New quinoxaline 1,4-di- N-oxides. Part 1: Hypoxia-selective cytotoxins and anticancer agents derived from quinoxaline 1,4-di- N-oxides (original) (raw)
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New quinoxaline 1, 4-di-N-oxides: Anticancer and hypoxia-selective therapeutic agents
European Journal of Medicinal Chemistry, 2010
A new series of quinoxaline 1,4-di-N-oxides was synthesized and evaluated for antitumor and hypoxicselective cytotoxic activities. Antitumor activity against liver carcinoma (Hepg2) and brain tumor (U251) human cell lines were evaluated, among the tested compounds, 5b and 9b exhibited potential cytotoxic effect against Hepg2 with IC50 values of 0.77 and 0.50 mg/mL respectively, whereas, all the tested compounds lack antitumor activity against U251 human cell line. Moreover, compound 4 was the most potent hypoxia selective-cytotoxin on EAC cell line; IC50 2.5 mg/mL, potency 22 mg/mL, and was approximately 5.4-times more selective cytotoxin (HCR > 40) than 3-amino-2-quinoxalinecarbonitrile1,4-dioxide (standard, HCR > 7.4). Compounds 8b and 9b were more selective than the standard.
Hypoxia-Selective Agents Derived from Quinoxaline 1,4-Di-N-oxides
Journal of Medicinal Chemistry, 1995
Hypoxic cells, which are a common feature of solid tumors, but not normal tissues, are resistant to both anticancer drugs and radiation therapy. Thus the identification of drugs with selective toxicity toward hypoxic cells is a n important objective in anticancer chemotherapy. The benzotriazine di-N-oxide (SR 4233, Tirapazamine) has been shown to be a n efficient and selective cytotoxin for hypoxic cells. Since the bioreductive activation of Tirapazamine is thought to be due to the presence of the l,4-di-N-oxide moiety, a series of 3-aminoquinoxaline-2-carbonitrile 1,Cdi-N-oxides with a range of electron-donating and -withdrawing substituents in the 6and/or 7-positions has been synthesized and evaluated for toxicity to hypoxic cells.
Quinoxalines display diverse and interesting pharmacological activities as antibacterial, antiviral, antiparasitic and anticancer agents. Particularly, their 1ˏ4-diN oxide derivatives have proved to be cytotoxic agents that are active under hypoxic conditions as that of solid tumours. A new series of quinoxaline 1ˏ4-diN oxide substitutes at 7-position with esters group were synthetized and characterized by infrared (IR), proton nuclear magnetic resonance (1 H-NMR), spectroscopy, and elemental analysis. Seventeen derivatives (M1-M3, E1-E8, P1-P3 and DR1-DR3) were selected and evaluated for antitumor activities using the NCI-60 human tumor cell lines screen. Results showed that E7, P3 and E6 were the most active compounds against the cell lines tested. Substitutions at 7-position with esters group not necessarily affect the biological activity, but the nature of the esters group could exert an influence on the selectivity. Additionally, substitutions at 2-position influenced the cytotoxic activity of the compounds.
