6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline amides and corresponding ester isosteres as multidrug resistance reversers

Figures & data

Chart 1. Tariquidar and elacridar.

Figure 1. (A) Compounds described in the previous study³⁴; (B) compounds synthesised in the present work.

Scheme 1. Reagents and conditions: (a) 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline HCl, K₂CO₃, an. CH₃CN; (b) H₂, Pd/C, EtOH; (c) SOCl₂, ethanol-free CHCl₃, an. Et₃N; (d) 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline HCl, K₂CO₃, an. CH₃CN.

Scheme 2. Reagents and conditions: (a) ArCOCl, ethanol-free CHCl₃ or an. CH₃CN; (b) ArCOOH, EDCI, DMAP, an. CH₂Cl₂ or CH₃CN.

Scheme 3. Reagents and conditions: (a) R = H, CuBr₂, t-BuOOH, an. CH₃CN; R = OCH₃, Na₂CO₃, KMnO₄, acetone.

Scheme 4. Reagents and conditions: (a) H₂SO₄ (water sol. 10%), MnO₂, CrO₃, NH₃ (15 N).

Table 1. MDR-reversing activity, P-gp interaction profile and calculated human plasma half-life of compounds 1–26.

			(EC50) µM^a
Compound	X	Ar	P-gp	MRP1	BCRP	ATP cell depletion	Papp^b	t1/2 (min)^c
1	NH	a	0.53 ± 0.10	NA	21.2 ± 4.2	No	7.0	≥240
2	NH	b	0.44 ± 0.082	NA	40%	No	5.9	≥240
3	NH	c	0.0405 ± 0.008	31%^d	1.0 ± 0.2	No	7.4	≥240
4	NH	d	7.20 ± 1.39	NA	NA	No	5.5	≥240
5	NH	e	0.26 ± 0.050	NA	41%^d	No	5.0	≥240
6	NH	f	0.67 ± 0.12	NA	NA	No	3.6	≥240
7	NH	g	0.12 ± 0.022	NA	NA	No	11.8	≥240
8	NH	h	0.0478 ± 0.0093	47%^d	NA	No	5.5	≥240
9	NH	i	6.40 ± 1.26	NA	NA	No	7.3	≥240
10	NH	j	2.30 ± 0.44	NA	NA	No	7.5	≥240
11	NH	k	1.90 ± 0.32	NA	NA	No	4.9	≥240
12	NH	l	0.87 ± 0.17	NA	NA	No	6.0	≥240
13	NH	m	0.66 ± 0.13	NA	NA	No	6.5	≥240
I^e	NH	n	1.04 ± 0.20	NA	NA	No	5.1	≥240
14	O	a	0.36 ± 0.069	69.7 ± 13.9	15.1 ± 2.89	No	9.0	≥240
15	O	b	0.73 ± 0.14	NA	47%^d	No	5.4	63 ± 14
16	O	c	0.10 ± 0.02	87.0 ± 17.0	11.0 ± 2.0	No	7.1	88 ± 22
17	O	d	0.15 ± 0.03	NA	NA	No	6.2	≥240
18	O	e	0.34 ± 0.07	NA	44%^d	No	4.1	54 ± 9
19	O	f	0.84 ± 0.16	NA	35%^d	No	5.1	≥240
20	O	g	0.11 ± 0.02	NA	7.3 ± 1.4	No	4.8	≥240
21	O	h	0.10 ± 0.02	NA	43%^d	No	5.4	≥240
22	O	i	29.40 ± 4.98	NA	NA	No	5.0	≥240
23	O	j	9.24 ± 1.81	NA	NA	No	5.6	≥240
24	O	k	1.90 ± 0.32	NA	NA	No	4.9	42 ± 20
25	O	l	0.22 ± 0.04	NA	NA	No	4.7	6 ± 1
26	O	m	1.40 ± 0.26	NA	NA	No	8.7	124 ± 27
II^e	O	n	0.93 ± 0.18	NA	17.0 ± 3.2	No	5.5	≥240
tariq			0.044 ± 0.001	ND	0.010 ± 0.005	Yes^f	>20	ND
elacr			0.014 ± 0.003	NA	10.0 ± 2.0	Yes^g	>20	ND

^a Values are the mean ± SEM of two independent experiments, with samples in triplicate.

^b Apparent permeability estimation: values are from two independent experiments, with samples in duplicate.

^c The half-life (t_1/2) values were referred to the human plasma matrix.

^d Percentage of the effect at a concentration of 100 μM.

^e See reference³⁴.

^f 30% at a concentration of 50 μM.

^g 25% at a concentration of 10 μM. NA: not active; ND: not determined.

Figure 2. In vitro cell growth experiments performed on MDCK-MDR1 cells in the presence of different concentrations of the two compounds 3 (A) and 8 (B). Each bar represents the mean ± SEM of two experiments performed in triplicate. One-way ANOVA analysis: ****p < 0.0001.

Figure 3. In vitro cell growth experiments performed on MDCK-MDR1 cells in the presence of 10 μM doxorubicin (Doxo) alone and in the presence of different concentrations of the tested compounds 3 (A) and 8 (B). Each bar represents the mean ± SEM of two experiments performed in triplicate. One-way ANOVA analysis: ****p < 0.0001.

Figure 4. In vitro cell growth experiments performed on HT29 (A), HT29/DX cells (B), A549 (C) and A549/DX cells (D) in the presence of compound 3 alone at different concentrations and in co-administration of 10 μM doxorubicin (Doxo) (after the dotted line). Each bar represents the mean ± SEM of two experiments performed in triplicate. CTR represents the untreated cells, while ctr is the same cell lines treated with 10 μM Doxo alone. One-way ANOVA analysis: *p < 0.05; **p ≤ 0.005; ****p ≤ 0.0001.

Figure 5. In vitro cell growth experiments performed on HT29 (A), HT29/DX cells (B), A549 (C) and A549/DX cells (D) in the presence of compound 8 alone at different concentrations and in co-administration of 10 μM doxorubicin (Doxo) (after the dotted line). Each bar represents the mean ± SEM of two experiments performed in triplicate. CTR represents the untreated cells, while ctr is the same cell lines treated with 10 μM Doxo alone. One-way ANOVA analysis: *p < 0.05; **p ≤ 0.005; ***p ≤ 0.001; ****p < 0.0001.

Figure 6. Degradation plots of the ester compound 25 (top) and the corresponding amide derivative 12 (bottom) in PBS (square blue) and human plasma (red triangle) samples. The ester compound 25 suffered a quickly enzymatic hydrolysis (t_1/2 about 6 min), while the amide derivative 12 was stable over 120 min in human plasma samples. Both the concentration profiles resulted unmodified in PBS solutions.

Teodori E, Dei S, Bartolucci G, et al. Structure-activity relationship studies on 6,7-dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline derivatives as multidrug resistance reversers. ChemMedChem 2017;12:1369–79.

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