Abstract
Structure–activity relationship (SAR) studies confirm that modifications at C-3′ position can lead to the development of highly potent novel taxoids. We designed and synthesized a series of novel isoxazole-docetaxel analogues A1–A5 by introducing isoxazolyl groups to C3′-N position. All of the synthesized compounds exhibited similar to better cytotoxic activities than docetaxel against human cancer cell lines, Hela, A2780, A549, MCF-7, and SK-OV-3. These compounds also possessed higher inhibition than docetaxel against drug-resistant cancer cell lines, A2780-MDR and MCF-7-MDR. Binding model analysis of A1–A5 molecule to microtubule (MT) showed that these compounds were anchored to the active site, explaining their inhibitory effects on MT in vitro. The calculated binding free energy values were in positive correlation with the IC50 values of A1–A5 compounds against cancer cells. These results strongly support the statement that the introduction of isoxazolyl groups to C-3′ position indeed improves the cytotoxic activities of taxoids.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Baruchello R, Simoni D, Grisolia G, Barbato G, Marchetti P, Rondanin R, Mangiola S, Giannini G, Brunetti T, Alloatti D et al. (2011) Novel 3,4-isoxazolediamides as potent inhibitors of chaperone heat shock protein 90. J Med Chem 54:8592–8604
Baxter CA, Murray CW, Clark DE, Westhead DR, Eldridge MD (1998) Flexible docking using tabu search and an empirical estimate of binding affinity. Protein: Struct, Funct, Bioinforma 33:367–382
Case TADDA, Cheatham ITE, Simmerling JWCL (2012) AMBER12. University of California, San Francisco
Chang J, Hao XD, Hao YP, Lu HF, Yu JM, Sun X (2013) Design, synthesis and cytotoxicity of novel 3′-n-alkoxycarbonyl docetaxel analogs. Bioorg Med Chem Lett 23:6834–6837
Chen X, Liu J, Zhang Y (2014) Cantharidin impedes the activity of protein serine/threonine phosphatase in plutella xylostella. Mol Biosyst 10:240–250
DeLano WL (2002) PyMOL molecular graphics system,version 1.3.0.4. LLC, Schrödinger
Didier E, Fouque E, Commerçon A (1994) Expeditious semisynthesis of docetaxel using 2-trichloromethyl-1,3-oxazolidine as side-chain protection. Tetrahedron Lett 35:3063–3064
Eldridge MD, Murray CW, Auton TR, Paolini GV, Mee RP (1997) Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. J Comput Aided Mol Des 11:425–445
Fu Y, Li S, Zu Y, Yang G, Yang Z, Luo M, Jiang S, Wink M, Efferth T (2009) Medicinal chemistry of paclitaxel and its analogues. Curr Med Chem 16:3966–3985
Georg GI, Cheruvallath ZS, Himes RH, Mejillano MR, Burke CT (1992a) Synthesis of biologically active taxol analogues with modified phenylisoserine side chains. J Med Chem 35:4230–4237
Georg GI, Cheruvallath ZS, Himes RH, Mejillano MR (1992b) Novel biologically active taxol analogues: Baccatin iii 13-(n-(p-chlorobenzoyl)-(2′r,3′s)-3′-phenylisoserinate) and baccatin iii 13-(n-benzoyl-(2′r,3′s)-3′-(p-chlorophenyl)isoserinate). Bioorg Med Chem Lett 2:295–298
Georg GI, Boge TC, Cheruvallath ZS, Harriman GCB, Hepperle M, Park H, Himes RH (1994) Cheminform abstract: Schotten-baumann acylation of n-debenzoyltaxol; an efficient route to n-acyl taxol analogues and their biological evaluation. ChemInform 25:no–no
Gunda IG, Zacharia SC, Himes RH, Mejillano MR (1992) Semisynthesis and biological activity of taxol analogues: Baccatin iii 13-(n-benzoyl-(2′r,3′s)-3′-(p-tolyl)isoserinate), baccatin iii 13-(n-(p-toluoyl)-2′r,3′s)-3′-phenylisoserinate), baccatin iii 13-(n-benzoyl-(2′r,3′s) -3′-(p- trifluoromethylphenyl)isoserinate), and baccatin iii 13-(n-(p-trifluoromethylbenzoyl)- (2′r,3′s)-3′-phenyl- isoserinate). Bioorg Med Chem Lett 2:1751–1754
Hayashi Y, Skwarczynski M, Hamada Y, Sohma Y, Kimura T, Kiso Y (2003) A novel approach of water-soluble paclitaxel prodrug with no auxiliary and no byproduct: design and synthesis of isotaxel. J Med Chem 46:3782–3784
Hummer G, Rasaiah JC, Noworyta JP (2001) Water conduction through the hydrophobic channel of a carbon nanotube. Nature 414:188–190
Ji Z, Ahmed AA, Albert DH, Bouska JJ, Bousquet PF, Cunha GA, Diaz G, Glaser KB, Guo J, Harris CM et al. (2008) 3-amino-benzo[d]isoxazoles as novel multitargeted inhibitors of receptor tyrosine kinases. J Med Chem 51:1231–1241
Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) Development and validation of a genetic algorithm for flexible docking. J Mol Biol 267:727–748
Jones G, Willett P, Glen RC (1995) Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. J Mol Biol 245:43–53
Kingston DG, Snyder JP (2014) The quest for a simple bioactive analog of paclitaxel as a potential anticancer agent. Acc Chem Res 47:2682–2691
