Anti-inflammatory activity of a naphthyridine derivative (7-chloro-6-fluoro-N-(2-hydroxy-3-oxo-1-phenyl-3-(phenylamino)propyl)-4- oxo-1-(prop-2-yn-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide) possessing in vitro anticancer potential

作者：Madaan Alka^*; Kumar Vivek; Verma Ritu; Singh Anu T; Jain S K; Jaggi Manu

来源：International Immunopharmacology, 2013, 15(3): 606-613.

DOI：10.1016/j.intimp.2013.01.011

• 1,8-Naphthyridine-3-carboxamide
• Anticancer
• Anti-inflammatory
• Dendritic cells
• Cytokines

We have previously synthesized a series of 1,8-naphthyridine-3-carboxamide derivatives to identify potential anti-cancer/anti-inflammatory compounds. Three derivatives, 7-chloro-N-(3-(cyclopentylamino)-3-oxo-1-phenylpropyl)-6-fluoro-4-oxo-1-(prop-2-yn-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (C-22), 7-chloro-N-(2-hydroxy-3-oxo-1-phenyl-3-(phenylamino)propyl)-4-oxo-1-(prop-2-yn-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (C-31) and 7-chloro-6-fluoro-N-(2-hydroxy-3-oxo-1-phenyl-3-(phenylamino)propyl)-4-oxo-1-(prop-2-yn-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (C-34) demonstrated high cytotoxicity against a number of cancer cell lines and inhibited secretion of IL-1-beta and IL-6. In the present study, C-22, C-31 and C-34 were assessed for modulation of pro-inflammatory cytokines, TNF-alpha and IL-8, chemokine RANTES and NO produced by lipopolysaccharide (LPS)-treated mouse Dendritic cells (DCs). Among the 3 compounds, C-34 showed the most potent inhibition of inflammatory markers in DC model at 02 and 2 mu M. C-34 also significantly downregulated the secretion of TNF-alpha, IL-1-beta and IL-6 by murine splenocytes and THP-1 cells against IFS induced levels. In vitro effects of C-34 on bone marrow toxicity were assessed in CFU-GM assay. Human CPU-GM population was comparatively more sensitive to C-34 (0.1-10 mu M) than murine CPU-GM. IC50 values for murine and human CPU-GM were not attained. C-34 was further examined for in vivo suppression of LPS induced cytokines in a mice model. At doses ranging from 125 to 5 mg/kg, C-34 led to significant inhibition of TNF-alpha, IL-1-beta and MIP-1-alpha. At the highest dose of 5 mg/kg, C-34 also protected LPS-treated mice against endotoxin-induced lethality. In conclusion, C-34 demonstrates anti-inflammatory activity in vitro and in vivo in addition to cytotoxic properties. This finding suggests its potential for further development as a synthetic naphthyridine derivative with dual anti-cancer and anti-inflammatory (cytokine inhibition) properties.

• 出版日期2013-3