4752-10-7Relevant articles and documents
Synthesis and anti-inflammatory activity evaluation of a novel series of 6-phenoxy-[1,2,4]triazolo[3,4-a]phthalazine-3-carboxamide derivatives
Liu, Da-Chuan,Gong, Guo-Hua,Wei, Cheng-Xi,Jin, Xue-Jun,Quan, Zhe-Shan
, p. 1576 - 1579 (2016)
The transcription factor nuclear factor-κB (NF-κB) controls many physiological processes including inflammation, immunity, and apoptosis. In this study, a novel series of 6-phenoxy-[1,2,4]triazolo[3,4-a]phthalazine-3-carboxamide derivatives were synthesized as potent anti-inflammatory agents, which acted on tumor necrosis factor (TNF-α) as inhibitors of NF-κB activation. We showed that compounds 6h (6-(2,4-dichlorophenoxy)-[1,2,4]triazolo[3,4-a]phthalazine-3-carboxamide) and 6i (6-(3-tolyloxy)-[1,2,4]triazolo[3,4-a]phthalazine-3-carboxamide) showed more prominent anti-inflammatory activity than other compounds, with similar activities as the reference drug dihydrotanshinone; compound 6i showed the lowest cellular toxicity among the tested compounds. In vivo evaluation of the anti-inflammatory activity showed that compound 6i exhibited excellent anti-inflammatory activity with 58.19% inhibition at 50?mg/kg intraperitoneal (i.p.), with equal efficacy as the positive control indomethacin (100?mg/kg i.p.; 59.21% inhibition).
Discovery of novel triazolophthalazine derivatives as DNA intercalators and topoisomerase II inhibitors
Sakr, Helmy,Ayyad, Rezk R.,El-Helby, Ali A.,Khalifa, Mohamed M.,Mahdy, Hazem A.
, (2021/02/16)
A new series of triazolophthalazine derivatives was designed and synthesized as topoisomerase II (Topo II) inhibitors and DNA intercalators. The synthesized derivatives were evaluated in vitro for their cytotoxic activities against three human cancer cell lines: HepG2, MCF-7, and HCT-116 cells. Compound IXb was the most potent counterpart with IC50 values of 5.39 ± 0.4, 3.81 ± 0.2, and 4.38 ± 0.3 μM, as it was about 1.47, 1.77, and 1.19 times more active than doxorubicin (IC50 = 7.94 ± 0.6, 6.75 ± 0.4, and 5.23 ± 0.3 μM) against HepG2, MCF-7, and HCT-116 cells, respectively. Additionally, the binding affinity of the synthesized compounds toward the DNA molecule was assessed using the DNA/methyl green assay. Compound?IXb showed an excellent DNA binding affinity with an IC50 value of 27.16 ± 1.2 μM, which was better than that of the reference drug doxorubicin (IC50 = 31.02 ± 1.80 μM). Moreover, compound IXb was the most potent member among the tested compounds when investigated for their Topo II inhibitory activity. Furthermore, compound IXb induced apoptosis in HepG2 cells and arrested the cell cycle at the G2/M phase. Additionally, compound IXb showed Topo II poisoning effects at 2.5 μM and Topo II catalytic inhibitory effects at 5 and 10 μM. Finally, molecular docking studies were carried out against the DNA–Topo II complex and DNA, to investigate the binding patterns of the designed compounds.
Discovery and biological evaluation of phthalazines as novel non-kinase TGFβ pathway inhibitors
Frett, Brendan,Kharbanda, Anupreet,Leung, Yuet-Kin,Li, Hong-yu,Li, Ming O.,Saha, Debasmita,Tran, Phuc,Xu, Ke,Zhang, Lingtian
supporting information, (2021/07/13)
TGFβ is crucial for the homeostasis of epithelial and neural tissues, wound repair, and regulating immune responses. Its dysregulation is associated with a vast number of diseases, of which modifying the tumor microenvironment is one of vital clinical interest. Despite various attempts, there is still no FDA-approved therapy to inhibit the TGFβ pathway. Major mainstream approaches involve impairment of the TGFβ pathway via inhibition of the TGFβRI kinase. With the purpose to identify non-receptor kinase-based inhibitors to impair TGFβ signaling, an in-house chemical library was enriched, through a computational study, to eliminate TGFβRI kinase activity. Selected compounds were screened against a cell line engineered with a firefly luciferase gene under TGFβ-Smad-dependent transcriptional control. Results indicated moderate potency for a molecule with phthalazine core against TGFβ-Smad signaling. A series of phthalazine compounds were synthesized and evaluated for potency. The most promising compound (10p) exhibited an IC50 of 0.11 ± 0.02 μM and was confirmed to be non-cytotoxic up to 12 μM, with a selectivity index of approximately 112-fold. Simultaneously, 10p was confirmed to reduce the Smad phosphorylation using Western blot without exhibiting inhibition on the TGFβRI enzyme. This study identified a novel small-molecule scaffold that targets the TGFβ pathway via a non-receptor-kinase mechanism.
