A One-pot Multicomponent ‘Click’ Approach to the Synthesis of Novel Tamoxifen-triazole Conjugates using Nano Iron Oxide Catalyst and their Preliminary Antiproliferative Activity Studies

Mohana    Rao    Katiki; Dileep       Kommula; Sowjanya      Polepalli; Nishant       Jain; Madugula    Sree Rama   Murty

Abstract

Background: In an effort to establish new drug candidates with improved antiproliferative activity, we report here a novel class of compounds designed rationally by the replacement of an ethyl group in tamoxifen with a methylene (1H-1,2,4-triazole) and the introduction of 1,4- substituted 1,2,3-triazoles in the basic side chain.

Methods: Magnetically separable iron oxide nanoparticles have been found to effectively catalyze the one-pot multicomponent click synthesis of 1,4-disubstituted 1,2,3-triazole conjugates in water. IR, 1HNMR, 13CNMR and HRMS experiments have been implemented for the unmistakable determination of the regiochemistry of the process. The novel compounds were evaluated for their antiproliferative activity against four human tumor cell lines, namely, MCF-7, MDA-MB-231, HeLa, and A549. Cell growth inhibition was assessed according to the standard Sulforhodamine B (SRB) cell proliferation method.

Results: The most active compounds 4h, 4n and 5a have been identified with superior GI50 values in the range of 0.13–0.31 µM as compared with the reference drug, tamoxifen (0.25-0.72 µM).

Conclusion: Additionally, taking the stereochemistry into consideration, E isomers seem slightly more active towards the tested cancer cell lines with respect to Z isomers.

Keywords: Tamoxifen, triazole, click chemistry, nano iron oxide, antiproliferative activity, stereochemistry.

« Previous Next »

