Abstract
Herein, a series of imidazo[4,5-f][1,10] phenanthroline derivatives RPIP (PIP = imidazo [4,5-f][1,10] phenanthroline, R = NO2, 1; CF3, 2; Cl, 3; OH, 4) have been synthesized in yields of 82.3–94.7% at 100 °C under the irradiation of microwave. MTT assay has been utilized to evaluate the inhibitory activity (IC50) of these compounds against the growth of various tumor cells, and the results revealed that these compounds, especially 1, exhibited excellent inhibitory activity against the growth of A549 cells with IC50 of 15.03 μM. Moreover, it’s also confirmed that 1 can penetrate into the membrane of tumor cells and distribute in mitochondria when observed under microscopy, resulting apoptosis of tumor cells. The further studies showed that 1 can bind to bcl-2 G-quadruplex DNA, which demonstrated by the increase of melting point of bcl-2 G4 DNA in the presence of 1, as well as electronic titration and emission spectra. In a word, this kind of compound may develop as a potential apoptosis inducer in cancer chemotherapy via binding and stabilizing to the bcl-2 G-quadruplex DNA.
Highlights
It’s worthy to indicate that 1 exhibited excellent inhibitory activity against A549 cells (IC50 = 15.03 μM) but low toxicity in normal cells
At concentration of 20 μM for 1, the ratio of G1-phase reached about 67.37%, which was about 12% higher than that of the control (55.75%) [17,18]. These data indicating that 1 may inhibit the growth of A549 cells through inducing apoptosis of tumor cells since arrest was more related to cell apoptosis, and pro-apoptotic proteins like 4Bcl-2
The further study displayed 1 can distribute at mitochondria, and inhibit tumor cells at G1 phase thisthis compound can can bindbind to thetobcl-2
Summary
1,10-Phenanthroline derivatives with an extended π-conjugated unit of fused imidazole, which can bind to duplex DNA and G-quadruplex DNA through π-π stacking, exhibit great antitumor, anti-inflammatory and antiviral activity [1], as well as probes of DNA due to their strong fluorescence sensory properties towards acid [2]. It’s revealed that di-substituted phenanthroline derivatives can imidazo[4,5-f][1,10]phenanthroline-dione derivatives might increase the chemosensitivity of induce apoptosis tumor [3]. A number[11], of small like pyridostatin analog [9], DNA metal have been [10], reported to inhibit the transcription of Bcl-2 and inducing apoptosis of tumor complexes quindoline derivatives [11], with high affinity to bcl-2 G-quadruplex. Attributed to derivatives exhibit effectively in inducing apoptosis various tumorderivatives cells, and exhibit it’s possible that the high ability to bind and stabilize. DNA,ofphenanthroline effectively this kind of apoptosis compounds may inhibit theand growth of tumor cells in inducing of various tumor cells, it’s possible that thisthrough kind of interacting compoundswith maybcl-2 . Scheme imidazo[4,5-f][1,10]phenanthroimidazole derivatives
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