Novel drug isolated from mistletoe (1 E,4 E)-1,7-bis(4-hydroxyphenyl)hepta-1,4-dien-3-one for potential treatment of various cancers: synthesis, pharmacokinetics and pharmacodynamics

Abstract

(1E,4E)-1,7-Bis(4-hydroxyphenyl)hepta-1,4-dien-3-one (DHDK) is a novel curcuminoid analogue isolated from mistletoe. DHDK exhibits better anti-tumour activity, higher bioavailability and superior stability than curcumin. DHDK is difficult to isolate from Viscum coloratum, but it can be synthesised. MTT (methylthiazolyldiphenyl tetrazolium bromide) assay was used to evaluate the in vitro cytotoxic activity of synthesised DHDK on 12 cancer cell lines. Results showed that DHDK exhibited excellent potential as an anticancer agent, especially for breast and lung cancer. Efficacy was further evaluated in vivo by using MCF-7 breast cancer models. DHDK showed a dose-dependent relationship without weight reduction, mortality growth inhibition or tissue toxicity. Pharmacokinetics and tissue distribution statistics were determined by LC-ESI-MS/MS. This work provided preliminary data on this natural compound and could open up new prospects for changing related parameters to improve drug efficacy.

Fig. 1. (1E,4E)-1,7-Bis(4-hydroyphenyl)hepta-1,4-dien-3-one.

Scheme 1. Reagents and conditions: (a) CH₃OH, H₂SO₄, 4 h, 35 °C (b) DIPEA, DCM, acetone, MOMBr, 2 h, reflux (c) LiAlH₄, dry THF, 3 h, rt (d) DMP, DCM, NaHCO₃, 4 h, 0 °C (e) MOMBr, K₂CO₃, acetone, 5 h, reflux (f) H₂O, 10% NaOH, acetone, rt (g) LDA, THF, 5 h, −78 °C (h) HCl (6 mol L⁻¹), methanol, 15 min, 60 °C, reflux.

Fig. 2. Curves of the inhibitory effects of DHDK and cisplatin on the growth of different tumour cell lines.

Fig. 3. Inhibition rate of different DHDK concentrations to LO2 human normal liver cell.

Fig. 4. Inhibition rate of different DHDK concentrations to GES-1 human normal gastric mucosal cell.

Fig. 5. Inhibition rate of different DHDK concentrations to BEAS-2B human normal lung epithelial cell.

Fig. 6. (a) Mean tumour volume–time curve of various groups after tail vein injection of DHDK solution. (b) Mean weight–time curve of various groups after tail vein injection of DHDK solution. (c) Tumour picture of various groups obtained after the mice were sacrificed ((A) negative control group, (B) low-dose group, (C) medium-dose group, (D) high-dose group, (E) positive control group, n = 6).

Fig. 7. Heart histopathology of various groups obtained after the mice were sacrificed ((A) negative control group, (B) low-dose group, (C) medium-dose group, (D) high-dose group, (E) positive control group).

Fig. 8. Tumour histopathology of various groups obtained after the mice were sacrificed ((A) negative control group, (B) low-dose group, (C) medium-dose group, (D) high-dose group, (E) positive control group).

Fig. 9. Mean plasma concentration–time curves of DHDK after the tail vein injection of 14 mg kg⁻¹ DHDK solution (n = 6).

Fig. 10. (a) Mean tissue concentration–time curves of DHDK after tail vein injection of 14 mg kg⁻¹ DHDK solution (n = 6). (b) Mean DHDK concentrations in various tissues at indicated time points after tail vein injection of 14 mg kg⁻¹ DHDK solution (n = 6).