Benzylidene hydrazides as potential anticancer agents

Boykin, David W.; Varma, Rajender S.

doi:10.1021/jm00297a072

Cited by 4 publications

(2 citation statements)

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“…Thus, the compounds described here are unique in their ability to activate this response via a GPCR. On the other hand, compounds with this scaffold have been reported among agents with antitumor (Boykin and Varma, 1970), proapoptotic (Zhang et al, 2004), antiprion (Bertsch et al, 2005), analgesic (Almasirad et al, 2006), and antioxidant (Simunek et al, 2005) properties. Hence, our findings suggest the possibility that the antitumor and proapoptotic effects reported for arylcarboxylic acid hydrazides could be due, in part, to activation of TNF-␣ production.…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Formyl Peptide Receptor-Like 1 Agonists That Induce Macrophage Tumor Necrosis Factor α Production

et al. 2008

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Development of immunomodulatory agents that enhance innate immune responses represents a promising strategy for combating infectious diseases. In the present studies, we screened a series of 71 arylcarboxylic acid hydrazide derivatives for their ability to induce macrophage tumor necrosis factor ␣ (TNF-␣) production and identified six such compounds, including one compound previously shown to be a formyl peptide receptor (FPR/FPRL1) agonist. The two most potent compounds [compound 1, nicotinic acid [5-(3-bromophenyl)-2-furyl]methylene-hydrazide; compound 2, 4-fluoro-benzoic acid [5-(3-trifluoromethyl-phenyl)-2-furyl]-methylene-hydrazide] were selected for further analysis. These compounds induced de novo production of TNF-␣ in a doseand time-dependent manner in human and murine monocyte/ macrophage cell lines and in primary macrophages. These compounds also induced mobilization of intracellular Ca 2ϩ , production of reactive oxygen species, and chemotaxis in human and murine phagocytes. Induction of macrophage TNF-␣ production was pertussis toxin-sensitive, and analysis of the cellular target of these compounds showed that they were FPRL1-specific agonists and that this response was blocked by FPR/FPRL1 and FPRL1-specific antagonists. In addition, pharmacophore modeling showed a high degree of similarity for low-energy conformations of these two compounds to the current pharmacophore model for FPR ligands (Mol Pharmacol 68:1301-1310, 2005). Overall, these compounds represent novel FPRL1 agonists that induce TNF-␣, a response distinct from those induced by other known FPR and FPRL1 agonists.

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