Design, Synthesis and Docking Studies of Flavokawain B Type Chalcones and Their Cytotoxic Effects on MCF-7 and MDA-MB-231 Cell Lines
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Structure–Activity Relationships
2.3. Computational Studies
3. Materials and Methods
3.1. Chemistry
3.2. Docking Analysis Method
3.3. Synthesis of Flavokawain B derivatives
3.4. Characterization Data
3.5. X-ray Crystallographic Analysis
3.6. Anticancer Activity
3.6.1. Sample preparation
3.6.2. MTT Cell Viability Assay
4. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
References
- Polyak, K. Breast cancer: Origins and evolution. J. Clin. Investig. 2007, 117, 3155–3163. [Google Scholar] [CrossRef] [PubMed]
- Perou, C.M.; Sørlie, T.; Eisen, M.B.; Van de Rijn, M.; Jeffrey, S.S.; Rees, C.A.; Pollack, J.R.; Ross, D.T.; Johnsen, H.; Akslen, L.A.; et al. Molecular portraits of human breast tumours. Nature 2000, 406, 747–752. [Google Scholar] [CrossRef] [PubMed]
- Sørlie, T.; Perou, C.M.; Tibshirani, R.; Aas, T.; Geisler, S.; Johnsen, H.; Hastie, T.; Eisen, M.B.; Van de Rijn, M.; Jeffrey, S.S.; et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. PNAS 2001, 98, 10869–10874. [Google Scholar] [CrossRef] [PubMed]
- Rao, S.D.; Kumar, P.G.; Harika, G.; Pooja, B.; Rao, S.; Kumar, A.Y. Recent advances and potential pharmacological activities of chalcones and their heterocyclic derivatives a valuable insight. J. Chem. Pharm. Res. 2016, 8, 458–477. [Google Scholar]
- Patil, C.B.; Mahajan, S.K.; Katti, S.A. Chalcone: A Versatile Molecule. J. Pharm. Sci. Res. 2009, 1, 11–22. [Google Scholar]
- Dyrager, C.; Wickström, M.; Fridén-Saxin, M.; Friberg, A.; Dahlén, K.; Wallén, E.A.A.; Gullbo, J.; Grøtli, M.; Luthman, K. Inhibitors and promoters of tubulin polymerization: Synthesis and biological evaluation of chalcones and related dienones as potential anticancer agents. Bioorg. Med. Chem. 2011, 19, 2659–2665. [Google Scholar] [CrossRef] [PubMed]
- Echeverria, C.; Santibañez, J.F.; Donoso-Tauda, O.; Escobar, C.A.; Ramirez-Tagle, R. Structural Antitumoral Activity Relationships of Synthetic Chalcones. Int. J. Mol. Sci. 2009, 10, 221–231. [Google Scholar] [CrossRef] [PubMed]
- Ilango, K.; Valentina, P.; Saluja, G.S. Synthesis and in vitro anticancer activity of some substituted chalcone derivatives. Res. J. Pharm. Biol. Chem. Sci. 2010, 1, 354–359. [Google Scholar]
- Kamal, A.; Ramakrishna, G.; Raju, P.; Viswanath, A.; Ramaiah, M.J.; Balakishan, G.; Pal-Bhadra, M. Synthesis and anti-cancer activity of chalcone linked imidazolones. Bioorg. Med. Chem. Lett. 2010, 20, 4865–4869. [Google Scholar] [CrossRef] [PubMed]
- Szliszka, E.; Czuba, Z.P.; Mazur, B.; Sedek, L.; Paradysz, A.; Krol, W. Chalcones Enhance TRAIL-Induced Apoptosis in Prostate Cancer Cells. Int. J. Mol. Sci. 2010, 11, 1–13. [Google Scholar] [CrossRef] [PubMed]
- Bandgar, B.P.; Gawande, S.S.; Bodade, R.G.; Totre, J.V.; Khobragade, C.N. Synthesis and biological evaluation of simple methoxylated chalcones as anticancer, anti-inflammatory and antioxidant agents. Bioorg. Med. Chem. 2010, 18, 1364–1370. [Google Scholar] [CrossRef] [PubMed]
