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

被引:29
作者
Abu Bakar, Addila [1 ]
Akhtar, Muhammad Nadeem [1 ]
Ali, Norlaily Mohd [2 ]
Yeap, Swee Keong [3 ]
Quah, Ching Kheng [4 ]
Loh, Wan-Sin [4 ]
Alitheen, Noorjahan Banu [5 ]
Zareen, Seema [1 ]
Ul-Haq, Zaheer [6 ]
Shah, Syed Adnan Ali [7 ]
机构
[1] Univ Malaysia Pahang, Fac Ind Sci & Technol, Lebuhraya Tun Razak, Kuantan 26300, Malaysia
[2] Univ Tunku Abdul Rahman, Fac Med & Hlth Sci, Sungai Long 43400, Malaysia
[3] Xiamen Univ Malaysia, Chine ASEAN Coll Marine Sci, Jalan Sunsuria, Bandar Sunsuria 43900, Sepang, Malaysia
[4] Univ Sains Malaysia, Sch Phys, Xray Crystallog Unit, George Town 11800, Malaysia
[5] Univ Putra Malaysia, Fac Biotechnol & Biomol Sci, Dept Cell & Mol Biol, Serdang 43400, Selangor Darul, Malaysia
[6] Univ Karachi, Dr Panjwani Ctr Mol Med & Drug Res, Int Ctr Chem & Biol Sci, Karachi 75270, Pakistan
[7] Univ Teknol MARA, Fac Pharm, Res Inst Nat Prod Drug Discovery, Puncak Alam Campus, Bandar Puncak Alam 42300, Malaysia
来源
MOLECULES | 2018年 / 23卷 / 03期
关键词
chalcone synthesis; breast cancer cell lines; SARs; anti-cancer; flavokawain B derivatives; IN-VIVO ANTITUMOR; BREAST-CANCER; STRUCTURAL REQUIREMENTS; ANTIOXIDANT ACTIVITIES; ANTICANCER ACTIVITY; C-13; NMR; DERIVATIVES; INHIBITORS; POTENT; APOPTOSIS;
D O I
10.3390/molecules23030616
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 mu g/mL), 15 (IC50 = 5.50 +/- 0.35 and 6.50 +/- 1.40 mu g/mL) and 13 (IC50 = 7.12 +/- 0.80 and 4.04 +/- 0.30 mu g/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 mu g/mL) and 22 (IC50 = 8.80 +/- 0.35 and 14.16 +/- 1.10 mu g/mL) exhibited good cytotoxicity. The lead compound FKB (1) showed potential cytotoxicity (IC50 = 7.70 +/- 0.30 and 5.90 +/- 0.30 mu g/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 H-1-NMR, EI-MS, IR and UV and X-ray crystallographic spectroscopy techniques.
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页数:14
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