Synthesis and antitumor activity of 5-[1-(3-(dimethylamino)propyl)-5-halogenated-2-oxoindolin-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamides

We report herein the design and synthesis of novel 1-[3-(dimethylamino)propyl]indolin-2-one derivatives based on the structural features of Sunitinib, a known multitargeted receptor tyrosine kinase inhibitor, and TMP-20, a previously discovered compound with good antitumor activity in our lab. These newly synthesized derivatives were evaluated for in vitro activity against five human cancer cell lines and VEGF/bFGF-stimulated HUVECs. Results revealed that all of the target compounds 1a–p show potent antitumor activity, compounds 1e–h (IC50’s: 0.45–5.08 μM) are more active than Sunitinib (IC50’s: 1.35–6.61 μM), and the most active compound 1h (IC50: 0.47–3.11 μM) is 2.1–4.6-fold more potent than Sunitinib against all five cancer cell lines. In addition, like Sunitinib, 1a–p have higher selectivity on VEGF-stimulated HUVEC other than bFGF-stimulated HUVEC.

We report herein a series of novel 1-[3-(dimethylamino)propyl]indolin-2-one derivatives. Results revealed that all compounds show potent antitumor activity, compounds 1e–h (IC50’s: 0.45–5.08 μM) are more active than Sunitinib (IC50’s: 1.35–6.61 μM), and the most active compound 1h (IC50: 0.47–3.11 μM) is 2.1–4.6-fold more potent than Sunitinib against all five cancer cell lines. In addition, 1a–p have higher selectivity on VEGF-stimulated HUVEC other than bFGF-stimulated HUVEC.Figure optionsDownload as PowerPoint slide