Structural identification between phthalazine-1,4-diones and n-aminophthalimides via vilsmeier reaction: Nitrogen cyclization and tautomerization study
Chung, Cheng-Yen,Li, Sin-Min,Lin, Hui-Yi,Tsai, Shuo-En,Tseng, Ching-Chun,Wong, Fung Fuh
, (2021/05/31)
N-aminophthalimides and phthalazine 1,4-diones were synthesized from isobenzofuran1,3-dione, isoindoline-1,3-dione, furo [3,4-b] pyrazine-5,7-dione, or 1H-pyrrolo [3,4-c] pyridine-1,3dione with monohydrate hydrazine to carry out the 5-exo or 6-endo nitrogen cyclization under the different reaction conditions. Based on the control experimental results, 6-endo thermodynamic hydrohydrazination and kinetical 5-exo cyclization reactions were individually selective formation. Subsequently, Vilsmeier amidination derivatization was successfully developed to probe the structural divergence between N-aminophthalimide 2 and phthalazine 1,4-dione 3. On the other hand, the best tautomerization of N-aminophthalimide to diazinone was also determined under acetic acid mediated solution.
N-Chlorination-induced, oxidative ring contraction of 1,4-dimethoxyphthalazines
Im, Jeong Kyun,Yang, ByeongDo,Jeong, Ilju,Choi, Jun-Ho,Chung, Won-jin
, (2020/06/03)
A rarely explored oxidative ring contraction of electron-rich 1,2-diazine is described. Upon treatment with an electrophilic chlorinating reagent (TCICA), 1,4-dimethoxyphthalazines undergo an N-chlorination-induced ring contraction that is accompanied by the loss of one nitrogen atom. The scope of this unusual reactivity was examined with a range of 1,4-dimethoxyphthalazine derivatives. In addition, a mechanism proceeding via a bicyclic species was proposed on the basis of an isolated reaction intermediate and DFT calculations.
Novel triazolophthalazine-hydrazone hybrids as potential PCAF inhibitors: Design, synthesis, in vitro anticancer evaluation, apoptosis, and molecular docking studies
Abulkhair, Hamada S.,Ahmed, Hany E. A.,Bayoumi, Ashraf H.,Ghiaty, Adel,Turky, Abdallah
, (2020/05/28)
Three novel series of triazolophthalazine derivatives bearing hydrazone moiety were designed, synthesized, and evaluated for their anticancer activity against four human cancer cell lines by MTT assay. Six derivatives demonstrated comparable activity with Doxorubicin reference drug against the selected cancer cells. Especially, compound 16 showed the most potent activity with IC50 values of 5.70, 8.04, 11.15, and 4.25, μM against HePG2, MCF-7, PC3, and HCT-116 respectively. Also, compound 26 exhibited comparable inhibitory effect with that of Doxorubicin against the selected cancer cell lines with IC50 values of 6.45, 8.63, 12.28, and 7.03 μM against HePG2, MCF-7, PC3, and HCT-116 respectively. Investigation of the apoptotic activity of the two most active compounds revealed that compounds 16 and 26 could induce both the early and the late apoptosis of HePG2. Further mechanistic study of the HePG2 cell cycle confirmed the spectacular cytotoxic and apoptotic effects of both compounds. Compounds 16 and 26 showed a pronounced increase in cells in G2/M and Pre G1 phases with a concomitant reduction of cells in G0-G1 and S phases. A follow up enzymatic assay indicated that these two compounds have comparable activities with that of bromosporine as PCAF inhibitors with IC50 values of 8.13 and 5.31 μM respectively. Moreover, molecular docking study for all the synthesized compounds was performed to predict their binding affinities toward the active site of histone acetyltransferase GCN5. Results of molecular docking were strongly correlated with that of the cytotoxicity study.
Design, synthesis, and antitumor activity of novel compounds based on 1,2,4-triazolophthalazine scaffold: Apoptosis-inductive and PCAF-inhibitory effects
Turky, Abdallah,Bayoumi, Ashraf H.,Ghiaty, Adel,El-Azab, Adel S.,A.-M. Abdel-Aziz, Alaa,Abulkhair, Hamada S.
