Design, synthesis and in vitro antitumor activity of novel N-substituted-4-phenyl/benzylphthalazin-1-ones

• Phthalazin-1-ones 14a–g and 19a–g were designed and synthesized.
• Antitumor activity of 14a–g and 19a–g was evaluated against HepG2, HT-29 and MCF-7.
• 19d (IC50 = 1.2 ± 0.09 μM) was found to be the most potent derivative against HepG2.
• 14e, 14g and 19d showed IC50 = 3.29, 3.5 and 1.2 μM, respectively, against HepG2.
• 14e, 14g and 19d were able to induce apoptosis in HepG2.

A novel series of N-substituted-4-phenylphthalazin-1-ones 14a–g bearing different anilines at the N-2 of phthalazin-1-one scaffold via acetyl-flexible linker was designed and synthesized for the development of potential anticancer agents. Compounds 19a–g were synthesized by insertion of methylene (CH2) bridge at C4-position of 14a–g to provide a flexibility for the phenyl group. The newly synthesized compounds 14a–g and 19a–g were evaluated for their anti-proliferative activity against three human tumor cell lines HepG2 hepatocellular carcinoma, HT-29 colon cancer and MCF-7 breast cancer. In particular, HepG2 and HT-29 cancer cell lines were more susceptible to the synthesized derivatives. Compound 19d (IC50 = 1.2 ± 0.09 μM) was found to be the most potent derivative against HepG2 as it was 2.9 times more active than doxorubicin (IC50 = 3.45 ± 0.54) and sorafenib (IC50 = 3.5 ± 1.04 μM). Compounds 14e, 14g, 19d and 19g with IC50 = (3.29 ± 0.45), (3.50 ± 0.846), (1.20 ± 0.09) and (3.52 ± 0.70) μM, respectively, were found to be active candidates against HepG2 cancer cells. Compounds 14e, 14g, 19d and 19g were able to induce apoptosis in HepG2, this was assured by; the significant increase in the percentage of annexin V–FITC-positive apoptotic cells (UR + LR), the down-regulation of the anti-apoptotic protein Bcl-2 and the up-regulation of the pro-apoptotic protein Bax, in addition to boosting caspase-3 levels. Moreover, cytotoxicity evaluation of the newly synthesized compounds in HT-29 revealed that compounds 14e, 14f, 19e and 19f (IC50 = 3.05 ± 0.78, 4.02 ± 1.18, 3.68 ± 0.79 and 2.98 ± 0.47 μM, respectively) were more potent than doxorubicin (IC50 = 7.70 ± 1.78 μM).

Phthalazin-1-ones 14a–g and 19a–g were designed and synthesized to evaluate their antitumor activity against HepG2, HT-29 and MCF-7. Compounds 14e, g and 19d, g showed an excellent activity against HepG2 while 14e, f and 19e, f were more potent than doxorubicin against HT-29.Figure optionsDownload as PowerPoint slide