Abstract
Cancer remains as one of the top leading causes of death worldwide in the last decade. In an attempt to develop a potent anticancer agent, herein we are reporting the synthesis of two novel series of piperazinyltriazolophthalazines as potential anticancer agents with potential inhibitory activity against PARP-1. All the newly synthesized compounds were evaluated for their anti-proliferative activity against four human cancer cell lines namely; Hepatocellular carcinoma (HePG-2), Mammary gland breast cancer (MCF-7), Human prostate cancer (PC3) and Colorectal carcinoma (HCT-116)). The results of cytotoxicity evaluation showed that most of the synthesized compounds displayed moderate cytotoxic activity against the selected cell lines. Compound 23 showed the highest inhibitory effect followed by compound 24 against hepatocellular carcinoma (HePG2) with IC50 values of 15.05 and 17.23 µM respectively. The same two compounds also showed moderate activity against colorectal carcinoma cell line (HCT-116) with IC50 values of 21.93 and 24.06 µM respectively.
Highlights
Triazolopthalazine rings presented in many anticancer agents with potent bromodomain inhibitory effects
Many synthetic [1,2,4]triazolo[3,4a]phthalazines (Figure 1) have been reported to exhibit potent anticancer activities against hepatocellular carcinoma with IC50 values range of 1.60-6.04 (El-Helby et al 2017, 2018; Xue et al 2014)
Chemistry: The general route for the synthesis of starting triazolophthalazines is illustrated in Scheme 1. 4-Methylbenzoic acid converted into the ethyl ester by the action of ethanol in the presence of catalytic amount of sulfuric acid
Summary
Phthalazine derivatives are biologically important heterocycles and are known to possess variety of biological activities such as antitumor (Fedorov et al 2014), anticonvulsant (Sun et al 2011; Sun, Wei, et al 2010), anti-inflammatory (Abd alla et al 2010; Liu et al 2016; Sun, Hu, et al 2010), antidiabetic (Awadallah, El-Eraky, and Saleh 2012), antihypertensive (Olmo et al 2006), muscle relaxant (Haack et al 2005) and antimicrobial (Holló et al 2014; Khalil, Berghot, and Gouda 2009; Salvi et al 2006). Inspired by the versatility of the[1,2,4]triazolo[3,4-a]phthalazine pharmacophoric ring skeleton of L-45 and the piperazine moiety mentioned above, nine novel compounds were synthesized to evaluate their anticancer activities. All the synthesized compounds were evaluated for their in vitro anticancer activity against four cancer cell lines namely; hepatocellular carcinoma (HePG-2), mammary gland breast cancer (MCF-7), human prostate cancer (PC3) and colorectal carcinoma (HCT-116).
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