Abstract: Lipid A, 1, is a toxic component of Gram -ve bacterial lipopolysaccharide (LPS) and is amphiphilic in nature, with a polar disaccharide head group linked to a variable number of lipophilic chains.1 It is now understood that the initial interaction of LPS with the Toll-like receptor-4 (TLR4) for the initiation of immune response is mediated through lipid A.2 Inflammation as a part of the immune response, although good for the defence mechanism, excessive and uncontrolled inflammation particularly following infection through Gram-ve bacteria has been the cause of Sepsis3 and Cancer.4 The role of lipid A in signal transduction has inspired the synthesis of several lipid A analogues and their evaluation for modulation of the TLR4 activation process.5 The pharmacological interest of these analogues as a vaccine adjuvant, immunotherapeutic or antisepsis, and anti-inflammatory agent, have merited these studies. The seminar will cover an overview of the TLR4 activation process and the understanding resulting from synthetic lipid-A analogues. Inspired by this understanding, we are attempting at the synthesis of azepane-based lipid A analogues 2 and 3.

Figure 1: General structure of lipid A 1 and our synthetic targets 2 and 3.
References:
1. (a) Peri, F.; Marinzi, C.; Barath, M.; Granucci, F.; Urbanoa M.; Nicotraa, F. Bioorg. Med. Chem., 2006, 14, 190–199. (b) Lewicky, J. D.; Ulanova, M.; Jiang, Z. H. Carbohydrate Research, 2011, 346, 1705–1713. (c) Peri, F.; Marinzi, C.; Barath, M.; Granucci, F.; Urbanoa M.; Nicotraa, F. Bioorg. Med. Chem., 2006, 14, 190–199.
2. Lewicky, J. D.; Ulanova, M.; Jiang, Z. H. Bioorg. Med. Chem., 2013, 21, 2199-2209.
3. Jiang, Z. H.; Budzynski W. A.; Skeels, L. N.; Krantz M. J.; Koganty, R. R. Tetrahedron, 2002, 58, 8833–8842.
4. Rice, T. W.; Bernard, G. R. Annu. Rev. Med. 2005, 56, 225-248.
5. Cighetti, R.; Ciaramelli, C.; Sestito, S. E.; Zanoni, I.; Kubik, L.;Freire, A. A.; Calabrese, V.; Granucci, V.; Jerala, R.; Santamara, S. M.; Barbero, J. J.; Peri, F. Chem.BioChem. 2014, 15, 250-258. (in Text Citations)