Design and synthesis of benzopyran-based inhibitors of the hypoxia-inducible factor-1 pathway with improved water solubility

Figures & data

Figure 1. Lead compounds 1 (KCN1) and 2 (64b).

Figure 2. Classes of analogs. (A) Class A, morpholinomethylphenyl in ortho, meta, or para positions, or morpholinophenyl in para position; (B) Class B, morpholinomethylphenyl in ortho, meta, or para positions, or morpholinophenyl in para position; (C) Class C, n = 2 or 3; (D) Class D.

Table 1. Structures, HRE-luciferase reporter inhibitory activity, cLog D, and cLog S of analogs.

Compound	Structure	IC50 (μM)	cLog D	cLog S
1		∼0.6	4.99	−6.37
2		∼0.3	3.34	−4.53
3a		0.9	3.69	−4.39
3b		>5	3.71	−4.41
3c		>5	3.80	−4.50
3d		3.8	3.98	−5.19
4a		1.0	2.94	−3.36
4b		>5	2.96	−3.38
4c		>5	3.05	−3.47
4d		2.6	3.24	−4.15
5a		>5	3.13	−4.23
5b		>5	3.17	−4.37
6a		>5	2.97	−5.17
6b		>5	2.22	−4.12

Scheme 1. Synthesis of Class A & B compounds. (A) Synthesis of precursors. (B) Synthesis of Class A. (C) Synthesis of Class B. Reagents and conditions: (a) morpholine, K₂CO₃, ACN, room temperature, overnight; (b) BuLi, DMF, THF, −78 °C, 1 h; (c) aniline, InCl₃, NaBH₄, ACN, 20 min; (d) 3,4-dimethoxybenzenesulfonyl chloride, K₂CO₃, DCM, overnight; (e) cyclobutylamine, NaBH₄, MeOH, overnight.

Scheme 2. Synthesis of Class C compounds. Reagents and conditions: (a) amine, NaBH₄, MeOH, overnight; (b) 3,4-dimethoxybenzenesulfonyl chloride, K₂CO₃, DCM, overnight.

Scheme 3. Synthesis of Class D compounds. Reagents and conditions: (a) aniline, InCl₃, NaBH₄, ACN, 20 min or cyclobutylamine, NaBH₄, MeOH, overnight; (b) 4-morpholinosulfonyl chloride, pyridine, DCE, reflux 2 days.

Figure 3. Structures of compounds used for dynamic light scattering.

Table 2. Measured solubility of selected compounds.

Name	Concentration of particle appearance in water (μM)	Concentration of particle appearance in PBS (μM)
1	1	1
2	10	10
3a	10	15
4a	>100	>50