- Herencia, F.; Lo, M.P.; Ubeda, A.; Ferrándiz, M.L. Nitric oxide-scavenging properties of some chalcone derivatives. Nitric Oxide 2002, 6, 242–246. [Google Scholar] [CrossRef] [PubMed]
- Yadav, H.L.; Gupta, P.; Pawar, R.S.; Singour, P.K.; Patil, U.K. Synthesis and biological evaluation of anti-inflammatory activity of 1,3 diphenyl propenone derivatives. Med. Chem. Res. 2010, 20, 461–465. [Google Scholar] [CrossRef]
- Zhang, X.W.; Zhao, D.H.; Quan, Y.C.; Sun, L.P.; Yin, X.M.; Guan, L.P. Synthesis and evaluation of antiinflammatory activity of substituted chalcone derivatives. Med. Chem. Res. 2010, 19, 403–412. [Google Scholar] [CrossRef]
- Awasthi, S.K.; Mishra, N.; Kumar, B.; Sharma, M.; Bhattacharya, A.; Mishra, L.C.; Bhasin, V.K. Potent antimalarial activity of newly synthesized substituted chalcone analogs in vitro. Med. Chem. Res. 2009, 18, 407–420. [Google Scholar] [CrossRef]
- Hans, R.H.; Guantai, E.M.; Lategan, C.; Smith, P.J.; Wan, B.; Franzblau, S.G.; Gut, J.; Rosenthal, P.J.; Chibale, K. Synthesis, antimalarial and antitubercular activity of acetylenic chalcones. Bioorg. Med. Chem. Lett. 2010, 20, 942–944. [Google Scholar] [CrossRef] [PubMed]
- Boeck, P.; Falcão, C.A.B.; Leal, P.C.; Yunes, R.A.; Filho, V.C.; Torres-Santos, E.C.; Rossi-Bergmann, B. Synthesis of chalcone analogues with increased antileishmanial activity. Bioorg. Med. Chem. 2006, 14, 1538–1545. [Google Scholar] [CrossRef] [PubMed]
- Roussaki, M.; Lima, S.C.; Kypreou, A.M.; Kefalas, P.; Silva, A.C.D.; Detsi, A. Aurones: A promising heterocyclic scaffold for the development of potent antileishmanial agents. Int. J. Med. Chem. 2012, 2012, 1–8. [Google Scholar] [CrossRef] [PubMed]
- Zainuri, D.A.; Arshad, S.; Khalib, N.C.; Razak, I.A.; Pillai, R.R.; Sulaiman, S.F.; Hashim, N.S.; Ooi, K.L.; Armaković, S.; Armaković, S.J.; et al. Synthesis, XRD crystal structure, spectroscopic characterization (FT-IR, 1H and 13C NMR), DFT studies, chemical reactivity and bond dissociation energy studies using molecular dynamics simulations and evaluation of antimicrobial and antioxidant activities of a novel chalcone derivative, (E)-1-(4-bromophenyl)-3-(4-iodophenyl)prop-2-en-1-one. J. Mol. Struct. 2017, 1128, 520–533. [Google Scholar] [CrossRef]
- Wang, Y.H.; Dong, H.H.; Zhao, F.; Wang, J.; Yan, F.; Jiang, Y.Y.; Jin, Y.S. The synthesis and synergistic antifungal effects of chalcones against drug resistant Candida albicans. Bioorg. Med. Chem. Lett. 2016, 26, 3098–3102. [Google Scholar] [CrossRef] [PubMed]
- Doan, T.N.; Tran, D.T. Synthesis, Antioxidant and Antimicrobial Activities of a Novel Series of Chalcones, Pyrazolic Chalcones, and Allylic Chalcones. Pharmacol. Pharm. 2011, 2, 282–288. [Google Scholar] [CrossRef]
