Sukumar Bepary * , Tran Quang De and Ge Hyeong Lee

* Correspondence: Sukumar Bepary (email: sukumarsb@yahoo.com)

Main Article Content

Abstract

Phosphoinositide 3-kinase gamma enzymes play significant roles in inflammatory cell recruitment to tumors and accordingly lot of studies have targeted development of small molecule inhibitors against these enzymes for managing various chronic inflammatory disorders. In this study, a number of Pyrazole substituted Resorcinol derivatives have been synthesized in the laboratory and then were evaluated for the inhibitory potential against the gamma isozyme. Highest inhibitory potential was observed from the introduction of non-polar phenyl or methylbenzyl substitution (66.4% and 59.5%) on the OH group of the resorcinol. Addition of relatively polar moiety resulted in decrease in the inhibitory potential and lowest inhibition was observed from 4-pyridyl methyl and 2-morpholino ethyl moieties (23.6% and 24.5% inhibition respectively). The results were encouraging due to remarkable inhibition showed by these compounds against the PI3K enzyme. Thus the scaffold appears as interesting pharmacophore suitable for further development.
Keywords: PI3K gamma, pyrazole, Resorcinol

Article Details

References

Bodendiek, S. B., Mahieux, C., Hänsel, W. et al., 2009. 4-​Phenoxybutoxy-​substituted heterocycles - A structure-​activity relationship study of blockers of the lymphocyte potassium channel Kv1.3. Eur. J. Med. Chem. 44(5): 1838-1852.

Bradbury, R. H. and Kettle, J. G., 2004. Preparation of (anilino)quinazoline derivatives as antiproliferative agents. PCT Int. Appl., WO2004093880.

Baroudi, A., Mauldin, J. and Alabugin, I. V., 2010. Conformationally gated fragmentations and rearrangements promoted by interception of the Bergman cyclization through intramolecular H-abstraction: a possible mechanism of auto-​resistance to natural enediyne entibiotics? J. Am. Chem. Soc. 132(3): 967-979.

Cardenas, M., Marder, M., Blank, V. C. et al., 2006. Antitumor activity of some natural flavonoids and synthetic derivatives on various human and murine cancer cell lines. Bioorg. Med. Chem. 14(9): 2966-2971.

Joshi, S., Singh, A. R., Zulcic, M. et al., 2014. A macrophage-dominant PI3K isoform controls hypoxia-induced HIF1α and HIF2α stability and tumor growth, angiogenesis, and metastasis. Mol Cancer Res. 12(10): 1520- 1531.

Manna. F., Chimenti, F., Fioravanti et al., 2005. Synthesis of some pyrazole derivatives and preliminary investigation of their affinity binding to P-glycoprotein. Bioorg. Med. Chem. Let. 15(20): 4632-4635.

Marie-Claude, S., Fargeau-Bellassoued, M. C. and Graffe, B., 1991. Synthesis of 2-pyrimidinyl phenols and of 2-pyrazolylphenols. J. Het. Chem. 28(3): 667-72.

Okkenhaug, K., 2013. Two birds with one stone: dual p110δ and p110γ inhibition. Chem Biol. 20(11): 1309-1310.

Rommel, C., Camps, M. and Ji, H., 2007. PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond? Nat Rev Immunol. 7(3): 191-201.

Schmid. M, C., Avraamides, C. J., Dippold, H. C. et al., 2011. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kγ, a single convergent point promoting tumor inflammation and progression. Cancer Cell. 19(6): 715-727.

Bepary, S., Youn, I. K., Lim, H. J. et al., 2013. Inhibition of PI3 kinase gamma enzyme by novel phenylpyrazoles. Bull. Korean Chem. Soc. 34(9): 2829.

Bepary, S., Yoon, I. K. and Lee, G. H., 2016. Novel 3-amino-7-(aminomethyl)-1H-indazol-4-ol as the PI3Kγ enzyme Inhibitor. Bull. Korean Chem. Soc. 37: 2054–2057.

Vanhaesebroeck, B., Julie, G. G., Graupera et al., B., 2010. The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol. 11(5): 329-341.

Winkler, D. G., Faia, K. L., DiNitto, J. P. et al., 2013. PI3K-δ and PI3K-γ inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem Biol. 20(11): 1364- 1374.

Most read articles by the same author(s)