Kirikae T, Ojima I, Kirikae F, Ma Z, Kuduk SD, Slater JC, Takeuchi CS, Bounaud PY, Nakano M (1996) Structural requirements of taxoids for nitric oxide and tumor necrosis factor production by murine macrophages. Biochem Biophys Res Commun 227:227–235
Kirikae T, Ojima I, Ma Z, Kirikae F, Hirai Y, Nakano M (1998) Structural significance of the benzoyl group at the c-3’-n position of paclitaxel for nitric oxide and tumor necrosis factor production by murine macrophages. Biochem Biophys Res Commun 245:698–704
Lamberth C, Kempf HJ, Kriz M (2007) Synthesis and fungicidal activity of n-2-(3-methoxy-4- propargyloxy) phenethyl amides. Part 3: stretched and heterocyclic mandelamide oomyceticides. Pest Manage Sci 63:57–62
Lilienkampf A, Mao J, Wan B, Wang Y, Franzblau SG, Kozikowski AP (2009) Structure-activity relationships for a series of quinoline-based compounds active against replicating and nonreplicating mycobacterium tuberculosis. J Med Chem 52:2109–2118
Liu JY, Chen XE, Zhang YL (2015) Insights into the key interactions between human protein phosphatase 5 and cantharidin using molecular dynamics and site-directed mutagenesis bioassays. Sci Rep 5:12359
Liu J, Tian Z, Zhang Y (2016) Structure-based discovery of potentially active semiochemicals for cydia pomonella (l.). Sci Rep 6:34600
Liu J, Yang X, Zhang Y (2014) Characterization of a lambda-cyhalothrin metabolizing glutathione s-transferase cpgstd1 from cydia pomonella (l.). Appl Microbiol Biotechnol 98:8947–8962
Lu HF, Xie C, Chang J, Lin GQ, Sun X (2011) Synthesis, cytotoxicity, metabolic stability and pharmacokinetic evaluation of fluorinated docetaxel analogs. Eur J Med Chem 46:1743–1748
Mekhail TM, Markman M (2002) Paclitaxel in cancer therapy. Expert Opin Pharmacother 3:755–766
Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63
Ojima I, Fumero-Oderda CL, Kuduk SD, Ma Z, Kirikae F, Kirikae T (2003) Structure–activity relationship study of taxoids for their ability to activate murine macrophages as well as inhibit the growth of macrophage-like cells. Bioorg Med Chem 11:2867–2888
Roh EJ, Kim D, Lee CO, Choi SU, Song CE (2002) Structure–activity relationship study at the 3′-n-position of paclitaxel: Synthesis and biological evaluation of 3′-n-acyl-paclitaxel analogues. Bioorg Med Chem 10:3145–3151
Roh EJ, Song CE, Kim D, Pae HO, Chung HT, Lee KS, Chai KB, Lee CO, Un CS (1999) Synthesis and biology of 3′-n-acyl-n-debenzoylpaclitaxel analogues. Bioorg Med Chem 7:2115–2119
Rowbottom MW, Faraoni R, Chao Q, Campbell BT, Lai AG, Setti E, Ezawa M, Sprankle KG, Abraham S, Tran L et al. (2012) Identification of 1-(3-(6,7-dimethoxyquinazolin- 4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropa n-2-yl)isoxazol-3-yl)urea hydrochloride (cep-32496), a highly potent and orally efficacious inhibitor of v-raf murine sarcoma viral oncogene homologueb1 (braf) v600e. J Med Chem 55:1082–1105
Rowinsky EK (1997) The development and clinical utility of the taxane class of antimicrotubule chemotherapy agents. Annu Rev Med 48:353–374
Shang YJ, Wang YG (2002) Synthesis of isoxazolines and isoxazoles using poly (ethylene glycol) as Suppor. Synthesis 12:1663–1668
Swindell CS, Krauss N (2001) Syntheses of taxol, taxol analogs and their intermediates with variable A-ring side chain structures and compositions thereof. US Patent 6262281B1
Tian Z, Liu J, Zhang Y (2016a) Key residues involved in the interaction between cydia pomonella pheromone binding protein 1 (cpompbp1) and codlemone. J Agric Food Chem 64:7994–8001
Tian Z, Liu J, Zhang Y (2016b) Structural insights into cydia pomonella pheromone binding protein 2 mediated prediction of potentially active semiochemicals. Sci Rep 6:22336
Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general amber force field. J Comput Chem 25:1157–1174
Yang XQ, Liu JY, Li XC, Chen MH, Zhang YL (2014) Key amino acid associated with acephate detoxification by cydia pomonella carboxylesterase based on molecular dynamics with alanine scanning and site-directed mutagenesis. J Chem Inf Model 54:1356–1370
Acknowledgements
We gratefully acknowledge financial support of this work by the National Natural Science Foundation of China (21172262), the Chinese National Science & Technology Major Project (grants 2010ZXJ0900X-007), the Foundation of the 309th hospital (2015MS-011), the National Natural Science Foundation of China (grant number 21503272) and the General Financial Grant from the China Postdoctoral Science Foundation (grant number 2015M572753).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Chen, M., Liu, J., Tian, Z. et al. Synthesis, cytotoxic activity and binding model analysis of novel isoxazole-docetaxel analogues with C3′-N modification. Med Chem Res 27, 1355–1365 (2018). https://doi.org/10.1007/s00044-018-2151-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-018-2151-7