Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole–Based RalA Inhibitors Against Hepatocellular Carcinoma

Abstract

The activation of Ras small GTPases, including RalA and RalB, plays an important role in carcinogenesis, tumor progress, and metastasis. In the current study, we report the discovery of a series of 6-sulfonylamide-pyrano [2,3-c]-pyrazole derivatives as novel RalA inhibitors. ELISA-based biochemical assay results indicated that compounds 4k–4r suppressed RalA/B binding capacities to their substrates. Cellular proliferation assays indicated that these RalA inhibitors potently inhibited the proliferation of HCC cell lines, including HepG2, SMMC-7721, Hep3B, and Huh-7 cells. Among the evaluated compounds, 4p displayed good inhibitory capacities on RalA (IC50 = 0.22 μM) and HepG2 cells (IC50 = 2.28 μM). Overall, our results suggested that a novel small-molecule RalA inhibitor with a 6-sulfonylamide-pyrano [2, 3-c]-pyrazole scaffold suppressed autophagy and cell proliferation in hepatocellular carcinoma, and that it has potential for HCC-targeted therapy.

Recent Synthesis of Mono‐ & Bis‐Pyranopyrazole Derivatives

“…Sulfonamide pyranopyrazole derivatives ( 8) have also been synthesized as novel RalA inhibitors. [131] Among these compounds, only methyl, methoxy, trifluoromethyl, thienyl and pyridyl substituents showed excellent RalA inhibition against the proliferation of HCC cell lines, including SMMC-7721, Hep3B, HepG2, and Huh-7 cells. The 6-sulfonylamidepyrano[2,3-c]-pyrazole scaffold as RalA inhibitor suppressed cell proliferation and autophagy in hepatocellular carcinoma which indicates its potential for HCC-targeted therapy.…”

“…The 6-sulfonylamidepyrano[2,3-c]-pyrazole scaffold as RalA inhibitor suppressed cell proliferation and autophagy in hepatocellular carcinoma which indicates its potential for HCC-targeted therapy. [131] N-(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles (9) were synthe-sized and showed potential for anticancer activity and inhibit kinases against glioma cell lines. With unsubstituted compound (9) exhibited strong glioma growth inhibitory properties [58] (Scheme 4).…”

“…Among these compounds, only methyl, methoxy, trifluoromethyl, thienyl and pyridyl substituents showed excellent RalA inhibition against the proliferation of HCC cell lines, including SMMC‐7721, Hep3B, HepG2, and Huh‐7 cells. The 6‐sulfonylamide‐pyrano[2,3‐c]‐pyrazole scaffold as RalA inhibitor suppressed cell proliferation and autophagy in hepatocellular carcinoma which indicates its potential for HCC‐targeted therapy [131] . N ‐(4‐chlorophenyl) substituted pyrano[2,3‐c]pyrazoles ( 9 ) were synthesized and showed potential for anticancer activity and inhibit kinases against glioma cell lines.…”

“…Sulfonamide pyranopyrazole derivatives ( 8 ) have also been synthesized as novel RalA inhibitors [131] . Among these compounds, only methyl, methoxy, trifluoromethyl, thienyl and pyridyl substituents showed excellent RalA inhibition against the proliferation of HCC cell lines, including SMMC‐7721, Hep3B, HepG2, and Huh‐7 cells.…”