Anticancer activity of pyrimidodiazepines based on 2-chloro-4-anilinoquinazoline: synthesis, DNA binding and molecular docking

Cuartas, Viviana; Aragón-Muriel, Alberto; Liscano, Yamil; Polo-Cerón, Dorian; Crespo-Ortiz, María del Pilar; Quiroga, Jairo; Abonı́a, Rodrigo; Insuasty, Braulio

doi:10.1039/d1ra03509f

Cited by 12 publications

(10 citation statements)

References 63 publications

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“…Moreover, the isoxazole moiety was involved in a unique interaction with Leu889 in the HYD-II region of the receptor. These results are consistent with the previous data obtained for tivozanib [ 60 ].…”

Section: Resultssupporting

confidence: 94%

“…Therefore, in the present paper, an attempt was made to predict the binding mode of the designed ligands to the active site of VEGFR-2 using molecular docking. The validation of the docking procedure was performed by docking the co-crystalized ligand tivozanib to the binding site of VEGFR-2, as described in detail in previous studies [ 60 , 61 ]. Due to its ability to bind in the hinge region and hydrophobicity region of the protein (HYD-II)—also referred to as an allosteric pocket—tivozanib was classified as a type II selective inhibitor of VEGFR-2 [ 33 ].…”

Section: Resultsmentioning

confidence: 99%

“…The position was optimal when its RMSD was found to be less than 1.5 Å. The protein and ligand preparation and the docking procedure were described in detail in previous studies [ 60 , 61 ]. The data were visualized using a Chimera and a BIOVIA Discovery Studio visualizer [ 89 , 90 ].…”

Section: Methodsmentioning

confidence: 99%

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New Oxazolo[5,4-d]pyrimidines as Potential Anticancer Agents: Their Design, Synthesis, and In Vitro Biological Activity Research

Sochacka-Ćwikła

Mączyński

Czyżnikowska

et al. 2022

IJMS

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Cancer is a large group of diseases in which the rapid proliferation of abnormal cells generally leads to metastasis to surrounding tissues or more distant ones through the lymphatic and blood vessels, making it the second leading cause of death worldwide. The main challenge in designing a modern anticancer therapy is to develop selective compounds that exploit specific molecular targets. In this work, novel oxazolo[5,4-d]pyrimidine derivatives were designed, synthesized, and evaluated in vitro for their cytotoxic activity against a panel of four human cancer cell lines (lung carcinoma: A549, breast adenocarcinoma: MCF7, metastatic colon adenocarcinoma: LoVo, primary colon adenocarcinoma: HT29), along with their P-glycoprotein-inhibitory ability and pro-apoptotic activity. These oxazolo[5,4-d]pyrimidine derivatives, which are structurally similar to nucleic purine bases in general, are characterized by the presence of a pharmacologically favorable isoxazole substituent at position 2 and aliphatic amino chains at position 7 of the condensed heterocyclic system. In silico analysis of the obtained compounds identified their potent inhibitory activity towards human vascular endothelial growth factor receptor-2 (VEGFR-2). Molecular docking was performed to assess the binding mode of new derivatives to the VEGFR-2 active site. Then, their physicochemical, pharmacokinetic, and pharmacological properties (i.e., ADME—administration, distribution, metabolism, and excretion) were also predicted to assess their druglikeness. In particular, compound 3g (with a 3-(N,N-dimethylamino)propyl substituent) was found to be the most potent against the HT29 cell line, with a 50% cytotoxic concentration (CC50) of 58.4 µM, exceeding the activity of fluorouracil (CC50 = 381.2 μM) and equaling the activity of cisplatin (CC50 = 47.2 µM), while being less toxic to healthy human cells (such as normal human dermal fibroblasts (NHDFs)) than these reference drugs. The results suggest that compound 3g is a potentially promising candidate for the treatment of primary colorectal cancer.

