Potential Inhibitors of Angiogenesis. Part I: 3-(Imidazol-4(5)-ylmethylene)indolin-2-ones

Abstract

The synthesis and pharmacological evaluation of new 3-(imidazol-4(5)-ylmethylene)indolin-2-ones, analogues of SU-5416, are reported. The final compounds 20 -51 were obtained by Knoevenagel coupling between the substituted indolin-2-ones 1 -15 and either the formylimidazole derivatives 16 -18 or 2-formyl-3,5-dimethylpyrrole 19. Methylation at the nitrogen atom of the indolin-2-one and/or imidazole moities was carried out in the presence of the couple NaH/DMF. A Mannich reaction afforded the 1-dimethylaminomethyl derivatives 43 and 48. The antiangiogenic activity of these compounds was evaluated in a three dimensional in vitro rat aortic ring assay. In this test, compound 20 induced a decrease of angiogenesis comparable to that observed with SU-5416; the vascular density indexes at 1 mM were 30 6 18 and 22 6 4 % of control, respectively. The compounds were also evaluated, in an independent manner, as inhibitors of the human EGF-receptor tyrosine kinase activity. As expected, only minor activities were observed with four compounds, out of thirty-one, exerting inhibitory effects in the range of 40 -55 % at 10 mM concentration.

Computational Study of Solvent Effects on Characterizations of (E)‐3‐X‐Indoline‐2‐thiones Derivatives as Antivirus and Anticancer Compounds

“…This may be attributed to the higher dipole moment (polarity) of III and its higher aptitude for hydrogen bonding (Table 1). Neither change of point group nor dihedral angle D (3,7,10,12) is observed for structures insensitive to the solvent effect, such as I and IV with C 1 and C s symmetry, respectively. In contrast, in going from gas phase to different solvents, considerable changes of point group as well as D (3,7,10,12) occur for structures sensitive to the solvent effect, such as II and III.…”

“…The shorter 1.77 Å in III implies its larger intra-molecular interactions in solution. In contrast to I, II, and IV, in structure III the angle confined between atom numbers 7, 10, and 12 (A (7,10,12)) changes considerably, in going from gas phase to different solvents (see Supporting Information). This may be attributed to the higher dipole moment (polarity) of III and its higher aptitude for hydrogen bonding (Table 1).…”

“…4 In 1994, oxoindole (2) changing to thioindole (3) was carried out by using P 2 S 5 and Na 2 CO 3 in THF. 5 The resulted compound (4) was synthesized by condensation of thioindole (3) with substituted aryl aldehydes in the presence of a base 6,7 (Scheme 1). Solvent effects on physical or chemical processes are usually studied by means of empirical solvent parameters.…”

Potential Inhibitors of Angiogenesis. Part II: 3-(Azolylmethylene)-2,3-dihydrobenzo[b]furan-2-ones

“…We have recently reported the synthesis and pharmacological evaluation of 3-(imidazol-4(5)-ylmethylene)indolin-2-ones as potential inhibitors of angiogenesis. 5 Compound 1, the most active compound on the rat aortic rings test, induced a decrease in angiogenesis comparable to that of SU-5416.…”

Synthesis and Biological Evaluation of 3-(Substituted-benzylidene)-1,3-dihydro-indolin Derivatives as Human Protein Kinase CK2 and p60c-Src Tyrosine Kinase Inhibitors

“…The 3-(substituted-benzylidene)-1,3-dihydro-indolin-2-thione and 2-one derivatives 3-16 were synthesized by condensing compounds 1, 2, and substituted aryl aldehydes in the presence of different bases (Knovenagel reaction) 31) (Chart 1). Although knovenagel reaction was reported for the synthesis of 3-(substituted-benzylidene)-1,3-dihydro-indolin-2-one derivatives, it was successfully applied for the synthesis of 3-(substituted-benzylidene)-1,3-dihydro indolin-2-thione derivatives in our laboratory.…”