, (2020/07/03)
The antitumor activity of newly synthesised triazolophthalazines (L-45 analogues) 10–32 was evaluated in human hepatocellular carcinoma (HePG-2), breast cancer (MCF-7), prostate cancer (PC3), and colorectal carcinoma (HCT-116) cells. Compounds 17, 18, 25, and 32 showed potent antitumor activity (IC50, 2.83–13.97 μM), similar to doxorubicin (IC50, 4.17–8.87 μM) and afatinib (IC50, 5.4–11.4 μM). HePG2 was inhibited by compounds 10, 17, 18, 25, 26, and 32 (IC50, 3.06–10.5 μM), similar to doxorubicin (IC50, 4.50 μM) and afatinib (IC50, 5.4 μM). HCT-116 and MCF-7 were susceptible to compounds 10, 17, 18, 25, and 32 (IC50, 2.83–10.36 and 5.69–11.36 μM, respectively), similar to doxorubicin and afatinib (IC50 = 5.23 and 4.17, and 11.4 and 7.1 μM, respectively). Compounds 17, 25, and 32 exerted potent activities against PC3 (IC50, 7.56–12.28 μM) compared with doxorubicin (IC50, 8.87 μM) and afatinib (IC50 7.7 μM). Compounds 17 and 32 were the strongest PCAF inhibitors (IC50, 5.31 and 10.30 μM, respectively) and compounds 18 and 25 exhibited modest IC50 values (17.09 and 32.96 μM, respectively) compared with bromosporine (IC50, 5.00 μM). Compound 17 was cytotoxic to HePG2 cells (IC50, 3.06 μM), inducing apoptosis in the pre-G phase and arresting the cell cycle in the G2/M phase. Molecular docking for the most active PCAF inhibitors (17 and 32) was performed.
Design, synthesis, molecular modeling, in vivo studies and anticancer activity evaluation of new phthalazine derivatives as potential DNA intercalators and topoisomerase II inhibitors
Khalifa, mohamed m.,Radwan, mohamed m.,Rashed, mahmoud,Sakr, Helmy,ayyad, Rezk R.,belal, amany,eissa, Ibrahim H.,el-Helby, abdel-Ghany a.,el-Sharkawy, abdou,elSohly, mahmoud a.,elhendawy, mostafa a.,mahdy, Hazem a.,metwaly, ahmed m.
, (2020/09/03)
Herein we report the design and synthesis of a new series of phthalazine derivatives as Topo II inhibitors and DNA intercalators. The synthesized compounds were in vitro evaluated for their cytotoxic activities against HepG-2, MCF-7 and HCT-116 cell lines. Additionally, Topo II inhibitory activity and DNA intercalating affinity were investigated for the most active compounds as a potential mechanism for the anticancer activity. Compounds 15h, 23c, 32a, 32b, and 33 exhibited the highest activities against Topo II with IC50 ranging from 5.44 to 8.90 μM, while compounds 27 and 32a were found to be the most potent DNA binders at IC50 values of 36.02 and 48.30 μM, respectively. Moreover, compound 32a induced apoptosis in HepG-2 cells and arrested the cell cycle at the G2/M phase. Besides, compound 32a showed Topo II poisoning effect at concentrations of 2.5 and 5 μM, and Topo II catalytic inhibitory effect at a concentration of10 μM. In addition, compound 32b showed in vivo a significant tumor growth inhibition effect. Furthermore, molecular docking studies were carried out against DNA-Topo II complex and DNA to investigate the binding patterns of the designed compounds.
Efficient Phosphorus-Free Chlorination of Hydroxy Aza-Arenes and Their Application in One-Pot Pharmaceutical Synthesis
Wang, Jian,Li, Yan-Hui,Pan, Song-Cheng,Li, Ming-Fang,Du, Wenting,Yin, Hong,Li, Jing-Hua
supporting information, p. 146 - 153 (2020/03/10)
The chlorination of hydroxy aza-arenes with bis(trichloromethyl) carbonate (BTC) and SOCl2 has been effectively performed by refluxing with 5 wt % 4-dimethylaminopyridine (DMAP) as a catalyst. Various substrates are chlorinated with high yields. The obtained chlorinated aza-arenes can be used directly with simple workup for succedent one-pot synthesis on a large scale.
TOLL-LIKE RECEPTOR 8 (TLR8)-SPECIFIC ANTAGONISTS AND METHODS OF MAKING AND USES THEREOF
-
, (2019/05/22)
Toll-like receptor 8 (TLR8)-specific inhibitors and methods of using the same in individuals having an autoimmune disease or an inflammatory disorder.