- Shenvi, S.; Kumar, K.; Hatti, K.S.; Rijesh, K.; Diwakar, L.; Reddy, G.C. Synthesis, anticancer and antioxidant activities of 2,4,5-trimethoxy chalcones and analogues from asaronaldehyde: Structure-activity relationship. Eur. J. Med. Chem. 2013, 62, 435–442. [Google Scholar] [CrossRef] [PubMed]
- Sivakumar, P.M.; Prabhakar, P.K.; Doble, M. Synthesis, antioxidant evaluation, and quantitative structure-activity relationship studies of chalcones. Med. Chem. Res. 2011, 20, 482–492. [Google Scholar] [CrossRef]
- Kaushik, S.; Kumar, N.; Drabu, S. Synthesis and anticonvulsant activities of phenoxychalcones. Pharma Res. 2010, 3, 257–262. [Google Scholar]
- Sukumaran, S.D.; Chee, C.F.; Viswanathan, G.; Buckle, M.J.; Othman, R.; Abd Rahman, N.; Chung, L.Y. Synthesis, Biological Evaluation and Molecular Modelling of 2′-Hydroxychalcones as Acetylcholinesterase Inhibitors. Molecules 2016, 21, 955. [Google Scholar] [CrossRef] [PubMed]
- Akhtar, M.N.; Sakeh, N.M.; Zareen, S.; Gul, S.; Lo, K.M.; Ul-Haq, Z.; Shah, S.A.A.; Ahmad, S. Design and synthesis of chalcone derivatives as potent tyrosinase inhibitors and their structural activity relationship. J. Mol. Struct. 2015, 1085, 97–103. [Google Scholar] [CrossRef]
- Chimenti, F.; Fioravanti, R.; Bolasco, A.; Chimenti, P.; Secci, D.; Rossi, F.; Yáñez, M.; Orallo, F.; Ortuso, F.; Alcaro, S. Chalcones: A valid scaffold for monoamine oxidases inhibitors. J. Med. Chem. 2009, 52, 2818–2824. [Google Scholar] [CrossRef] [PubMed]
- Dharmaratne, H.R.W.; Nanayakkara, N.P.D.; Khan, I.A. Kavalactones from Piper methysticum, and their 13C-NMR spectroscopic analyses. Phytochemistry 2002, 59, 429–433. [Google Scholar] [CrossRef]
- Abu, N.; Ho, W.Y.; Yeap, S.K.; Akhtar, M.N.; Abdullah, M.P.; Omar, A.R.; Alitheen, N.B. The flavokawain: Uprising medicinal chalcones. Cancer Cell Int. 2013, 13, 1–7. [Google Scholar] [CrossRef] [PubMed]
- Abu, N.; Mohamed, N.E.; Yeap, S.K.; Lim, K.L.; Akhtar, M.N.; Zulfadli, A.J.; Kee, B.B.; Abdullah, M.P.; Omar, A.R.; Alitheen, N.B. In vivo antitumor and antimetastatic effects of flavokawain B in 4T1 breast cancer cell-challenged mice. Drug Des. Dev. Ther. 2015, 9, 1401–1417. [Google Scholar] [CrossRef]
- Abu, N.; Akhtar, M.N.; Yeap, S.K.; Lim, K.L.; Ho, W.Y.; Abdullah, M.P.; Ho, C.L.; Omar, A.R.; Ismail, J.; Alitheen, N.B. Flavokawain B induced cytotoxicity in two breast cancer cell lines, MCF-7 and MDA-MB231 and inhibited the metastatic potential of MDA-MB231 via the regulation of several tyrosine kinases in vitro. BMC Complement. Altern. Med. 2016, 16, 1–14. [Google Scholar] [CrossRef] [PubMed]
- Kamaldin, M.N.; Akhtar, M.N.; Mohamad, A.S.; Lajis, N.; Perimal, E.K.; Akira, A.; Ming-Tatt, L.; Israf, D.A.; Sulaiman, M.R. Peripheral antinociception of a chalcone, flavokawin B and possible involvement of the nitric oxide/cyclic guanosine monophosphate/potassium channels pathway. Molecules 2013, 18, 4209–4220. [Google Scholar] [CrossRef] [PubMed]
