Synthesis and characterization of analogues of natural orbitide [1-8-NαC]-zanriorb A1 and evaluation of their bioactivity Anila Bashir 1 , Nadeem ul Haque 1 , Humira Karim 1 , Sadiq Noor Khan 1 , Almas Jabeen 2 , Shaista Qayyum 2 , M. Iqbal Choudhary 1,2 , Farzana Shaheen 1 1 H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Pakistan, 2 Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Pakistan The [1-8-N C]-zanriorb A1 (1) was reported as natural orbitide constituent of traditional medicinal plant Zanthoxylum riedelianum. In the current study, new cyclic analogues of zanriorb A1 were designed and synthesized by replacing glycine and proline residues of this peptide. These peptides were synthesized through solid-phase peptide synthetic strategy and cyclized via two ways, solution-phase macrocyclization and on-resin solid-phase macrocyclization. These peptide analogues were fully characterized by using mass, 1D, and 2D-NMR techniques. The natural orbitide was reported cytotoxic to Jurket leukemia T-cells (IC50 = 218.0 nM), while our synthetic analogs were inactive against Jurkat cell line but many of them inhibited the production of nitric oxide in LPS stimulated macrophages. The most active synthetic analogue showed an IC50 = 22 µM and it was more potent as compared to the standard L-NMMA (IC50 = 98 µM) indicating its strong anti-inflammatory potential. References 1. Nadeem ‐ ul ‐ Haque, M., Bashir, A., Karim, H., Khan, S.N., Shah, Z.A., Jabeen, A., Qayyum, S., Ganesan, A., Choudhary, M.I. and Shaheen, F., Synthesis of [1 ‐ 8 ‐ NαC] ‐ zanriorb A1, alanine-containing analogues, and their cytotoxic and anti- inflammatory activity. Journal of Peptide Science, p.e3405. -dos S. Beirigo, P.J., Torquato, H.F., Dos Santos, C.H., Carvalho, M.G.D., Castro, R.N., Paredes-Gamero, E.J., de Sousa Jr, P.T., Jacinto, M.J. and da Silva, V.C., 2016. [1-8-NαC]-Zanriorb A1, a proapoptotic orbitide from leaves of Zanthoxylum riedelianum. Journal of Natural Products, 79(5), pp.1454-1458.
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