Methanethiosulfonate derivatives as ligands of the STAT3-SH2 domain

Figures & data

Figure 1. Structure of S3I-201.

Figure 2. Structures of the studied thiosulfonate drug hybrids and of compound 8.

Scheme 1. Reagents and conditions: (a) DCC, DMAP, CH₂Cl₂, rt, 1.5 h.

Scheme 2. Reagents and conditions: (a) anh. DMF, N₂, 60 °C, 4 h.

Scheme 3. Reagents and conditions: (a) acetone, rt, 20 h; 80%. (b) HOBt, EDC-HCl, DIPEA, anh. DMF, Ar, 0 °C to rt, 5 h; 6%.

Figure 3. Left: ORTEP34 drawing of 8, showing the arbitrary atomic numbering (displacement ellipsoids at 40% probability). Right: Intermolecular interactions viewed about along a-axis.

Table 1. Comparative SH2 domain inhibitory activity and cytotoxicity on HCT-116 cell line of the tested compounds.

	STAT3			STAT1			Grb2	HCT-116
	% Inhibition			% Inhibition			% Inhibition
Compound	30 μM	3 μM	IC50 (μM) ± SD	30 μM	3 μM	IC50 (μM) ± SD	3 μM	IC50 (μM) ± SD
1	101.7^a	101.2 ± 2.2	0.7 ± 0.1	n.t.	44.9 ± 10.5	>3	76.0^a	135.5 ± 2.2
2	105.8^a	67.2 ± 11.0	1.4 ± 0.1	n.t.	1.9 ± 2.2	>3	−23.3^a	NA^b
3	101.8^a	105.2 ± 8.2	0.5 ± 0.1	n.t.	46.7 ± 1.1	>3	74.6^a	104 ± 10.9
4	100.0 ± 0.1	93.5 ± 2.6	1.4 ± 0.1	99.8 ± 0.4	44.2 ± 0.8	3.6 ± 0.0	15.9^a	87.9 ± 11.4
5	101.8^a	110.5 ± 2.2	0.5 ± 0.2	n.t.	35.4 ± 2.1	>3	77.8^a	NA
6	58.4 ± 1.1	46.0 ± 0.8	4.9 ± 0.4	39.6 ± 0.8	18.0 ± 0.2	>30	n.t.	NA
8	41.8 ± 0.9	n.t.	>30	n.t.	n.t.	n.t.	n.t.	26.3 ± 11.6
VA	0.2 ± 3.2	n.t.	>30	2.7 ± 3.0	n.t.	>30	n.t.	NA
Sulindac	4.2 ± 3.2	n.t.	>30	4.9 ± 2.0	n.t.	>30	n.t.	NA
ASA	3.8 ± 1.9	n.t.	>30	6.3 ± 1.7	n.t.	>30	n.t.	NA
Diclofenac sodium salt	4.5 ± 2.4	n.t.	>30	6.5 ± 2.1	n.t.	>30	n.t.	NA
9	11.6^a	n.t.	>30	n.t.	n.t.	n.t.	n.t.	NA^b
10	−10.2^a	46.8 ± 10.1	>3	n.t.	14.5 ± 7.1	>3	12.3^a	NA^b
15	n.t.	n.t.	n.t.	n.t.	n.t.	n.t.	n.t.	NA
S3I-301	7.2 ± 1.7	n.t.	>30	n.t.	n.t.	n.t.	n.t.	39.5 ± 7.7

n.t.: not tested; NA: not active up to 200 μM.

^a Mean of two experiments.

^b Not active at 100 μM.

Farrugia LJ. Win GX. Suite for small-molecule single-crystal crystallography. J Appl Cryst 1999;32:837–8.

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