- Mohamad, A.S.; Akhtar, M.N.; Khalivulla, S.I.; Perimal, E.K.; Khalid, M.H.; Ong, H.M.; Zareen, S.; Akira, A.; Israf, D.A.; Lajis, N.; et al. Possible Participation of Nitric Oxide⁄Cyclic Guanosine Monophosphate⁄Protein Kinase C/ATP-Sensitive K+ Channels Pathway in the Systemic Antinociception of Flavokawin B. Basic Clin. Pharmacol. Toxicol. 2011, 108, 400–405. [Google Scholar] [CrossRef] [PubMed]
- Abu, N.; Akhtar, M.N.; Yeap, S.K.; Lim, K.L.; Ho, W.Y.; Zulfadli, A.J.; Omar, A.R.; Sulaiman, M.R.; Abdullah, M.P.; Alitheen, N.B. Flavokawain A induces apoptosis in MCF-7 and MDA-MB231 and inhibits the metastatic process in vitro. PLoS ONE 2014, 9, 1–12. [Google Scholar] [CrossRef] [PubMed]
- Abu, N.; Mohamed, N.E.; Yeap, S.K.; Lim, K.L.; Akhtar, M.N.; Zulfadli, A.J.; Kee, B.B.; Abdullah, M.P.; Omar, A.R.; Alitheen, N.B. In Vivo Anti-Tumor Effects of Flavokawain A in 4T1 Breast Cancer Cell-Challenged Mice. Anticancer Agents Med. Chem. 2015, 15, 905–915. [Google Scholar] [CrossRef] [PubMed]
- Ali, N.M.; Akhtar, M.N.; Ky, H.; Lim, K.L.; Abu, N.; Zareen, S.; Ho, W.Y.; Alan-Ong, H.K.; Tan, S.W.; Alitheen, N.B.; et al. Flavokawain derivative FLS induced G2/M arrest and apoptosis on breast cancer MCF-7 cell line. Drug Des. Dev. Ther. 2016, 10, 1897–1907. [Google Scholar] [CrossRef]
- Bandgar, B.P.; Patil, S.A.; Gacche, R.N.; Korbad, B.L.; Hote, B.S.; Kinkar, S.N.; Jalde, S.S. Synthesis and biological evaluation of nitrogen-containing chalcones as possible anti-inflammatory and antioxidant agents. Bioorg. Med. Chem. Lett. 2010, 20, 730–733. [Google Scholar] [CrossRef] [PubMed]
- Mai, C.W.; Yaeghoobi, M.; Abd-Rahman, N.; Kang, Y.B.; Pichika, M.R. Chalcones with electron-withdrawing and electron-donating substituents: Anticancer activity against TRAIL resistant cancer cells, structure-activity relationship analysis and regulation of apoptotic proteins. Eur. J. Med. Chem. 2014, 77, 378–387. [Google Scholar] [CrossRef] [PubMed]
- Pouget, C.; Lauthier, F.; Simon, A.; Fagnere, C.; Basly, J.P.; Delage, C.; Chulia, A.J. Flavonoids: Structural Requirements for Antiproliferative Activity on Breast Cancer Cells. Bioorg. Med. Chem. Lett. 2001, 11, 3095–3097. [Google Scholar] [CrossRef]
- Jin, F.; Jin, X.Y.; Jin, Y.L.; Sohn, D.W.; Kim, S.A.; Sohn, D.H.; Kim, Y.C.; Kim, H.S. Structural Requirements of 2′,4′,6′-Tris(methoxymethoxy) chalcone Derivatives for Anti-inflammatory Activity: The Importance of a 2′-Hydroxy Moiety. Arch. Pharm. Res. 2007, 30, 1359–1367. [Google Scholar] [CrossRef] [PubMed]
- Nakhjiri, M.; Safavi, M.; Alipour, E.; Emami, S.; Atash, A.F.; Jafari-Zavareh, M.; Ardestani, S.K.; Khoshneviszadeh, M.; Foroumadi, A.; Shafie, A. Asymmetrical 2,6-bis(benzylidene)cyclohexanones: Synthesis, cytotoxic activity and QSAR study. Eur. J. Med. Chem. 2012, 50, 113–123. [Google Scholar] [CrossRef] [PubMed]
- Alnemri, E.S.; Livingston, D.J.; Nicholson, D.W.; Salvesen, G.; Thornberry, N.A.; Wong, W.W.; Yuan, J. Human ICE/CED-3 Protease Nomenclature. Cell 1996, 87, 171. [Google Scholar] [CrossRef]
- Molecular Operating Environment (MOE). Available online: https://www.chemcomp.com/MOE-Molecular_Operating_Environment.htm (accessed on 23 November 2017).
