Abstract
In order to investigate for a new effective and safe anticancer drug, we synthesized a novel series of quinazoline containing biologically active substituted-sulfonamide moiety at 3- position 4a–n. The structure of the newly prepared compounds was proved by microanalysis, IR, 1H-NMR, 13C-NMR and mass spectral data. All the synthesized compounds were evaluated for their in vitro cytotoxic activity in numerous cancer cell lines including A549, HepG-2, LoVo and MCF-7 and normal HUVEC cell line. The two most active compounds 4d and 4f were then tested for their apoptosis induction using DNA content and Annexin V-FITC/PI staining. Moreover, apoptosis initiation was also confirmed using RT-PCR and Western blot. To further understand the binding preferences of quinazoline sulfonamides, docking simulations were used. Among the fourteen new synthesized compounds, we found that compounds 4d and 4f exerted the strongest cytotoxicity against MCF-7 cells with an IC50 value of 2.5 and 5 μM, respectively. Flow cytometry data revealed the ability of compounds 4d and 4f to mediate apoptosis and arrest cell cycle growth at G1 phase. Furthermore, RT-PCR and Western blot results suggested that both 4d and 4f activates apoptotic cell death pathway in MCF-7 cells. Molecular docking assessments indicated that compounds 4d and 4f fit perfectly into Bcl2’s active site. Based on the biological properties, we conclude that both compounds 4d and 4f could be used as a new type of anticancer agent, which provides a scientific basis for further research into the treatment of cancer.
Highlights
Quinazoline and sulfonamide moieties have been identified as classes of chemotherapeutic agents with substantial therapeutic value against solid tumors [1,2,3,4]
Scheme 1 shows the synthesis of quinazoline carrying biologically active substituted- benzenesulfonamide moieties 4a–n
The required strategic starting material 4-(2-mercapto-8-methoxy-4oxoquinazolin-3(4H)-yl) benzenesulfonamide 3 was synthesized in quantitative yield by cyclocondensation of 2-amino-3-methoxybenzoic acid 1 with 4-isothiocyanatobenzenesulfonamide 2 [19], in refluxing 1,4-dioxan containing triethylamine (Scheme 1)
Summary
Quinazoline and sulfonamide moieties have been identified as classes of chemotherapeutic agents with substantial therapeutic value against solid tumors [1,2,3,4]. Due to the great performances of quinazoline compounds in antitumor applications, the enhancement of new quinazoline candidates as anticancer agents is a promising topic. In the new drug design, the development of hybrid derivatives through the combination of several pharmacophores may assign compounds with remarkable biological profiles [12]. Various quinazoline sulfonamide derivatives were evaluated as anticancer agents against numerous cell lines, and many compounds had displayed a promising activity [3,13,14]. Several previous studies have demonstrated that quinazoline scaffolds had a remarkable antiproliferative capacity against a variety of cancer cells, highlighting their efficiency in the development of apoptosis inducers drugs. Numerous novel quinazoline-derived compounds which exert effective anticancer activity via apoptosis induction have been synthesized [10,16]. As a continuation of our previous efforts [13,20,21]
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