Synthesis and in vitro pharmacological evaluation of N-[(1-benzyl-1,2,3-triazol-4-yl)methyl]-carboxamides on d-secoestrone scaffolds

Figures & data

Scheme 1. Synthesis of N-(prop-2-yn-1-yl)carboxamides 5–8 and the related triazoles 10–13.

Table 1. Antiproliferative properties of the synthetized compounds 5–8 and 10–13.

	Inhibition of proliferation (%) ± SEM
	HeLa		A431		A2780		MCF-7
	10 µM	30 µM	10 µM	30 µM	10 µM	30 µM	10 µM	30 µM
5	15.5 ± 2.4	40.7 ± 1.6	12.3 ± 1.8	19.4 ± 0.9	16.0 ± 2.5	41.2 ± 1.9	12.7 ± 2.7	18.0 ± 2.7
6	26.7 ± 2.5	28.7 ± 32	19.6 ± 1.0	67.7 ± 1.5	42.4 ± 1.7	49.5 ± 0.3	21.7 ± 0.7	40.3 ± 1.4
7	<10*	15.4 ± 1.9	<10	10.3 ± 3.4	<10	12.9 ± 3.0	<10	<10
8	42.6 ± 1.8	61.5 ± 1.4	14.4 ± 1.9	28.4 ± 1.2	25.3 ± 1.9	48.7 ± 1.4	11.0 ± 1.3	33.3 ± 0.5
10a	36.1 ± 1.3	48.2 ± 1.9	15.1 ± 1.6	45.4 ± 1.3	29.9 ± 0.8	52.1 ± 1.0	24.8 ± 2.1	48.2 ± 1.1
10b	26.8 ± 2.8	36.9 ± 1.1	18.3 ± 2.2	34.6 ± 1.1	<10	41.9 ± 1.6	10.8 ± 2.3	35.0 ± 0.8
10c	23.7 ± 1.3	32.1 ± 1.9	<10	57.9 ± 0.6	29.1 ± 1.5	92.7 ± 0.5	11.3 ± 1.6	90.4 ± 0.6
11a†	27.9 ± 1.5	31.3 ± 1.4	13.9 ± 1.2	24.4 ± 1.8	79.8 ± 0.5	88.6 ± 0.1	44.6 ± 0.4	72.3 ± 0.4
11b	32.1 ± 1.9	29.6 ± 2.1	14.9 ± 0.4	13.0 ± 0.7	75.9 ± 0.4	78.3 ± 0.1	52.5 ± 0.6	56.4 ± 0.2
11c‡	19.3 ± 1.1	26.5 ± 1.1	15.5 ± 1.6	17.4 ± 1.0	80.6 ± 0.4	81.3 ± 0.5	51.7 ± 1.9	63.7 ± 0.8
11d	52.0 ± 1.2	61.0 ± 0.7	15.2 ± 2.1	<10	72.3 ± 0.4	95.1 ± 0.2	53.9 ± 1.5	72.3 ± 0.3
11e	52.0 ± 0.7	54.1 ± 1.2	11.9 ± 3.2	13.3 ± 2.3	80.4 ± 0.3	94.3 ± 0.3	63.2 ± 1.6	72.6 ± 0.5
12a	37.7 ± 2.1	51.7 ± 2.2	22.3 ± 2.3	32.5 ± 2.1	25.9 ± 1.7	33.5 ± 1.5	17.0 ± 1.8	34.8 ± 2.2
12b	24.5 ± 5.6	34.3 ± 3.3	25.3 ± 2.0	29.3 ± 1.2	35.8 ± 1.9	60.1 ± 1.2	20.1 ± 3.2	68.1 ± 0.4
12c	37.2 ± 1.5	38.0 ± 2.0	12.3 ± 2.2	55.7 ± 1.1	23.6 ± 2.1	64.9 ± 0.3	25.0 ± 0.5	90.0 ± 0.6
13a	35.7 ± 0.9	44.9 ± 2.2	<10	45.1 ± 5.4	<10	47.7 ± 3.3	<10	47.9 ± 1.5
13b	38.6 ± 1.6	48.9 ± 1.8	<10	20.6 ± 0.9	<10	36.6 ± 1.5	13.3 ± 0.9	30.1 ± 1.4
13c	43.0 ± 1.6	58.5 ± 1.3	<10	<10	22.2 ± 0.3	35.9 ± 4.4	23.5 ± 2.0	41.8 ± 0.7
CP^‖	42.6 ± 2.3	99.9 ± 0.3	88.6 ± 0.5	90.2 ± 1.8	83.6 ± 1.2	95.0 ± 0.3	53.0 ± 2.3	86.9 ± 1.2

*Inhibition values <10% are not detailed.

†Experimentally determined IC₅₀§ value on A2780: 1.1 μM.

‡Experimentally determined IC₅₀ value on A2780: 0.8 μM.

§Mean values from two independent determinations with five parallel wells; standard deviation <15%, reference agent: cisplatin (IC₅₀ value on A2780: 0.8 μM).

^‖Cisplatin (reference compound).

Table 2. In vitro inhibition of human placenta cytosol 17β-HSD1 activity by test compounds 5–8 and 10–13.

Compound	Relative conversion (%) ± S.D. (n = 3)	IC50 (µM) ± S.D.
5	68 ± 13
6	73 ± 23
7	75 ± 12
8	78 ± 10
10a	53 ± 16
10b	25 ± 2	1.3 ± 0.4
10c	42 ± 11	4.5 ± 0.8
11a	60 ± 9
11b	60 ± 9
11c	72 ± 12
11d	86 ± 12
11e	64 ± 8
12a	87 ± 10
12b	89 ± 9
12c	80 ± 15
13a	34 ± 5	3.6 ± 0.4
13b	71 ± 17
13c	78 ± 6
Estrone (reference)		1.8 ± 0.2

Relative conversions (control incubation with no inhibition is 100%) measured in the presence of 10 μM concentration of the compound tested. S.D.: standard deviation.