- Baffert, F.; Régnier, C.H.; De Pover, A.; Pissot-Soldermann, C.; Tavares, G.A.; Blasco, F.; Brueggen, J.; Chéne, P.; Drueckes, P.; Erdmann, D.; et al. Potent and selective inhibition of polycythemia by the quinoxaline JAK2 inhibitor NVP-BSK805. Mol. Cancer Ther. 2010, 9, 1945–1955. [Google Scholar] [CrossRef] [PubMed]
- Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera—A visualization system for exploratory research and analysis. J. Comput. Chem. 2004, 25, 1605–1612. [Google Scholar] [CrossRef] [PubMed]
- Case, D.A.; Cheatham III, T.E.; Darden, T.; Gohlke, H.; Luo, R.; Merz, K.M., Jr.; Onufriev, A.; Simmerling, C.; Wang, B.; Woods, R.J. The Amber Biomolecular Simulation Programs. J. Comput. Chem. 2005, 26, 1668–1688. [Google Scholar] [CrossRef] [PubMed]
- Roe, D.R.; Cheatham, T.E., III. PTRAJ and CPPTRAJ: Software for processing and analysis of molecular dynamics trajectory data. J. Chem. Theory Comput. 2013, 9, 3084–3095. [Google Scholar] [CrossRef] [PubMed]
- Case, D.A.; Betz, R.M.; Cerutti, D.S.; Cheatham III, T.E.; Darden, T.A.; Duke, R.E.; Giese, T.J.; Gohlke, H.; Goetz, A.W.; Homeyer, N.; Izadi, S.; et al. AMBER 2016 Reference Manual; University of California: San Francisco, CA, USA, 2016; pp. 1–923. [Google Scholar]
- Lagunin, A.; Stepanchikova, A.; Filimonov, D.; Poroikov, V. PASS: prediction of activity spectra for biologically active substances. Bioinformatics 2000, 16, 747–748. [Google Scholar] [CrossRef] [PubMed]
- Kadir, F.A.; Kassim, N.M.; Abdulla, M.A.; Yehye, W.A. Hepatoprotective Role of Ethanolic Extract of Vitex negundo in Thioacetamide-Induced Liver Fibrosis in Male Rats. Evid. Based Complement. Alternat. Med. 2013, 2013, 1–9. [Google Scholar] [CrossRef] [PubMed]
- Jänicke, R.U.; Sprengart, M.L.; Wati, M.R.; Porter, A.G. Caspase-3 Is Required for DNA Fragmentation and Morphological Changes Associated with Apoptosis. J. Biol. Chem. 1998, 273, 9357–9360. [Google Scholar] [CrossRef] [PubMed]
- Yang, X.H.; Sladek, T.L.; Liu, X.; Butler, B.R.; Froelich, C.J.; Thor, A.D. Reconstitution of Caspase 3 Sensitizes MCF-7 Breast Cancer Cells to Doxorubicin- and Etoposide-induced Apoptosis. Cancer Res. 2001, 61, 348–354. [Google Scholar] [PubMed]
- Fulda, S.; Debatin, K.M. Caspase activation in cancer therapy. In Madame Curie Bioscience Database [Internet]; Landes Bioscience: Austin, TX, USA, 2013; pp. 1–29. [Google Scholar]
- Sun, H.; Nikolovska-Coleska, Z.; Lu, J.; Qiu, S.; Yang, C.Y.; Gao, W.; Meagher, J.; Stuckey, J.; Wang, S. Design, synthesis, and evaluation of a potent, cell-permeable, conformationally constrained second mitochondria derived activator of caspase (Smac) mimetic. J. Med. Chem. 2006, 49, 7916–7920. [Google Scholar] [CrossRef] [PubMed]