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Section: Resultssupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

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New Oxazolo[5,4-d]pyrimidines as Potential Anticancer Agents: Their Design, Synthesis, and In Vitro Biological Activity Research

Sochacka-Ćwikła

Mączyński

Czyżnikowska

et al. 2022

IJMS

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“…The results of each tested PQ analogue were reported in terms of percent growth inhibition (GI% = 100 − G%) and lethality [ 32 ] ( Table 2 ) and were also depicted as bars in the single-dose mean graphs ( Supplementary Materials, Figures S1–S3 ). Overall, consistent with the previous data, PQ analogues showed the most notable anticancer activity against leukemia cancer cell lines.…”

Section: Resultsmentioning

confidence: 99%

In Vitro Cytotoxicity Evaluation of Plastoquinone Analogues against Colorectal and Breast Cancers along with In Silico Insights

et al. 2022

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Colorectal cancer (CRC) and breast cancer are leading causes of death globally, due to significant challenges in detection and management. The late-stage diagnosis and treatment failures require the discovery of potential anticancer agents to achieve a satisfactory therapeutic effect. We have previously reported a series of plastoquinone analogues to understand their cytotoxic profile. Among these derivatives, three of them (AQ-11, AQ-12, and AQ-15) were selected by the National Cancer Institute (NCI) to evaluate their in vitro antiproliferative activity against a panel of 60 human tumor cell lines. AQ-12 exhibited significant antiproliferative activity against HCT-116 CRC and MCF-7 breast cancer cells at a single dose and further five doses. MTT assay was also performed for AQ-12 at different concentrations against these two cells, implying that AQ-12 exerted notable cytotoxicity toward HCT-116 (IC50 = 5.11 ± 2.14 μM) and MCF-7 (IC50 = 6.06 ± 3.09 μM) cells in comparison with cisplatin (IC50 = 23.68 ± 6.81 μM and 19.67 ± 5.94 μM, respectively). This compound also augmented apoptosis in HCT-116 (62.30%) and MCF-7 (64.60%) cells comparable to cisplatin (67.30% and 78.80%, respectively). Molecular docking studies showed that AQ-12 bound to DNA, forming hydrogen bonding through the quinone scaffold. In silico pharmacokinetic determinants indicated that AQ-12 demonstrated drug-likeness with a remarkable pharmacokinetic profile for future mechanistic anti-CRC and anti-breast cancer activity studies.

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“…Molecular docking studies were performed using LeDock software [ 46 ]. A receptor grid was set for each target, restraining it to include position of co-crystalized inhibitor and surrounding cavities in accordance with previous reports for new inhibitor search [ 47 , 48 , 49 , 50 , 51 , 52 , 53 ] (resulting search volumes shown in Table 3 ), generated poses were set to 100 and 0.5 of RMSD. Generated poses and interactions were analyzed in BIOVIA Discovery Studio Visualizer v19.1.…”

Section: Methodsmentioning

confidence: 99%

Apoptotic and Cell Cycle Effects of Triterpenes Isolated from Phoradendron wattii on Leukemia Cell Lines

et al. 2022

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Current antineoplastic agents present multiple disadvantages, driving an ongoing search for new and better compounds. Four lupane-type triterpenes, 3α,24-dihydroxylup-20(29)-en-28-oic acid (1), 3α,23-dihydroxy-30-oxo-lup-20(29)-en-28-oic acid (2), 3α,23-O-isopropylidenyl-3α,23-dihydroxylup-20(29)-en-28-oic acid (3), and 3α,23-dihydroxylup-20(29)-en-28-oic acid (4), previously isolated from Phoradendron wattii, were evaluated on two cell lines of chronic (K562) and acute (HL60) myeloid leukemia. Compounds 1, 2, and 4 decreased cell viability and inhibit proliferation, mainly in K562, and exhibited an apoptotic effect from 24 h of treatment. Of particular interest is compound 2, which caused arrest in active phases (G2/M) of the cell cycle, as shown by in silico study of the CDK1/Cyclin B/Csk2 complex by molecular docking. This compound [3α,23-dihydroxy-30-oxo-lup-20(29)-en-28-oic acid] s a promising candidate for incorporation into cancer treatments and deserves further study.

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Anticancer activity of pyrimidodiazepines based on 2-chloro-4-anilinoquinazoline: synthesis, DNA binding and molecular docking

Abstract: A new series of quinazoline-based chalcones and pyrimidodiazepines were tested against 60 human tumor cell lines.

Cited by 12 publications

References 63 publications

New Oxazolo[5,4-d]pyrimidines as Potential Anticancer Agents: Their Design, Synthesis, and In Vitro Biological Activity Research

New Oxazolo[5,4-d]pyrimidines as Potential Anticancer Agents: Their Design, Synthesis, and In Vitro Biological Activity Research

In Vitro Cytotoxicity Evaluation of Plastoquinone Analogues against Colorectal and Breast Cancers along with In Silico Insights

Apoptotic and Cell Cycle Effects of Triterpenes Isolated from Phoradendron wattii on Leukemia Cell Lines

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