Synthesis and biological evaluation of novel hydrogen sulfide releasing glycyrrhetic acid derivatives

Figures & data

Figure 1. Chemical structures of ADT-OH and ADT-OH derivatives.

Figure 2. Chemical structures of glycyrrhetic acid and its derivatives.

Scheme 1. Reagents and conditions: (a) K₂CO₃, cat. KI, 60 °C, 12 h, chromatography, 86.2% for V₁, 86.6% for V₂, and 89.2% for V₃.

Scheme 2. Reagents and conditions: (a) Ac₂O, Py, rt, 3 h, chromatography 92.7% for 4; (b) K₂CO_3, cat. KI, 3a, or 3b or 3c, 60 °C, 12 h, chromatography, 86.0% for V₄, 89.5% for V₅, and 89.6% for V₆.

Scheme 3. Reagents and conditions: (a) Zn (containing 10% HgCl₂), concentrated. HCl, 1,4-dioxane, 20 °C, 2 h, chromatography, 74.0% for 5; (b) K₂CO₃, cat. KI, 3b, 60 °C, 12 h, chromatography, 82.1% for V₇.

Scheme 4. Reagents and conditions: (a) ClCH₂COCl, Py, THF, rt, 4 h, 96.2% for 6; (b), Et₃N, THF, refluxing, 10 h, 89.2% for 7; (c) K₂CO₃, cat. KI, 3b or 3c, 60 °C, 12 h, chromatography, 81.6% for V₈ and 86.6% for V₉.

Table 1. Anti-inflammatory activities of GA derivatives against xylene-induced ear edema in mice*,†.

Compd.	Dose mg/kg	Edema weight (X ± SD mg)	Inhibitory rate (%)
CMC-Na	–	12.0 ± 1.8	0
V1	28.9	8.8 ± 2.6	26.7
V2	29.4	7.9 ± 2.3‡	34.2
V3	30.0	5.3 ± 1.9¶	55.6
V4	30.6	4.7 ± 1.0¶	60.7
V5	31.1	6.4 ± 1.3¶	47.0
V6	31.7	5.3 ± 1.1¶	56.1
V7	28.9	7.3 ± 1.5¶	39.4
V8	34.5	5.9 ± 1.2¶	50.3
V9	35.0	5.0 ± 1.8¶	58.4
GA	18.8	7.5 ± 1.3¶	37.8
Aspirin	200	7.1 ± 1.0¶	41.0
ADT-OH	9.1	8.4 ± 1.8	30.0

*All compounds were dissolved in 0.5% CMC –Na and administered orally at the dose of 40 μmol/kg except aspirin group at the dose of 200 mg/kg.

† Ten animals were used in each group (n = 10) and data were represented as mean ± SD.

‡ Compare to CMC–Na group, p < 0.05.

¶ Compare to CMC–Na group, p < 0.01.

Table 2. Antiproliferation of GA derivatives v*,†.

	Cancer cell line (IC50, μM)
Compd.	Hep G2	DU-145	MDA-MB-231
V1	>100	21.59 ± 3.22	24.66 ± 2.71
V2	>100	>100	89.40 ± 2.85
V3	>100	>100	>100
V4	10.01 ± 2.29	11.96 ± 1.42	17.80 ± 1.76
V5	>100	>100	79.30 ± 2.34
V6	36.37 ± 1.89	>100	40.65 ± 2.11
V7	>100	>100	>100
V8	>100	>100	>100
V9	>100	>100	>100
GA	74.35 ± 2.03	69.40 ± 2.37	72.65 ± 1.67
ADT-OH	>100	>100	>100

*IC₅₀ was the concentration in μM that inhibited human tumor cell growth by 50% in 48 h compared with cells that remained untreated.

† Each compound were tested three independent MTT assays (n  =  3) and data were represented as mean ± SD.