- Cheung, C.S.F.; Chung, K.K.W.; Lui, J.C.K.; Lau, C.P.; Hon, P.M.; Chan, J.Y.W.; Fung, K.P.; Au, S.W.N. Leachianone A as a potential anti-cancer drug by induction of apoptosis in human hepatoma HepG2 cells. Cancer Lett. 2007, 253, 224–235. [Google Scholar] [CrossRef] [PubMed]
- Kiss, R.; Sayeski, P.P.; Keserű, G.M. Recent developments on JAK2 inhibitors: A patent review. Expert Opin. Ther. Pat. 2010, 20, 471–495. [Google Scholar] [CrossRef] [PubMed]
- Mohamad, A.S.; Akhtar, M.N.; Zakaria, Z.A.; Perimal, E.K.; Khalid, S.; Mohd, P.A.; Khalid, M.H.; Israf, D.A.; Lajis, N.H.; Sulaiman, M.R. Antinociceptive activity of a synthetic chalcone, flavokawain B on chemical and thermal models of nociception in mice. Eur. J. Pharmacol. 2010, 647, 103–109. [Google Scholar] [CrossRef] [PubMed]
- Srinivas, K.V.N.S.; Koteswara Rao, Y.; Mahender, I.; Das, B.; Rama Krishna, K.V.S.; Hara Kishore, K.; Murty, U.S.N. Flavanoids from Caesalpinia pulcherrima. Phytochemistry 2003, 63, 789–793. [Google Scholar] [CrossRef]
- Rao, Y.K.; Fang, S.H.; Tzeng, Y.M. Differential effects of synthesized 2′-oxygenated chalcone derivatives: modulation of human cell cycle phase distribution. Bioorg. Med. Chem. 2004, 12, 2679–2686. [Google Scholar] [CrossRef] [PubMed]
- Chiaradia, L.D.; Mascarello, A.; Purificação, M.; Vernal, J.; Cordeiro, M.N.S.; Zenteno, M.E.; Villarino, A.; Nunes, R.J.; Yunes, R.A.; Terenzi, H. Synthetic chalcones as efficient inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase PtpA. Bioorg. Med. Chem. Lett. 2008, 18, 6227–6230. [Google Scholar] [CrossRef] [PubMed]
- Srinivasarao, V.; Krishna, C.R.; Ramesh, M.; Parthasarathy, T. Synthesis, in vitro anticancer activity evaluation and docking investigations of novel aromatic chalcones. Mod. Chem. 2013, 1, 1–7. [Google Scholar] [CrossRef]
- Bruker, S. APEX2 and SAINT; Bruker AXS Inc.: Madison, WI, USA, 2009. [Google Scholar]
- Sheldrick, G.M. A short History of SHELX. Acta Cryst. A 2008, 64, 112–122. [Google Scholar] [CrossRef] [PubMed]
- Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods 1983, 65, 55–63. [Google Scholar] [CrossRef]
Sample Availability: Samples of the compounds 1–23 are available from the authors. |
Carbon | 8 | 13′ | 23 | ||||||
---|---|---|---|---|---|---|---|---|---|
1H (δ) | Multiplicity | 13C (δ) | 1H (δ) | Multiplicity | 13C (δ) | 1H (δ) | Multiplicity | 13C (δ) | |
