Abstract
A total of eleven novel 1,2,3-triazole hybrids were synthesized in excellent yields from methyl β-orsellinate through a two-step protocol with 1,3-dipolar cycloaddition as the key step. The newly synthesized compounds have been evaluated for their anti-proliferative potential against a panel of cancer cell lines viz. DU-145, MCF-7, PC-3, IMR-32, and HEK-293T. Interestingly, one of the compounds exhibited higher cytotoxicity on MCF-7 cells with an IC50 of 5 µM as compared to non-cancerous HEK293T cells (23.28 µM). Flow cytometry analysis and acridine orange/ethidium bromide dual staining have showed the significant G0/G1 phase arrest and effective induction of apoptosis, respectively. Furthermore, the inhibition of CDK4/Cyclin D1 complex proteins and thereby downregulation of p-Rb and E2F1 showed that this compound can act as a potent cell-cycle inhibitor. Docking studies also indicated that the compound may act as a strong ATP competitive inhibitor of CDK4/Cyclin D1 complex. Evidently, the methyl β-orsellinate conjugates of 1,2,3-triazole hybrids could be the effective anticancer leads in breast cancer therapeutics.
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References
Harvey AL (2008) Drug Discov 13:894
Rostagno MA, Prado JM (2013) Natural product extraction: principles and applications. Royal Society of Chemistry, p 58
Atanasov AG, Waltenberger B, Pferschy Wenzing EM, Linder T, Wawrosch C, Uhrin P, Temml V, Wang L, Schwaiger S, Heiss EH (2015) Biotechnol Adv 33:1582
Koehn FE, Carter GT (2005) Nat Rev Drug Discov 4:206
Elix JA, Stocker-Wörgötter E (2008) Nash III TE (Ed.), Lichen biology. Cambridge University Press, Cambridge, p 104
Varol MJ (2015) Appl Pharmacol 8:e105
Dancık V, Seiler KP, Young DW, Schreiber SL, Clemons PA (2010) J Am Chem Soc 132:9259
Huneck S, Yoshimura I (1996) Identification of Lichen substances. Springer, Berlin
Nguyen DMT, Do LMT, Nguyen VT, Chavasiri W, Mortier J, Nguyen PPK (2017) J Nat Prod 80:261
Stocker-Wörgötter E (2008) Nat Prod Rep 25:188
Choudhary MI, Azizuddin, Jalil S (2005) Phytochemistry 66:2346
Lawrey JD (1986) Bryologist 89:111
Boustie J, Grube M (2005) Plant Gen Resour 3:273
Shrestha G, St. Clair LL (2013) Phytochem Rev 12:229
Thadhani VM, Choudhary MI, Ali S, Omar I, Siddique H, Karunaratne V (2011) Nat Prod Res 19:1827
Manojlovic NT, Vasiljevi P, Juskovi M, Najman S, Jankovic S, Andjelkovi (2010) J Med Plants Res 4:817
Huneck S (1999) Naturwissenschaften 86:559
Molnar K, Farkas EZ (2010) Z Naturforsch C 65:157
Buckle DR, Outred DJ, Rockell CJM, Smith H, Spicer BA (1983) J Med Chem 26:251
Giffin MJ, Heaslet H, Brik A, Lin YC, Cauvi G, Wong CH, McRee DE, Elder JH, Stout CD, Torbett BE (2008) J Med Chem 51:6263
Patpi SR, Pulipati L, Yogeeswari P, Sriram D, Jain N, Sridhar B, Murthy R, Anjana DT, Kalivendi SV, Kantevar S (2012) J Med Chem 55:3911
Demaray JA, Thuener JE, Dawson MN, Sucheck SJ (2008) Bioorg Med Chem Lett 18:4868
Singh P, Raj R, Kumar V, Mahajan MP, Bedi PMS, Kaur T, Saxena AK (2012) Eur J Med Chem 47:594
Khan I, Guru SK, Rath SK, Chinthakindi PK, Singh B, Koul S, Bhushan S, Sangwan PL (2016) Eur J Med Chem 108:104
Majeed R, Sangwan PL, Chinthakindi PK, Khan I, Dangroo NA, Thota N, Hamid A, Sharma PR, Saxena AK, Koul S (2013) Eur J Med Chem 63:782
Nguyen C, Kasinathan G, Cortijo IL, Buendia AM, Kaiser M, Brun R, Perez LMR, Johansson NG, Pacanowska DG, Gilbert IH (2005) J Med Chem 48:5942
Yamamoto I, Sekine M, Hata T (1980) J Chem Soc Perkin Trans 1:306
Sasaki T, Minamoto K, Suzuki T, Sugiura T (1979) J Org Chem 44:1424
Ribble D, Goldstein NB, Norris DA, Shellman YG (2005) BMC Biotechnol 5:12
Baker SJ, Reddy EP (2012) Genes Cancer 3:658
Hylands PJ, Ingolfsdottir K (1985) Phytochemistry 24:127
Asghar U, Witkiewicz AK, Turner NC, Knudsen ES (2015) Nat Rev Drug Discov 14:130
Dehong C, Sun X, Zhang X, Cao J (2020) Biomed Res Int 2020:9525207
Dalton S (2015) Trends Cell Biol 25:592
Barvian M (2000) J Med Chem 43:4606
Soni R, Muller L, Furet P, Schoepfer J, Stephan C, Zumstein-Mecker S, Fretz H, Chaudhuri B (2000) Biochem Biophys Res Commun 275:877
Chohan TA, Chen JJ, Qian HY, Pan YL, Chen JZ (2016) Mol BioSyst 12:1250
Roland WC, Smith G, Smith RL (2000) BMJ 320:987
Trott O, Olson AJ (2010) J Comput Chem 31:455
Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) J Comput Chem 25:1605
Acknowledgements
The authors acknowledge Y. Suresh for conducting flow cytometry analysis. We acknowledge CSIR-IICT for evaluating the manuscript and providing with communication number IICT/Pubs/2020/331. This work was supported by the Research Fund of DBT, Project Number: SAG-K-120917-0495.
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This article was funded by Council of Scientific and Industrial Research, India, Research Fellowship: STR, VKKM, JJM.
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Reddy, S.T., Ramakrishna, M., Makani, V.K.K. et al. Synthesis of novel 1,2,3-triazole hybrids of methyl β-orsellinate with capabilities to arrest cell cycle and induce apoptosis in breast cancer cells (MCF-7). Monatsh Chem 153, 461–473 (2022). https://doi.org/10.1007/s00706-022-02922-y
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DOI: https://doi.org/10.1007/s00706-022-02922-y