Ahamed Basheer ^C, Aman Shah Abdul Majid ^D, Amin Malik Shah Abdul Majid ^A,C,E*

Metal salts and base rosmarinates demonstrated potent anti-GBM efficacy as IL17A inhibitor with minimal toxicity.   

Abstract

Glioblastoma (GBM) is a highly angiogenic malignant primary brain tumor with very poor patient survival rates. Here, we present Rosmarinic acid and its new salt and base derivatives that show potential anti-glioblastoma (anti-GBM) activity via disruption of IL17A-mediated downstream angiogenesis pathway. These new compounds were rationally designed, synthesized and the oral CNS physicochemical properties were determined. The anti-GBM activity of the compounds were determined using cell migration and proliferation assays in U87 MG, DBTRG MG and EA.hy926 cells. The compounds activity on IL17A and VEGF expression was determined using ELISA and apoptotic activity was measured by caspase assays. The compounds showed stability in serum and at different pH similar to Rosmarinic acid stoichiometry.  Moreover, the salt derivatives were highly hydrophilic and bases were highly lipophilic. These derivatives showed blood-brain barrier permeability >2 fold more than rosmarinic acid (P<0.001). ROS were differentially expressed after treatment with salt and base rosmarinates in U87 MG (P<0.0001). The compounds showed cytostatic and anti-angiogenic activity. The IC₅₀ of the silver salts was found to be > 1200 µg/ml thus excluding them from being classed as toxic compounds. In conclusion, metal salts and base rosmarinates demonstrated potent anti-GBM efficacy as IL17A inhibitor with minimal toxicity.   

Key Words: IL17A, Chemotherapy, Glioblastoma, Anti-angiogenic activity, Rosmarinic acid, Caffeic acid, Synthetic derivatives

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