1′ | - | - | 106.89 | - | - | 106.38 | - | - | 106.25 |
2′ | - | - | 162.36 | - | - | 162.57 | - | - | 161.84 |
3′ | 6.16 | (d, J = 2.22 Hz, 1H) | 94.38 | 6.11 | (d, J = 2.40 Hz, 1H) | 93.81 | 6.00 | (d, J = 2.50 Hz, 1H) | 93.86 |
4′ | - | - | 165.98 | - | - | 168.42 | - | - | 165.57 |
5′ | 6.13 | (d, J = 2.46 Hz, 1H) | 91.59 | 5.96 | (d, J = 2.34 Hz, 1H) | 91.29 | 5.88 | (d, J = 2.35 Hz, 1H) | 91.06 |
6′ | - | - | 165.98 | - | - | 166.37 | - | - | 165.55 |
1 | - | - | 124.18 | - | - | 124.40 | - | - | 127.05 |
2 | - | - | 153.65 | - | - | 134.87 | - | - | 113.28 |
3 | 7.06 | (d, J = 9.06 Hz, 1H) | 113.65 | 7.11 | (m, 1H) | 116.29 | - | - | 140.87 |
4 | 7.03 | (d, J = 9.06 Hz, 1H) | 113.58 | 7.18 | (td, J = 7.56 Hz, 7.50 Hz, 1H) | 131.28 | - | - | 149.86 |
5 | - | - | 153.16 | 7.59 | (td, J = 7.56 Hz, 7.68 Hz, 1H) | 129.73 | 6.78 | (d, J = 8.55 Hz, 1H) | 110.95 |
6 | 7.22 | (brs, J = 2.76 Hz, 1H) | 118.10 | 7.35 | (m, 1H) | 130.27 | 7.20 | (d, J = 8.60 Hz, 1H) | 118.85 |
α | 7.84 | (d, J = 15.80 Hz, 1H, H-α) | 128.59 | 7.86 | (d, J = 15.78 Hz, 1H, H-α) | 123.73 | 7.67 | (d, J = 15.45 Hz, 1H, H-α) | 127.05 |
β | 7.86 | (d, J = 15.80 Hz, 1H, H-β) | 137.83 | 8.00 | (d, J = 15.78 Hz, 1H, H-β) | 160.83 | 8.02 | (d, J = 15.45 Hz, 1H, H-β) | 144.09 |
OCH3 (C4′) | 3.84 | (s, 3H) | 56.62 | 3.84 | (s, 3H) | 55.78 | 3.75 | (s, 3H) | 56.15 |
OCH3 (C6′) | 3.89 | (s, 3H) | 56.58 | 3.91 | (s, 3H) | 55.60 | 3.85 | (s, 3H) | 55.63 |
OCH3 (C2) | 3.82 | (s, 3H) | 55.95 | - | - | - | - | - | - |
OCH3 (C4) | - | - | - | - | - | - | 3.81 | (s, 3H) | 56.22 |
OCH3 (C5) | 3.77 | (s, 3H) | 56.16 | - | - | - | - | - | - |
OH (C2′) | 13.46 | (s, 1H) | - | 14.25 | (s, 1H) | - | - | (s, 1H) | - |
C=O | - | - | 193.03 | - | - | 192.62 | - | - | 191.86 |
Compounds Substituted Groups | IC50 Values (μg/mL) | ||||||
---|---|---|---|---|---|---|---|
Compounds | R1 | R2 | R3 | R4 | R5 | MCF-7 | MDA-MB-231 |
1 | H | H | H | H | H | 7.70 ± 0.30 | 5.90 ± 0.30 |
2 | H | H | CH3O | H | H | 8.90 ± 0.60 | 6.80 ± 0.45 |
3 | H | H | SCH3 | H | H | 12.30 ± 1.40 | 18.10 ± 1.10 |
4 | CH3O | CH3O | H | H | H | 25.00 ± 1.80 | 21.10 ± 1.20 |
5 | CH3O | H | CH3O | H | H | >30 | >30 |
6 | CH3O | H | CH3O | H | CH3O | >30 | >30 |
7 | H | CH3O | CH3O | H | H | 9.70 ± 0.70 | 8.30 ± 0.56 |
8 | CH3O | H | H | CH3O | H | >30 | >30 |
9 | H | CH3O | H | H | H | 8.43 ± 0.40 | 7.22 ± 0.70 |
10 | H | CH3O | H | CH3O | H | >30 | >30 |
11 | H | H | CH3 | H | H | >30 | >30 |
12 | CH3O | H | H | H | H | >30 | 9.50 ± 0.60 |
13 | F | H | H | H | H | 7.12 ± 0.80 | 4.04 ± 0.30 |
