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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2018-03, Vol.23 (3), p.616
• Main Authors: Abu Bakar, Addila, Akhtar, Muhammad Nadeem, Mohd Ali, Norlaily, Yeap, Swee Keong, Quah, Ching Kheng, Loh, Wan-Sin, Alitheen, Noorjahan Banu, Zareen, Seema, Ul-Haq, Zaheer, Shah, Syed Adnan Ali
• Format: Article
• Language: English
• Subjects: anti-cancer; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Binding Sites; Breast cancer; breast cancer cell lines; Catalytic Domain; Cell Proliferation - drug effects; Cell Survival - drug effects; chalcone synthesis; Chalcones - chemical synthesis; Chalcones - chemistry; Chalcones - pharmacology; Chemistry Techniques, Synthetic; Crystallography; Cytotoxicity; Drug Design; Drug Screening Assays, Antitumor; flavokawain B derivatives; Flavonoids - chemical synthesis; Flavonoids - chemistry; Flavonoids - pharmacology; Halogens; Humans; Infrared spectroscopy; Janus kinase; Lead compounds; Lymphocytes B; Magnetic Resonance Spectroscopy; MCF-7 Cells; Molecular Docking Simulation; Molecular dynamics; Molecular Structure; NMR; Nuclear magnetic resonance; Protein Binding; Reagents; SARs; Spectroscopy; Structure-Activity Relationship; Tumor cell lines
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules23030616

Flavokawain B ( ) is a natural chalcone extracted from the roots of 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 , and 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 (IC = 6.50 ± 0.40 and 4.12 ± 0.20 μg/mL), (IC = 5.50 ± 0.35 and 6.50 ± 1.40 μg/mL) and (IC = 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 (IC = 8.90 ± 0.60 and 6.80 ± 0.35 μg/mL) and (IC = 8.80 ± 0.35 and 14.16 ± 1.10 μg/mL) exhibited good cytotoxicity. The lead compound FKB ( ) showed potential cytotoxicity (IC = 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.