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

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.

Kava as a Clinical Nutrient: Promises and Challenges

“…Similar to flavokavain A, flavokavain B was reported to inhibit cancer cell proliferation [ 118 ], metastasis [ 128 , 129 ] and angiogenesis [ 130 ], and induce apoptosis [ 128 , 129 , 131 , 132 , 133 , 134 , 135 , 136 ], G2/M [ 128 , 132 , 136 , 137 ], G0/G1 [ 138 ] cell cycle arrest, autophagy [ 134 , 139 , 140 , 141 , 142 ], and the immune responses [ 143 ]. Unlike flavokavain A, flavokavain B induced G2/M cell cycle arrest in cancer cells regardless of the p53 status [ 128 , 131 , 132 , 134 , 136 , 137 ], which is intriguing given their similar structures ( Figure 2 ). Flavokavain B has also been reported to inhibit the uridine-cytidine kinase 2 (UCK2) enzyme in HT-29 cells, resulting in G0/G1 cell cycle arrest and subsequently led to cancer cell death through the MDM2-p53 signaling pathway (50 μM) [ 138 ].…”

Structure and Physical Properties of Cardamonin: A Spectroscopic and Computational Approach

“…An inversion (as a mirror image) of one molecule leads to an almost prefect overlay of molecules A and B (at the bottom of Figure 2 a). The angle of ~10° between the planes of the aromatic rings A and B indicates planarity of both molecules, as for the analogous structure of Flavokavain B [ 2 ]. The hydrogen bond lengths and valence angles in both CA molecules are equal (within the experimental error range) and are presented in Table 2 .…”

“…In recent decades, dietary compounds, such as naturally occurring chalcone, have enjoyed considerable interest due to the fact of their health-promoting properties. They have shown a wide range of bioactivity including antioxidant, anticancer, antimicrobial as well as anti-inflammatory properties [ 1 , 2 , 3 ]. Chalcones are assumed to serve as precursors of flavones in the biosynthesis of flavonoids.…”

Synthesis, Ant Proliferative Activity and Docking Study of New Quercetin Derivatives against MDA-MB231 Breast Cancer Cell Lines

“…In this study Jaunas kinase-2 (JAK2) was used because it is the target to produce the response of many anticancer drugs (Abu Bakar et al, 2018). In the docking study the crystal structure of JAK2 cocrystallized with a potent quinoxaline inhibitor, PDB: 3KRR, was downloaded.…”