Graphical Abstract

[1] 
Zhang, M.H.; Man, H.T.; Zhao, X.D.; Dong, N.; Ma, S.L. Estrogen receptor-positive breast cancer molecular signatures and therapeutic potentials. Biomed. Rep.,  2014, 2, 41-52. [Review].
[2] 
Sengupta, S.; Jordan, V.C. Selective estrogen modulators as an anticancer tool: mechanisms of efficiency and resistance. Adv. Exp. Med. Biol.,  2008, 630, 206-219.
[3] 
Martinkovich, S.; Shah, D.; Planey, S.L.; Arnott, J.A. Selective estrogen receptor modulators: tissue specificity and clinical utility. Clin. Interv. Aging,  2014, 9, 1437-1452.
[4] 
Jordan, V.C. Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 1. receptor interactions. J. Med. Chem.,  2003, 46, 883-908.
[5] 
Jordan, V.C. Tamoxifen: a most unlikely pioneering medicine. Nat. Rev. Drug Discov.,  2003, 2, 205-213.
[6] 
Baneshi, M.R.; Warner, P.; Anderson, N.; Edwards, J.; Cooke, T.G.; Bartlett, J.M.S. Tamoxifen resistance in early breast cancer: statistical modelling of tissue markers to improve risk prediction. Br. J. Cancer,  2010, 102, 1503-1510.
[7] 
Júnior, J.K.; Kulak, C.A.M.; Taylor, H.S. SERMs in the prevention and treatment of postmenopausal osteoporosis: an update. Arq. Bras. Endocrinol. Metabol,  2010, 52, 200-205.
[8] 
Neven, P.; Vergote, I. Tamoxifen, screening and new oestrogen receptor modulators. Best Pract. Res. Clin. Obstet. Gynaecol.,  2001, 15, 365-380.
[9] 
Jordan, V.C. Biochemical pharmacology of antiestrogen action. Pharmacol. Rev.,  1984, 36, 245-276.
[10] 
Lippman, M.E.; Bolan, G. Oestrogen-responsive human breast cancer in long term tissue culture. Nature,  1975, 256, 592-593.
[11] 
Catherino, W.H.; Jordan, V.C. Stereoisomers and drug toxicity. The value of single stereoisomer therapy. Drug Saf.,  1993, 8, 381-397.
[12] 
Dorssers, L.C.; Van der Flier, S.; Brinkman, A.; van Agthoven, T.; Veldscholte, J.; Berns, E.M.; Klijn, J.G.; Beex, L.V.; Foekens, J.A. Tamoxifen resistance in breast cancer: elucidating mechanisms. Drugs,  2001, 61, 1721-1733.
[13] 
Fabian, C.J. Clinical utilities of aromatase inhibitors in breast cancer. Int. J. Clin. Pract.,  2007, 61, 2051-2063.
[14] 
Smith, I.E.; Dowsett, M. Aromatase inhibitors in breast cancer. N. Engl. J. Med.,  2003, 348, 2431-2442.
[15] 
Geisler, J.; King, N.; Anker, G.; Ornati, G.; Di Salle, E.; Lønning, P.E.; Dowsett, M. In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in postmenopausal breast cancer patients. Clin. Cancer Res.,  1998, 4, 2089-2093.
[16] 
Geisler, J. Differences between the non-steroidal aromatase inhibitors anastrozole and letrozole – of clinical importance? Br. J. Cancer,  2011, 104, 1059-1066.
[17] 
Gonnelli, S.; Petrioli, R. Aromatase inhibitors, efficacy and metabolic risk in the treatment of postmenopausal women with early breast cancer. Clin. Interv. Aging,  2008, 3, 647-657.
[18] 
Thirumurugan, P.; Matosiuk, D.; Jozwiak, K. Click chemistry for drug development and diverse chemical-biology applications. Chem. Rev.,  2013, 113, 4905-4979.
[19] 
Ma, N.; Wang, Y.; Zhao, B.X.; Ye, W.C.; Jiang, S. The application of click chemistry in the synthesis of agents with anticancer activity. Drug Des. Devel. Ther.,  2015, 9, 1585-1599.
[20] 
Kolb, H.C.; Sharpless, K.B. The growing impact of click chemistry on drug discovery. Drug Discov. Today,  2003, 8, 1128-1137.
[21] 
Zhao, M.; Josephson, L.; Tang, Y.; Weissleder, R. Magnetic Sensors for Protease Assays. Angew. Chem. Int. Ed.,  2003, 42, 1375-1378.
[22] 
Mornet, S.; Vasseur, S.; Grasset, F.; Veverka, P.; Goglio, G.; Demourgues, A.; Portier, J.; Pollert, E.; Duguet, E. Magnetic Nanoparticle Design for Medical Applications. Prog. Solid State Chem.,  2006, 34, 237-247.
[23] 
Patel, D.; Moon, J.Y.; Chang, Y.; Kim, T.J.; Lee, G.H. Poly(d,l-lactide-co-glycolide) coated superparamagnetic iron oxide nanoparticles: Synthesis, characterization and in vivo study as MRI contrast agent. Colloid Surf. A.,  2008, 313-314, 91-94.
[24] 
Shokouhimehr, M.; Piao, Y.; Kim, J.; Jang, Y.; Hyeon, T. A Magnetically Recyclable Nanocomposite Catalyst for Olefin Epoxidation. Angew. Chem. Int. Ed.,  2007, 46, 7039-7043.
[25] 
Murty, M.S.R.; Rao, K.M.; Rao, B.R.; Babu, N.J.; Kumar, B.S.; Prakasham, R.S. Synth. Commun.,  2014, 44, 2724-2737.
[26] 
Anand, N.; Reddy, K.H.P.; Satyanarayana, T.; Rao, K.S.R.; Burri, D.R. A magnetically recoverable γ-Fe2O3 nanocatalyst for the synthesis of 2-phenylquinazolines under solvent-free conditions. Catal. Sci. Technol.,  2012, 2, 570-574.
[27] 
Shi, F.; Tse, M.K.; Pohl, M.M.; Brückner, A.; Zhang, S.; Beller, M. Tuning catalytic activity between homogeneous and heterogeneous catalysis: improved activity and selectivity of free nano-Fe2O3 in selective oxidations. Angew. Chem. Int. Ed.,  2007, 46, 8866-8868.
[28] 
Fingerhut, A.; Serdyuk, O.V.; Tsogoeva, S.B. Non-heme iron catalysts for epoxidation and aziridination reactions of challenging terminal alkenes: towards sustainability. Green Chem.,  2015, 17, 2042-2058.
[29] 
Jordan, V.C. estrogen receptor mutations found in breast cancer metastases integrated with the molecular pharmacology of selective ER modulators. J. Natl. Cancer Inst.,  1998, 90, 967-971.
[30] 
Murty, M.S.R.; Katiki, M.R.; Rao, B.R.; Narayanan, S.S.; Anto, R.J.; Buddana, S.K.; Prakasham, R.S.; Devi, B.L.A.P.; Prasad, R.B.N. An efficient nonconventional glycerol-based solid acid catalyzed synthesis and biological evaluation of phosphonate conjugates of 1,2,4-triazole thiones. Lett. Drug Des. Discov.,  2016, 13, 968-981.
[31] 
Murty, M.S.R.; Katiki, M.R.; Kommula, D. Multicomponent click synthesis of β-hydroxy/benzyl 1,2,3- triazoles catalyzed by magnetically recyclable nano iron oxide in water. Can. Chem. Trans.,  2016, 4, 47-61.
[32] 
Murty, M.S.R.; Rao, K.M.; Babu, N.J.; Srujana, G.; Sowjanya, P.; Jain, N.; Kumar, B.S.; Prakasham, R.S. Synthesis and biological evaluation of novel tamoxifen-1,2,4-triazole conjugates. Mol. Divers.,  2016, 20, 687-703.
[33] 
Dileep, K.; Murty, M.S.R. Synthesis of benzimidazoles/benzothiazoles by using recyclable, magnetically separable nano-Fe2O3 in aqueous medium. J. Iran. Chem. Soc.,  2017, 14, 1665-1671.
[34] 
Bedford, G.R.; Richardson, D.N. Preparation and Identification of cis and trans Isomers of a Substituted Triarylethylene. Nature,  1966, 212, 733-734.
[35] 
Kumaraswamy, G.; Ankamma, K.; Pitchaiah, A. Tandem epoxide or aziridine ring opening by azide/copper catalyzed [3+2] cycloaddition: Efficient synthesis of 1,2,3-triazolo β-hydroxy or β-tosylamino functionality motif. J. Org. Chem.,  2007, 72, 9822-9825.
[36] 
Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Multicomponent synthesis of 1,2,3‐triazoles in water catalyzed by copper nanoparticles on activated carbon. Adv. Synth. Catal.,  2010, 352, 3208-3214.
[37] 
Katzenellenbogen, B.S.; Norman, M.J.; Eckert, R.L.; Peltz, S.W.; Mangel, W.F. Bioactivities, estrogen receptor interactions, and plasminogen activator-inducing activities of tamoxifen and hydroxy-tamoxifen isomers in MCF-7 human breast cancer cells. Cancer Res.,  1984, 44, 112-119.

Rights & Permissions Print Cite

Article Metrics

35

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1570180815666180621100314	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X

Letters in Drug Design & Discovery

A One-pot Multicomponent ‘Click’ Approach to the Synthesis of Novel Tamoxifen-triazole Conjugates using Nano Iron Oxide Catalyst and their Preliminary Antiproliferative Activity Studies

Abstract

Graphical Abstract

Related Journals

Related Books