1-(3-Aminomethyl-4-hydroxyphenyl)-3-pyridinyl-2-propen-1-ones: A novel group of tumour-selective cytotoxins

Figures & data

Scheme 1.  Structure and synthesis of the compounds 1–4. The reagents used in the synthesis are i = NaOH, ii = HCHO/amine.

Figure 1.  Design of the compounds in series 2 and 4.

Table 1.  Cytotoxic evaluation of 1, 2a–f, 3 and 4a–e.

Compound	Tumour cell lines										Non-malignant cells				PSE
	HL-60		HSC-2		HSC-3		HSC-4		Ave	Ave	HGF	HPC	HPLF	Ave
	CC50	SI	CC50	SI	CC50	SI	CC50	SI	CC50	SI	CC50	CC50	CC50	CC50
1	5.7 ± 1.2	5.44	11.0 ± 4.4	2.82	5.5 ± 2.1	5.64	8.9 ± 2.7	3.48	7.78	4.35	23.7 ± 1.1	39.2 ± 4.3	30.0 ± 1.1	31.0	55.9
2a	12.0 ± 2.9	5.37	34.3 ± 7.5	1.88	13.3 ± 0.6	4.84	24.3 ± 4.5	2.65	21.0	3.69	41.9 ± 4.4	88.2 ± 6.2	63.0 ± 4.4	64.4	17.6
2b	7.5 ± 2.6	7.99	27.3 ± 2.3	2.19	13.5 ± 1.1	4.43	13.4 ± 0.5	4.47	15.4	4.77	38.3 ± 9.9	80.0 ± 6.9	61.3 ± 7.2	59.9	31.0
2c	10.3 ± 1.1	4.68	22.6 ± 4.6	2.13	6.8 ± 0.9	7.09	10.5 ± 2.2	4.59	12.6	4.62	29.0 ± 7.8	70.3 ± 18.0	45.3 ± 11.0	48.2	36.7
2d	95.6 ± 28.9	4.05	177.0 ± 40.7	2.19	164.0 ± 8.7	2.36	117.3 ± 32.7	3.30	139	2.98	320.2 ± 2.9	459.0 ± 28.8	381.0 ± 38.2	387	2.14
2e	5.4 ± 0.4	5.04	16.0 ± 2.6	1.70	9.5 ± 2.2	2.86	6.4 ± 1.5	4.25	9.33	3.46	18.3 ± 6.4	37.0 ± 7.0	26.3 ± 3.2	27.2	37.1
2f	10.9 ± 0.7	3.86	28.0 ± 0.2	1.50	17.3 ± 4.0	2.43	11.7 ± 0.6	3.60	17.0	2.85	22.9 ± 0.9	52.3 ± 18.9	51.1 ± 1.5	42.1	16.8
3	10.6 ± 0.8	4.73	14.0 ± 2.0	3.58	8.9 ± 1.3	5.63	7.0 ± 0.4	7.16	10.1	5.28	36.3 ± 0.3	58.1 ± 2.2	56.0 ± 18.0	50.1	52.3
4a	17.1 ± 1.0	6.55	42.0 ± 6.9	2.67	18.3 ± 1.5	6.12	23.8 ± 3.8	4.71	25.3	5.01	88.7 ± 0.4	151.3 ± 10.7	96.2 ± 20.9	112	19.8
4b	21.4 ± 0.7	6.03	44.3 ± 3.5	2.91	24.3 ± 0.6	5.31	25.3 ± 4.0	5.10	28.8	4.84	85.6 ± 8.8	159.7 ± 3.1	141.4 ± 1.2	129	16.8
4c	8.4 ± 2.7	9.94	25.8 ± 0.6	3.24	14.3 ± 2.1	5.84	14.3 ± 4.9	5.84	15.7	6.22	62.0 ± 17.5	112.7 ± 37.2	75.7 ± 11.9	83.5	39.6
4d	13.2 ± 1.1	7.44	29.1 ± 6.1	3.38	15.0 ± 4.4	6.55	18.7 ± 4.0	5.25	19.0	5.66	74.0 ± 10.1	142.3 ± 19.0	78.3 ± 9.1	98.2	29.8
4e	10.6 ± 0.9	6.16	21.3 ± 5.0	3.07	13.4 ± 0.8	4.87	12.6 ± 0.8	5.18	14.5	4.82	43.1 ± 1.9	88.7 ± 7.6	64.0 ± 6.2	65.3	33.2
Average	17.6	5.95	37.9	2.57	24.9	4.92	22.6	4.58	25.8	4.51	68.0	118	90.0	92.2	29.9
Melphalan	1.4 ± 1.2	150	8.7 ± 4.2	24.1	25 ± 7.7	8.4	32 ± 8.8	6.56	16.8	47.3	161 ± 27	269 ± 153	199 ± 60	210	282

CC₅₀ values refer to the concentrations of the compounds in micromoles which kill 50% of the cells. The letters SI indicate the selectivity index, i.e., the quotient of the average CC₅₀ figures towards HGF, HPC and HPLF non-malignant cells divided by the CC₅₀ figure of the compound towards a specific tumour cell line. The letters PSE indicate the potency selectivity expression which is the product of the reciprocal of the average CC₅₀ figure towards HL-60, HSC-2, HSC-3 and HSC-4 cell lines and the average SI value towards these neoplasms expressed as a percentage.

Table 2.  Determination of some atomic charges and torsion angles of 1–4 and their logP values.

Compound	q (esu)^†	θ1 (°)^‡	θ2 (°)^‡	LogP
1	−0.316	−21.35	34.60	2.08
2a	−0.321	−21.12	34.45	2.24
2b	−0.337	−20.42	34.86	2.90
2c	−0.291	19.49	−35.09	2.54
2d	−0.216	28.48	29.04	2.96
2e	−0.298	−21.26	34.42	1.98
2f	−0.211	−28.90	−32.67	1.83
3	−0.071	−24.74	15.57	1.86
4a	−0.086	−29.16	21.20	1.80
4b	−0.046	24.05	−12.77	2.48
4c	−0.037	25.19	2.54	2.11
4d	0.012	29.74	−1.03	2.53
4e	−0.055	−25.12	15.34	1.55

^†The q values are the charges on the β carbon atom as indicated in Supplementary Figure S1.

^‡The θ₁ and θ₂ figures are the torsion angles between the aryl and heterocyclic rings and the adjacent unsaturated groups are indicated in Supplementary Figure S1.