Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Design, Synthesis, Molecular Docking, Dynamics and in vitro Evaluation of Novel 2-substituted-1-hydroxyethane-1, 1-bis(phosphonic acid) Derivatives as Human Farnesyl Pyrophosphate Synthase Inhibitors with Expected Anticancer Activity

Author(s): Mohammed A. Khedr*, Reem I. Al-Wabli, Maha S. Almutairi and Wafaa A. Zaghary

Volume 29, Issue 1, 2023

Published on: 26 December, 2022

Page: [48 - 59] Pages: 12

DOI: 10.2174/1381612829666221202114947

Price: $65

Abstract

Background: Nitrogenous bisphosphonates (NBPs) are the major class of drugs that are used to treat osteoporosis. Recently, bisphosphonates (BPs) were reported to have an anticancer effect. These agents feature a high affinity that enables them to bind strongly to the human farnesyl pyrophosphate synthase enzyme. The correlation between this affinity and their anticancer effect was confirmed.

Objective: To date, the use of an oxygen atom as an isosteric replacement for the electronegative nitrogen atom in NBPs has not been reported, and its ability to retain the linker length and bisphosphonate pharmacophore remains unknown. The main aim of this work was to design some isosteric bisphosphonate analogs with oxygen atoms and evaluation of their binding affinity and anticancer activity.

Methods: The binding mode and stability of the designed compounds were achieved using human farnesyl pyrophosphate synthase (HFPPS) by docking and dynamic simulations. The compounds were synthesized, characterized, and screened for their anticancer activity against the breast cancer MCF-7 cell line and lung cancer A-549 cell line. The inhibitory activity of the tested compounds against HFPPS was evaluated.

Results: The compounds under investigation showed potential anticancer activity against the lung cell line with IC50 values of 41.7, 47.4, and 34.8 μg/ml in comparison to that of Risedronic acid (115 μg/ml). However, they do not exhibit potential activity against the breast cancer cell line.

Conclusion: Compounds VII and VIII showed in vitro inhibition of human farnesyl pyrophosphate synthase with IC50 values of 82.2 and 98.8 μg/ml, respectively. Further optimization may be required in the future.