Quinoxaline 1,4-dioxides as anticancer and hypoxia-selective drugs
Oncology Reports, 2001
Hypoxic cells which are found in solid tumors are resistant to anticancer drugs and radiation therapy. Thus, for effective anticancer chemotherapy, it is important to identify drugs with selective toxicity towards hypoxic cells. Quinoxaline 1,4-dioxides (QdNOs) are heterocyclic aromatic A'-oxides that have been found to possess potent antibacterial activities (inhibit microbial DNA synthesis) especially under anaerobic conditions; thus they are under evaluation as bioreductive drugs for the treatment of solid tumors (1). We investigated the ability of four differently substituted QdNOs to inhibit cell growth and induce cell cycle changes in two human tumorigenic epithelial cell lines under oxic conditions. We also evaluated the toxicity of these drugs to cancer cells cultured under hypoxic conditions. Two epithelial cell lines (the T-84 human colon cancer-derived cell line, and the SP-1 keratinocyte cell line) were treated with various doses of the QdNOs and harvested at different times after treatment. Proliferation and cell cycle results showed a structure-function relationship in the activity of the various QdNO compounds with the 2-benzoyl-3-phenyl-6,7dichloro-derivative of QdNO (DCBPQ) being the most potent cytotoxin and hypoxia-selective drug. The 2-benzoyl-3-phenyl (BPQ) and the 2-acyl-3-methyl-derivative of QdNO (AMQ) were less cytotoxic but arrested almost 50% of the cells in the G 2 M phase of the cell cycle at doses of 30 and 120 |xM,
European Journal of Medicinal Chemistry, 2005
Certain linear 4-anilinofuro[2,3-b]quinoline and angular 4-anilinofuro[3,2-c]quinoline derivatives were synthesized and evaluated in vitro against the full panel of NCI's 60 cancer cell lines. For the linear 4-anilinofuro[2,3-b]quinoline derivatives, 1-[4-(furo[2,3-b]quinolin-4ylamino)phenyl]ethanone (5a) is the most cytotoxic with a mean GI 50 value of 0.025 µM. Substitution at either furo[2,3-b]quinoline ring (2a, 2b, and 5b) or 4-anilino moiety (3-7) led to a decrease of cytotoxicity. For the angular 4-anilinofuro[3,2-c]quinoline derivatives, (E)-1-[3-(furo[3,2-c]quinolin-4-ylamino)phenyl]ethanone oxime (14a) exhibited potent inhibitory activities on UO-31, UACC-257, and UACC-62, with GI 50 values of 0.03, < 0.01, and < 0.01 µM respectively. The same cytotoxicity profile was observed for its methyl counterpart, 14b, in which the GI 50 values against UO-31, UACC-257, and UACC-62 was < 0.01, 0.04 and < 0.01 µM respectively. These results deserve full attention especially because 14a and 14b are relatively non-cytotoxic with the mean GI 50 value of 7.73 and 8.91 µM respectively.
Medicinal Chemistry Research, 2017
A series of twelve 4-methyl-2-(2-, 3-and 4-pyridinyl)quinolines 7-9 was synthesized using modified Kametani reaction protocol and their in vitro cytotoxicity was tested against human cancer cell lines MCF-7, SKBR-3, PC3, HeLa, comparing with human dermis fibroblast as non-tumor cells. In general, these molecules displayed potent anticancer properties, but also demonstrated a narrow safe margin, as it was observed for doxorubicin. Compounds 8a, 8b, 9a and 9d showed prominent selective cytotoxicity with higher IC 50 values compared with reference drug doxorubicin in prostate carcinoma, cervical epithelial carcinoma and breast carcinoma (no overexpresses the HER2/c-erb-2 gene), respectively. The 4-methyl-2-(3pyridinyl)quinoline (8a) stands out by its low unspecific cytotoxicity (IC 50 = 476.69 μM) and highly exceptional selectivity for PC3 cells (IC 50 = 4.40 μM) as an interesting model for antitumor drugs against prostate carcinoma. Its 4pyridinyl analog 9a showed superior potency against HeLa cells (IC 50 = 0.016 μM) and an outstanding selectivity (SI = 4168.1) compared to doxorubicin (IC 50 = 3.62 µM, SI = 0.7). Analog 9d revealed potent activity (IC 50 = 0.38 µM) against breast cancer MCF-7. In silico studies are also reported. ADME profiling, in silico toxicity and drug-score data of compounds 8a and 9a resulted to be favorable compared to doxorubicin.