14 | H | H | F | H | H | >30 | >30 |
15 | H | Cl | H | H | H | 5.50 ± 0.35 | 5.50 ± 0.40 |
16 | Cl | H | H | H | H | 6.50 ± 0.40 | 4.12 ± 0.20 |
17 | H | H | Cl | H | H | >30 | >30 |
18 | H | H | Br | H | H | >30 | >30 |
19 | H | CH3O | OH | H | H | >30 | 27.00 ± 1.50 |
20 | H | NO2 | H | H | H | 13.30 ± 3.10 | 17.10 ± 2.15 |
21 | H | H | N(CH3)2 | H | H | >30 | 20.5 ± 1.60 |
22 | OH | H | H | Br | H | 6.50 ± 0.35 | 14.16 ± 1.10 |
23 | Br | OH | OCH3 | H | H | >30 | >30 |
Compound | 7 | 9 |
---|---|---|
CCDC Number | 1548734 | 1548733 |
Molecular Formula | C19H20O6 | C18H18O5 |
Molecular Weight | 344.35 | 314.32 |
Crystal System | Triclinic | Orthorhombic |
Space Group | Pī | Pbca |
a (Å) | 8.4560 (17) | 14.447 (3) |
b (Å) | 8.4790 (17) | 7.9755 (15) |
c (Å) | 12.549 (3) | 26.203 (5) |
α (°) | 104.166 (3) | 90 |
β (°) | 92.063 (3) | 90 |
γ (°) | 106.227 (3) | 90 |
V (Å3) | 832.4 (3) | 3019.0 (10) |
Z | 2 | 8 |
Dcalc (g cm−3) | 1.374 | 1.383 |
Crystal dimensions (mm) | 0.58 × 0.18 × 0.11 | 0.55 × 0.27 × 0.14 |
μ (mm−1) | 0.10 | 0.10 |
Tmin/Tmax | 0.7665, 0.9584 | 0.8489, 0.9495 |
Reflections measured | 28,367 | 14,974 |
Ranges/indices (h, k, l) | −11→11; −11→11; −17→17 | −16→16; −9→9; −30→28 |
θ limit (°) | 1.7−29.2 | 1.6−24.6 |
Unique reflections | 4491 | 2516 |
Observed reflections (I > 2σ(I)) | 2352 | 1594 |
Parameters | 234 | 211 |
Goodness of fit on F2 | 1.02 | 1.05 |
R1, wR2 [I ≥ 2σ(I)] | 0.055, 0.176 | 0.056, 0.156 |
© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Abu Bakar, A.; Akhtar, M.N.; Mohd Ali, N.; Yeap, S.K.; Quah, C.K.; Loh, W.-S.; Alitheen, N.B.; Zareen, S.; Ul-Haq, Z.; Shah, S.A.A. Design, Synthesis and Docking Studies of Flavokawain B Type Chalcones and Their Cytotoxic Effects on MCF-7 and MDA-MB-231 Cell Lines. Molecules 2018, 23, 616. https://doi.org/10.3390/molecules23030616
Abu Bakar A, Akhtar MN, Mohd Ali N, Yeap SK, Quah CK, Loh W-S, Alitheen NB, Zareen S, Ul-Haq Z, Shah SAA. Design, Synthesis and Docking Studies of Flavokawain B Type Chalcones and Their Cytotoxic Effects on MCF-7 and MDA-MB-231 Cell Lines. Molecules. 2018; 23(3):616. https://doi.org/10.3390/molecules23030616
Chicago/Turabian StyleAbu Bakar, Addila, Muhammad Nadeem Akhtar, Norlaily Mohd Ali, Swee Keong Yeap, Ching Kheng Quah, Wan-Sin Loh, Noorjahan Banu Alitheen, Seema Zareen, Zaheer Ul-Haq, and Syed Adnan Ali Shah. 2018. "Design, Synthesis and Docking Studies of Flavokawain B Type Chalcones and Their Cytotoxic Effects on MCF-7 and MDA-MB-231 Cell Lines" Molecules 23, no. 3: 616. https://doi.org/10.3390/molecules23030616