Synthesis, biological evaluation and molecular modeling studies of Schiff bases derived from 4-methylsalicylic acid as p
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Med Chem Res DOI 10.1007/s00044-013-0561-0
ORIGINAL RESEARCH
Synthesis, biological evaluation and molecular modeling studies of Schiff bases derived from 4-methylsalicylic acid as potential immunosuppressive agents Ru Yan • Peng-Gang Liu • Zhi-Ming Zhang • Xian-Ying Fang Xue-Wei Zhang • Jia-Li Deng • Hai-Liang Zhu
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Received: 6 December 2012 / Accepted: 21 February 2013 Ó Springer Science+Business Media New York 2013
Abstract A series of Schiff bases derived from 4-methylsalicylic acid (4a–4s) were synthesized, 14 of which (4a– 4h, 4j–4l, 4n, 4q, and 4s) were reported for the first time. All the synthesized compounds were evaluated for their immunosuppressive activities for the first time. Among them, compound 4o displayed the most potent biological activity against lymph node cells (IC50 = 1.02 lM for lymph node cells and IC50 = 2.17 lM for PI3Kc). The results of apoptosis and western-blot assays demonstrated that the immunosuppressive activity of compound 4o might be mediated by the inhibition of PI3K/AKT signaling pathway. Docking simulation was performed to position compound 4o into the PI3Kc structure active site to determine the probable binding model. Keywords Schiff base Immunosuppressive activities PI3Kc Molecular modeling 4-Methylsalicylic acid
Introduction Immunosuppressant agents are an important class of clinical drugs for an array of medical processes, including transplant rejection and treatment of autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and psoriasis (Hackstein and Thomson, 2004; Kahan, 2003). Although immunosuppressive drugs such as
Ru Yan and Peng-Gang Liu equally contributed to this paper. R. Yan P.-G. Liu Z.-M. Zhang X.-Y. Fang X.-W. Zhang J.-L. Deng H.-L. Zhu (&) State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People’s Republic of China e-mail: [email protected]
glycocorticoids (e.g., cortisol), cyclosporin A (CsA), tacrolimus (FK506), and sirolimus (rapamycin), etc. have been clinically used for their undeniable clinical advantages, they were also proved to possess a number of undesired side effects including liver toxicity, malignancy, cosmetic effects, renal toxicity, infection, and other bad responses (Smith et al., 2003). Therefore, there is a clinical need for new and less toxic therapeutic agents with new mechanisms of action. The phosphatidylinositol 3-kinases (PI3Ks) belong to a family of enzymes that phosphorylate the inositol ring at the 0 3 -hydroxyl position of phosphatidylinositol and phosphoinositides. They are evolutionarily conserved from yeast to high mammals and are divided into class I, II, and III PI3Ks, according to their molecular structure, cellular regulation, and in vivo substrate specificities (Cantley, 2002; Rommel et al., 2007; Foster et al., 2003). The best known PI3Ks are class I PI3Ks, which include subclass IA (consisting of PI3Ka, PI3Kb, and PI3Kd isoforms) and subclass IB (consisting of PI3Kc only). Both subclasses phosphorylate phosphatidylinositol-4,5
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