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Molecules 2018, 23(3), 616; https://doi.org/10.3390/molecules23030616

Design, Synthesis and Docking Studies of Flavokawain B Type Chalcones and Their Cytotoxic Effects on MCF-7 and MDA-MB-231 Cell Lines

1
Faculty of Industrial Sciences & Technology, University Malaysia Pahang, Lebuhraya Tun Razak, Kuantan 26300, Malaysia
2
Faculty of Medicine and Health Sciences, University Tunku Abdul Rahman, Sungai Long 43400, Malaysia
3
Chine-ASEAN College of Marine Sciences, Xiamen University Malaysia, Jalan Sunsuria, Bandar Sunsuria, Sepang 43900, Malaysia
4
X-ray Crystallography Unit, School of Physics, University Sains Malaysia, Penang 11800, Malaysia
5
Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Science, University Putra Malaysia, Serdang, Selangor Darul Ehsan 43400, Malaysia
6
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
7
Research Institute of Natural Products for Drug Discovery, Faculty of Pharmacy, University Teknologi MARA, Puncak Alam Campus, Bandar Puncak Alam 42300, Malaysia
*
Authors to whom correspondence should be addressed.
Received: 26 January 2018 / Revised: 16 February 2018 / Accepted: 21 February 2018 / Published: 8 March 2018
(This article belongs to the Section Organic Chemistry)
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Abstract

Flavokawain B (1) is a natural chalcone extracted from the roots of Piper methysticum, and has been proven to be a potential cytotoxic compound. Using the partial structure of flavokawain B (FKB), about 23 analogs have been synthesized. Among them, compounds 8, 13 and 23 were found in new FKB derivatives. All compounds were evaluated for their cytotoxic properties against two breast cancer cell lines, MCF-7 and MDA-MB-231, thus establishing the structure–activity relationship. The FKB derivatives 16 (IC50 = 6.50 ± 0.40 and 4.12 ± 0.20 μg/mL), 15 (IC50 = 5.50 ± 0.35 and 6.50 ± 1.40 μg/mL) and 13 (IC50 = 7.12 ± 0.80 and 4.04 ± 0.30 μg/mL) exhibited potential cytotoxic effects on the MCF-7 and MDA-MB-231 cell lines. However, the methoxy group substituted in position three and four in compound 2 (IC50 = 8.90 ± 0.60 and 6.80 ± 0.35 μg/mL) and 22 (IC50 = 8.80 ± 0.35 and 14.16 ± 1.10 μg/mL) exhibited good cytotoxicity. The lead compound FKB (1) showed potential cytotoxicity (IC50 = 7.70 ± 0.30 and 5.90 ± 0.30 μg/mL) against two proposed breast cancer cell lines. It is evident that the FKB skeleton is unique for anticancer agents, additionally, the presence of halogens (Cl and F) in position 2 and 3 also improved the cytotoxicity in FKB series. These findings could help to improve the future drug discovery process to treat breast cancer. A molecular dynamics study of active compounds revealed stable interactions within the active site of Janus kinase. The structures of all compounds were determined by 1H-NMR, EI-MS, IR and UV and X-ray crystallographic spectroscopy techniques. View Full-Text
Keywords: chalcone synthesis; breast cancer cell lines; SARs; anti-cancer; flavokawain B derivatives chalcone synthesis; breast cancer cell lines; SARs; anti-cancer; flavokawain B derivatives
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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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.

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