Isocorydine derivatives and their anticancer activities

Abstract

In order to improve the anticancer activity of isocorydine (ICD), ten isocorydine derivatives were prepared through chemical structure modifications, and their in vitro and in vivo activities were experimentally investigated. 8-Amino-isocorydine (8) and 6a,7-dihydrogen-isocorydione (10) could inhibit the growth of human lung (A549), gastric (SGC7901) and liver (HepG2) cancer cell lines in vitro. Isocorydione (2) could inhibit the tumor growth of murine sarcoma S180-bearing mice, and 8-acetamino-isocorydine (11), a pro-drug of 8-amino-isocorydine (8), which is instable in water solution at room temperature, had a good inhibitory effect on murine hepatoma H22-induced tumors. The results suggested that the isocorydine structural modifications at C-8 could significantly improve the biological activity of this alkaloid, indicating its suitability as a lead compound in the development of an effective anticancer agent.

Figure 1

X-ray crystal structures of 1 and 2. The molecular planarity of 2 was superior to that of 1 due to the double bond of C-6a and C-7, which could conjugate with benzene rings in 2 and reduce the dihedral angle of biphenyl to zero. The chirality of C-6a in 1 resulted in non-rigid conformation of the ring of B and C.

Scheme 1

The synthetic route of isocorydine derivatives. Reagents and conditions: (A) ON(SO₃K)₂/H₂O/Na₂HPO₄, 25 °C, stir, 24.0 h; (B) NH₂OH·HCl/EtOH, 80 °C, reflux, 1.5 h; (C) HNO₃/H₂SO₄/CHCl₃/CH₂Cl₂, −30 °C, stir, 1.5 h; (D) 0.3 MPa H₂, Pd/C, EtOH, 25 °C, stir, 2.5 h; (E) NCS/CH₃COOH, 7 °C, stir, 2.0 h; (F) NaNO₂/HCl, 0 °C, stir, 1.0 h; (G) CH₃COCl, stir, 2.0 h.

Figure 2

Evaluation of the instability of 8-amino-isocorydine (8) using the HPLC-UV-MS method. (A) Representative chromatogram of the degradation products of 8-amino-isocorydine (8) in water solution at room temperature over 48 h. (a: Compound 8; b and c are the main degradation products.). The mobile phase conditions were as follows: UV detector set at 270 nm, a SinoCrom ODS-BP C18 column (4.6 × 250 mm, 5 μm) was used with the mobile phase consisting of MeOH: water (65:35, using aqua ammonia adjusted pH at 7.2) at a flow rate of 1.0 mL/min. The column temperature was maintained at 25 °C; (B) Total ion chromatogram (TIC) of 8 by the LC-MSD-trap method. MS detection was conducted by ESI and operated in positive mode; (C) MS spectra tracked for a, m/z = 357.2 at 6.1 min; (D) MS spectra tracked for b, m/z = 355.2 at 8.3 min; (E) MS spectra tracked for c, m/z = 357.2 at 10.6 min.

Scheme 2

The main degrade products and the degrade route of 8-amino-isocorydine (8) in water solution at room temperature.

Figure 3

Inhibitory effect of 8-acetamino-isocorydine (11) on murine hepatoma H₂₂-bearing mice. (A) Photograph of the tumors excised from H22-bearing mice (a, blank control group; b, 50 mg/kg group; c, 100 mg/kg group; d, 200 mg/kg group; e, CTX group). From the perspective of gross anatomy, the tumor size of treatment groups and the CTX group were all significantly different from that of the control group; (B) The mean tumor weights (X + SD) of all groups. The tumor weights of the high dosage group, the medium dosage group and the CTX group were all significantly different from that of the blank control group (** p < 0.01, * p < 0.05).

Figure 4

Influence of 8-acetamino-isocorydine (11) on body weight of mice bearing murine hepatoma H₂₂. (A) The trend of weight increase during the treatment period with 11. The body weights increased in the blank control and treatment groups, but decreased in the CTX group; (B) Body weight of all groups at 10 d. The body weight of the blank control group and treatment groups were significantly different from that of the CTX group (* p < 0.05). There was no significant difference between the blank control group and treatment groups.