Synthesis, molecular modeling and anti-cancer evaluation of a series of quinazoline derivatives
Carbohydrate Research, 2019
Quinazolines were surveyed as biologically relevant moieties against different cancer cell lines, so in the present study, we analyzed novel derivatives as target-oriented chemotherapeutic anti-cancer drugs. A series of 3-substituted 2-thioxo-2,3-dihydro-1H-quinazolin-4-ones 4a-e were synthesized via the reaction of 2-aminobenzoic acid (1) with isothiocyanate derivatives 2a-e. S-alkylation and S-glycosylation were carried via the reaction of 4a-e with alkyl halides and α-glycopyranosyl bromides 7a,b under anhydrous alkaline and glycoside conditions, respectively. The S-alkylated and S-glycosylated structures, and not that of the N-alkylated and N-glycosylated isomers, have been selected for the products. Conformational analysis has been studied by homo-and heteronuclear two-dimensional NMR methods (DQF-COSY, HMQC, and HMBC). The S site of alkylation and glycosylation were determined from the 1 H, 13 C heteronuclear multiple-quantum coherence (HMQC) experiments. All derivatives were subjected to molecular docking calculations, which selected some derivatives (5n, 8c, 8g, 9c, and 9a) as promising ones based on their excellent binding affinities towards the EGFR tyrosine kinase molecular target. The in vitro cytotoxic activity against MCF-7 and HepG2 cell lines showed effective anti-proliferative activity of the analyzed derivatives with lower IC 50 values especially 9a with IC 50 = 2.09 and 2.08 μM against MCF-7 and HepG2, respectively, and their treatments were safe against the normal cell line Gingival mesenchymal stem cells (GMSC). Moreover, RT-PCR reaction investigated the apoptotic pathway for the compound 9a, which activated the P53 genes and its related genes. So, further work is recommended for developing it as a chemotherapeutic drug.
2013
A series of 22 quinazolines, pyrido [2,3-d]pyrimidines and their hydroselenite salts were synthesized with the aim of evaluating in vitro their cytotoxicity against PC-3 cell line and their antioxidant properties related to DPPH (1,1-diphenyl-2-picrylhydrazylradical) activity, showing some of them better profile than the respective controls. Three of these derivatives (5d, 6d and 7f) were selected in order to gain preliminary insights to establish the mechanism of action. Caspase-3 activity and cell cycle regulation studies revealed that compound 6d provoked an increase in caspase-3 level accompanied by cell cycle perturbation in a time-dependent manner. a: POCl 3 /DMF; b: The corresponding amine, TEA, EtOH; c: SeO 2 , EtOH:H 2 O (1:1).
International Journal of Pharmacy and Pharmaceutical Sciences, 2017
Objective: Synthesis, characterization and evaluation of quinolin-2-one derivatives as possible anticancer agents. Methods: A series of novel 4-hydroxy-1-phenyl/methyl-3-(3-substituted-1-(substitutedimino)propyl)quinolin-2(1H)-one derivatives IIa(1-5)/IIb(1-5) and 4-hydroxy-1-phenyl/methyl-3-(1-(substituedimino)ethyl)quinolin-2(1H)-one derivatives IIIa(1-3)/IIIb(1-3) were synthesised by nucleophilic addition of substituted anilines on 3-acetyl-4-hydroxy-1-phenyl/methylquinolin-2(1H)-one (a/b) and 4-hydroxy-3-(3substitutedpropanoyl)-1-phenyl/methyl quinolin-2(1H)-one (Ia/Ib); respectively. The synthesised derivatives were characterised by spectral analysis and were tested for their in vitro anticancer activity against K562 and Hep 3b cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) assay method. Results: The compounds were tested for their in vitro anticancer activity against K562 and Hep 3b cell lines at 10, 20, 25, 30 and 50 µg/ml concentration using MTT assay method. The compound 4-hydroxy-3-(3-morpholino-1-(phenylimino)propyl)-1-phenylquinolin-2(1H)-one (IIa-1) showed anticancer activity with IC50 value 20 µg as compared to the control against K562 cell lines. The compound 4-hydroxy-1-phenyl-3-(1-(phenylimino) ethyl) quinolin-2(1H)-one (IIIa-1) showed anticancer activity with IC50 value less than 10 µg. Conclusion: The proposed method for the synthesis of novel derivatives is convenient and gives a good yield. Some of the synthesised compounds showed promising anticancer activity against K562 and Hep 3b cell lines. Compound IIa-1 (R=-C6H5; R1= morpholine; R2= C6H5-NH-) exhibited most potent activity against K562 cell lines. Compound IIIa-1 (R=-C6H5; R3= C6H5-NH-) has been proved to be the most cytotoxic compound among the other derivatives against Hep 3b cell lines.