. Author manuscript; available in PMC: 2022 Apr 13.

Published in final edited form as: J Med Chem. 2020 Oct 29;63(21):12957–12977. doi: 10.1021/acs.jmedchem.0c01398

Table 4.

Linker Fluorination and Pyridine Methylation


Compound	R	GLS IC₅₀ (nM)^a	A549 IC₅₀ (nM)^b	Microsomal Stability (mL/min/kg)^c		pH 7 Solubility (μM)
Compound	R	GLS IC₅₀ (nM)^a	A549 IC₅₀ (nM)^b	Hum	Rat	pH 7 Solubility (μM)
21		32	101	1	1	115^d
22 (enantiomer of 21)		62	208	4	2	ND
23		44	78	0.2	23	63^e
24		25	24	4	14	37^e
25		10	1	13	12	0.2^e
26		21	17	4	8	5^e
27		31	26	0.7	19	40^e

Inhibition of purified recombinant human GLS-1 (GAC isoform) assessed via a dual-coupled enzyme assay. IC₅₀ values are reported as the mean of at least three determinations. Standard deviations and counts are included in the supporting information.

Inhibition of proliferation of A549 cells. IC₅₀ values are reported as the mean of at least three determinations. Standard deviations and counts are included in the supporting information.

Liver microsomal intrinsic clearance (mL/min/kg protein).

Kinetic aqueous solubility (μM) in phosphate buffer (100 mM) at pH 7.4; shaken for 1 hour at RT.

Thermodynamic aqueous solubility (μM) in phosphate buffer (100 mM) at pH 7.0; shaken for 1 hour then equilibrated overnight at RT.