ADME/toxicity prediction and antitumor activity of novel nitrogenous heterocyclic compounds designed by computer targeting of alkylglycerone phosphate synthase

Zhu,Yu; Han,Yuan; Ma,Ying; Yang,Ping

doi:10.3892/ol.2018.8873

ADME/toxicity prediction and antitumor activity of novel nitrogenous heterocyclic compounds designed by computer targeting of alkylglycerone phosphate synthase

Authors:
- Yu Zhu
- Yuan Han
- Ying Ma
- Ping Yang
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Affiliations: Department of Clinical Laboratory, Tianjin Key Laboratory of Cerebral Vessels and Neural Degeneration, Tianjin Huanhu Hospital, Tianjin 300350, P.R. China, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, P.R. China
Published online on: June 1, 2018 https://doi.org/10.3892/ol.2018.8873
Pages: 1431-1438
Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Alkylglycerone phosphate synthase (AGPS) is an oncogene and can be considered as an antitumor drug target. The aim of the present study was to design novel nitrogenous heterocyclic compound improving targetability by computer‑aided drug design technology targeting AGPS. A total of 12 nitrogenous heterocyclic compounds were designed and predicted the absorption, distribution, metabolism and excretion parameters/toxicity. Their activity in terms of proliferation inhibition, cell cycle arrest and apoptosis induction was then measured using an MTS assay and a high‑content screening system in U251 cells. The results showed that anti‑glioma activity was present in compounds N4, N5, N6, N7, N8 and N12, which was in accordance with the computer prediction. Therefore, these compounds may be suitable for the development of a novel glioma therapeutic drug.

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1	Ames H, Halushka MK and Rodriguez FJ: miRNA regulation in gliomas: Usual suspects in glial tumorigenesis and evolving clinical applications. J Neuropathol Exp Neurol. 76:246–254. 2017. View Article : Google Scholar : PubMed/NCBI
2	Cives M, Ghayouri M, Morse B, Brelsford M, Black M, Rizzo A, Meeker A and Strosberg J: Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors. Endocr Relat Cancer. 23:759–767. 2016. View Article : Google Scholar : PubMed/NCBI
3	Dilillo M, Ait-Belkacem R, Esteve C, Pellegrini D, Nicolardi S, Costa M, Vannini E, Graaf EL, Caleo M and McDonnell LA: Ultra-high mass resolution MALDI imaging mass spectrometry of proteins and metabolites in a mouse model of glioblastoma. Sci Rep. 7:6032017. View Article : Google Scholar : PubMed/NCBI
4	Piano V, Benjamin DI, Valente S, Nenci S, Marrocco B, Mai A, Aliverti A, Nomura DK and Mattevi A: Discovery of inhibitors for the ether lipid-generating enzyme AGPS as anti-cancer agents. ACS Chem Biol. 10:2589–2597. 2015. View Article : Google Scholar : PubMed/NCBI
5	Zhu Y, Liu XJ, Yang P, Zhao M, Lv LX, Zhang GD, Wang Q and Zhang L: Alkylglyceronephosphate synthase (AGPS) alters lipid signaling pathways and supports chemotherapy resistance of glioma and hepatic carcinoma cell lines. Asian Pac J Cancer Prev. 15:3219–3226. 2014. View Article : Google Scholar : PubMed/NCBI
6	Zhu Y, Liu A, Zhang X, Qi L, Zhang L, Xue J, Liu Y and Yang P: The effect of benzyl isothiocyanate and its computer-aided design derivants targeting alkylglycerone phosphate synthase on the inhibition of human glioma U87MG cell line. Tumour Biol. 36:3499–3509. 2015. View Article : Google Scholar : PubMed/NCBI
7	Razeto A, Mattiroli F, Carpanelli E, Aliverti A, Pandini V, Coda A and Mattevi A: The crucial step in ether phospholipid biosynthesis: Structural basis of a noncanonical reaction associated with a peroxisomal disorder. Structure. 15:683–692. 2007. View Article : Google Scholar : PubMed/NCBI
8	Zhu Y, Zhu L, Lu L, Zhang L, Zhang G, Wang Q and Yang P: Role and mechanism of the alkylglycerone phosphate synthase in suppressing the invasion potential of human glioma and hepatic carcinoma cells in vitro. Oncol Rep. 32:431–436. 2014. View Article : Google Scholar : PubMed/NCBI
9	Battu MB, Chandra AM, Sriram D and Yogeeswari P: Pharmacophore-based 3DQSAR and molecular docking studies to identify new non-peptidic inhibitors of cathepsin S. Curr Med Chem. 21:1910–1921. 2014. View Article : Google Scholar : PubMed/NCBI
10	Verma SK and Thareja S: Structure based comprehensive modelling, spatial fingerprints mapping and ADME screening of curcumin analogues as novel ALR2 inhibitors. PLoS One. 12:e01753182017. View Article : Google Scholar : PubMed/NCBI
11	Silginer M, Weller M, Stupp R and Roth P: Biological activity of tumor-treating fields in preclinical glioma models. Cell Death Dis. 8:e27532017. View Article : Google Scholar : PubMed/NCBI
12	Lin CY and Huang HM: Unilateral malignant optic glioma following glioblastoma multiforme in the young: A case report and literature review. BMC Ophthalmol. 17:212017. View Article : Google Scholar : PubMed/NCBI
13	Louis DN, Perry A, Reifenberger G, et al: The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathol. 131:803–820. 2016. View Article : Google Scholar : PubMed/NCBI
14	Wang N, Zhang Q, Ning B, Luo L and Fang Y: β-Asarone promotes Temozolomide's entry into glioma cells and decreases the expression of P-glycoprotein and MDR1. Biomed Pharmacother. 90:368–374. 2017. View Article : Google Scholar : PubMed/NCBI
15	Holdhoff M, Ye X, Supko JG, Nabors LB, Desai AS, Walbert T, Lesser GJ, Read WL, Lieberman FS, Lodge MA, et al: Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas. Neuro Oncol. 19:845–852. 2017. View Article : Google Scholar : PubMed/NCBI
16	Cai Z, Zhang G, Zhang X, Liu Y and Fu X: Current insights into computer-aided immunotherapeutic design strategies. Int J Immunopathol Pharmacol. 28:278–285. 2015. View Article : Google Scholar : PubMed/NCBI
17	Medeiros Turra K, Pineda Rivelli D, Berlanga de Moraes Barros S and Mesquita Pasqualoto KF: Constructing and validating 3D-pharmacophore models to a set of MMP-9 inhibitors for designing novel anti-melanoma agents. Mol Inform. 35:238–252. 2016. View Article : Google Scholar : PubMed/NCBI
18	Valasani KR, Chaney MO, Day VW and Shidu Yan S: Acetylcholinesterase inhibitors: Structure based design, synthesis, pharmacophore modeling, and virtual screening. J Chem Inf Model. 53:2033–2046. 2013. View Article : Google Scholar : PubMed/NCBI
19	Cao D, Wang J, Zhou R, Li Y, Yu H and Hou T: ADMET evaluation in drug discovery. 11. PharmacoKinetics Knowledge Base (PKKB): A comprehensive database of pharmacokinetic and toxic properties for drugs. J Chem Inf Model. 52:1132–1137. 2012. View Article : Google Scholar : PubMed/NCBI
20	Gomeni R, Bani M, D'Angeli C, Corsi M and Bye A: Computer-assisted drug development (CADD): An emerging technology for designing first-time-in-man and proof-of-concept studies from preclinical experiments. Eur J Pharm Sci. 13:261–270. 2001. View Article : Google Scholar : PubMed/NCBI