Design, synthesis and anticancer activity of oxoaporphine alkaloid derivatives

Figures & data

Figure 1. Structure of oxoaporphine, liriodenine and dicentrinone.

Scheme 1. Synthesis of 7H-dibenzo[de,g]quinolin-7-one 4. Reagents and conditions: (1) DMAD/toluene/reflux/8 days; (2) KOH/CH₃OH/H₂O (85 °C); (3) Diphenyl ether (250 °C).

Figure 2. Structures of oxoaporphine alkaloid derivatives.

Figure 3. Synthesis of disubstituted derivatives. Reagents and conditions: (1) SOCl₂/C₆H₆; (2) NH₂ (CH₂)_nNR₂/Et₃N.

Figure 4 Inhibition of Topo I-catalyzed DNA relaxation by 7-oxoaporphine and Camptothecin. Lane 1, pBR322 DNA only. Lane 2, pBR322 DNA and Topo I. Lanes 3–7, pBR322 DNA, Topo I, and various drug concentrations.

Figure 5 Absorption titration of 7-oxoaporphine with CT DNA. Compound 7-oxoaporphine (20 µM) in 10 mM sodium phosphate buffer (pH 7.0) with 150 mM NaCl at increasing CT DNA concentration (arrow: 0–400 µM).

Table 1. Binding constants (K_i) and photometric properties of oxoaporphine derivatives in contact with CT DNA.

Compounds	Ki (× 10^−5M^−1)^a	λmax (nm)^b,d	Red shift (nm)^b,d	Hypochromicity (%)^b,d	Isosbestic point (nm)
4	0.21	412	5	6	420
2a	0.43^e	467	16	5	Unclear
2b	0.67^e	462	18	8	506
2c	0.82^e	465	17	8	514
2d	0.87^e	457	19	10	508
2e	1.02^e	466	20	12	511
2f	0.52^e	431	14	7	Unclear
3a	2.41^c	427	4	9	450
3b	2.26^c	425	1	8	Unclear
3c	3.16^c	432	5	16	452
3e	3.21^c	425	5	12	453
3f	2.45^c	430	5	15	452
3g	4.03^c	423	6	20	450

^a3 µM drug in 10 mM NaH₂PO₄-Na₂HPO₄ (pH 7.0) buffer containing 50 mM NaCl at room temperature.

^b20 µM drug in 10 mM NaH₂PO₄-Na₂HPO₄ (pH 7.0) buffer containing 150 mM NaCl at room temperature.

^cObtained from spectrofluorimetric titration at λ_ex = 430 nm and λ_em = 450 nm.

^dObtained at λ_max.

^eObtained from spectrofluorimetric titration at λ_ex = 464 nm and λ_em = 470 nm.

Table 2. IC₅₀ cytotoxicity values (µM) of oxoaporphine derivatives against tumor cells.

Compound	MCF-7	NCI-H460	GLC-82
4	15.0	45.4	35.4
2a	9.21	31.37	23.51
2b	9.01	17.00	26.28
2c	6.75	20.15	25.01
2d	5.11	11.06	21.22
2e	3.58	10.21	10.18
2f	8.28	18.33	20.91
3a	2.63	6.39	36.93
3b	2.96	8.43	9.90
3c	1.94	6.79	28.30
3e	1.86	2.45	43.01
3f	9.22	8.08	35.01
3g	1.16	4.12	5.42