« Previous Next »
[1]
Tsoumpra MK, Muniz JR, Barnett BL, et al. The inhibition of human farnesyl pyrophosphate synthase by nitrogen-containing bisphosphonates. Elucidating the role of active site threonine 201 and tyrosine 204 residues using enzyme mutants. Bone 2015; 81: 478-86.
[http://dx.doi.org/10.1016/j.bone.2015.08.020] [PMID: 26318908]
[2]
De Schutter JW, Zaretsky S, Welbourn S, Pause A, Tsantrizos YS. Novel bisphosphonate inhibitors of the human farnesyl pyrophosphate synthase. Bioorg Med Chem Lett 2010; 20(19): 5781-6.
[http://dx.doi.org/10.1016/j.bmcl.2010.07.133] [PMID: 20801032]
[3]
Boissier S, Ferreras M, Peyruchaud O, et al. Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 2000; 60(11): 2949-54.
[PMID: 10850442]
[4]
Senaratne SG, Mansi JL, Colston KW. The bisphosphonate zoledronic acid impairs Ras membrane (correction of impairs membrane) localisation and induces cytochrome c release in breast cancer cells. Br J Cancer 2002; 86(9): 1479-86.
[http://dx.doi.org/10.1038/sj.bjc.6600297] [PMID: 11986784]
[5]
Coxon JP, Oades GM, Kirby RS, Colston KW. Zoledronic acid induces apoptosis and inhibits adhesion to mineralized matrix in prostate cancer cells via inhibition of protein prenylation. BJU Int 2004; 94(1): 164-70.
[http://dx.doi.org/10.1111/j.1464-4096.2004.04831.x] [PMID: 15217454]
[6]
Nogawa M, Yuasa T, Kimura S, et al. Zoledronic acid mediates Ras-independent growth inhibition of prostate cancer cells. Oncol Res 2005; 15(1): 1-9.
[http://dx.doi.org/10.3727/096504005775082093] [PMID: 15839301]
[7]
Guenther A, Gordon S, Tiemann M, et al. The bisphosphonate zoledronic acid has antimyeloma activity in vivo by inhibition of protein prenylation. Int J Cancer 2010; 126(1): 239-46.
[http://dx.doi.org/10.1002/ijc.24758] [PMID: 19621390]
[8]
Lin YS, Park J, De Schutter JW, et al. Design and synthesis of active site inhibitors of the human farnesyl pyrophosphate synthase: Apoptosis and inhibition of ERK phosphorylation in multiple myeloma cells. J Med Chem 2012; 55(7): 3201-15.
[http://dx.doi.org/10.1021/jm201657x] [PMID: 22390415]
[9]
Mark G, Papich DV. Dacvcp. (4th ed.). Tiludronate Disodium. Saunders Handbook of Veterinary Drugs 2016; pp. 792-3.
[10]
Kotsikorou E, Song Y, Chan JMW, et al. Bisphosphonate inhibition of the exopolyphosphatase activity of the Trypanosoma brucei soluble vacuolar pyrophosphatase. J Med Chem 2005; 48(19): 6128-39.
[http://dx.doi.org/10.1021/jm058220g] [PMID: 16162013]
[11]
Molecular Operating Environment (MOE 2022.02), C. C. G. U., 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7.
[12]
Stresing V, Daubiné F, Benzaid I, Mönkkönen H, Clézardin P. Bisphosphonates in cancer therapy. Cancer Lett 2007; 257(1): 16-35.
[http://dx.doi.org/10.1016/j.canlet.2007.07.007] [PMID: 17697748]
[13]
Miller K, Erez R, Segal E, Shabat D, Satchi-Fainaro R. Targeting bone metastases with a bispecific anticancer and antiangiogenic polymer-alendronate-taxane conjugate. Angew Chem Int Ed 2009; 48(16): 2949-54.
[http://dx.doi.org/10.1002/anie.200805133] [PMID: 19294707]
[14]
Boyd K, Morgan G, Davies F, et al. Does zoledronic acid (ZOL) reduce skeletal-related events (SREs) and improve progression-free survival (PFS) in patients (Pts) with multiple myeloma (MM) with or without bone disease? MRC myeloma IX study results. J Clin Oncol 2010; 29(15): 8010.
[15]
Guenin E, Ledoux D, Oudar O, Lecouvey M, Kraemer M. Structure-activity relationships of a new class of aromatic bisphosphonates that inhibit tumor cell proliferation in vitro. Anticancer Res 2005; 25(2A): 1139-45.
[PMID: 15868957]
[16]
Erwann G, Maelle M, Nadia B, Thierry P, Marc L. Syntheses of phosphonic esters of alendronate, pamidronate and neridronate. Eur J Org Chem 2007; 20: 3380-91.
[17]
Dunford JE, Kwaasi AA, Rogers MJ, et al. Structure-activity relationships among the nitrogen containing bisphosphonates in clinical use and other analogues: Time-dependent inhibition of human farnesyl pyrophosphate synthase. J Med Chem 2008; 51(7): 2187-95.
[http://dx.doi.org/10.1021/jm7015733] [PMID: 18327899]
[18]
James E, Dunford KT, Fraser P, et al. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. American Society for Pharmacology and Experimental Therapeutics 2001; 296(2): 235-42.
[19]
Aihua CL, Li Z, Zhiquiang N, Weiming HL, Leming S, Jiaju Z. Quantitative structure-activity relationship study of bisphosphonates. Internet Electronic Journal of Molecular Design 2004; 3(10): 622-50.
[20]
Yanvarev DV, Korovina AN, Usanov NN, Kochetkov SN. Non-hydrolysable analogues of inorganic pyrophosphate as inhibitors of hepatitis C virus RNA-dependent RNA-polymerase. Russ J Bioorganic Chem 2012; 38(2): 224-9.
[http://dx.doi.org/10.1134/S1068162012020124]
[21]
Troev K, Todorov P, Naydenova E, Mitova V, Vassilev N. A study of the reaction of phosphorus trichloride with paraformaldehyde in the presence of carboxylic acids. Phosphorus Sulfur Silicon Relat Elem 2013; 188(9): 1147-55.
[http://dx.doi.org/10.1080/10426507.2012.745078]
[22]
Kavanagh KL, Guo K, Dunford JE, et al. The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc Natl Acad Sci USA 2006; 103(20): 7829-34.
[http://dx.doi.org/10.1073/pnas.0601643103] [PMID: 16684881]
[23]
Bond SD, Leimkuhler BJ, Laird BB. The nosé–poincaré method for constant temperature molecular dynamics. J Comput Phys 1999; 151(1): 114-34.
[http://dx.doi.org/10.1006/jcph.1998.6171]
[24]
Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65(1-2): 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[25]
Gomha SMR, Mahmmoud EA, Elaasser MM. Synthesis and anticancer activities of thiazoles, 1,3-thiazines, and thiazolidine using chitosan-grafted-poly(vinylpyridine) as basic catalyst. Heterocycles 2015; 91(6): 1227-43.
[http://dx.doi.org/10.3987/COM-15-13210]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy