Table 1.

Experimental and computational Mcl-1 and Bcl-x_L inhibitory profiles of first generation inhibitors. Experimental data determined by a fluorescence polarization competition assay.

Compound	R1	R2	Mcl-1 Ki (μM)a	Bcl-xL Ki (μM)a	Selectivity	Mcl-1 LGFE (kcal mol-1)	Bcl-xL LGFE (kcal mol-1)
3a	4-Br-C6H4	H	2.76 ± 1.26	51.4 ± 31.3	19	-39	-36
3b	H	H	99.0 ± 11.2	NA		-31
3c	Bn	H	56.3 ± 2.1	NA		-39
3d	CH2-(2-Cl-C6H4)	H	50.3 ± 11.8	-	-	-37
3e	CH2-(3-Cl-C6H4)	H	5.03 ± 2.78	-	-	-39
3f	CH2-(4-Cl-C6H4)	H	21.0 ± 3.9	338 ± 203	16	-41	-39
3g	CH2-C6H11	H	7.31 ± 1.42	77.6 ± 14.3	11	-42	-41
3h	Me	Me	25.7 ± 4.86	NA		-36
3i	-CH2CH2CH2CH2CH2-		2.95 ± 0.43	-		-43
3j	-CH2CH2N(Ph)CH2CH2-		4.54 ± 3.86	-		-45
3k	-CH2CH2N(Bn)CH2CH2-		3.41 ± 0.37	-		-34
3l	Ph	H	106 ± 26	NA		-37
3m	2-Br-C6H5	H	6.84 ± 2.23	-		-37
3n	3-Br-C6H5	H	5.64 ± 1.76	-		-39
3o	2,4-di-Br-C6H4	H	0.420 ± 0.163	2.31 ± 1.35	5.5	-39	-38
3p	1-Naphthyl	H	11.2 ± 2.0	110 ± 45	10	-40	-38
3q	2-Naphthyl	H	4.58 ± 1.56	68.5 ± 36.3	15	-39	-37
3r	2-Ph-C6H4	H	8.50 ± 1.34	-		-43
3s	3-Ph-C6H4	H	1.88 ± 0.62			-41
3t	4-Ph-C6H4	H	1.54 ± 0.46	-		-44
3u	2-CF3-C6H4	H	4.05 ± 2.11	19.3 ± 9.0	4.8	-42	-41
3v	4-Cl-C6H4	H	1.91 ± 0.26	-		-40
3w	4-CF3-C6H4	H	2.50 ± 0.65	-		-43
3x	4-Me-C6H4	H	34.3 ± 1.0	-		-39
3y	4-(iPr)-C6H4	H	3.86 ± 1.53	-		-42
3z	4-OMe-C6H4	H	11.9 ± 2.5	71.9 ± 21.0	6	-38	-36
3aa	4-(OiPr)-C6H4	H	54.0 ± 4.6	NA		-41
3ab	4-CN-C6H4	H	22.2 ± 1.6	-		-37
3ac	4-NO2-C6H4	H	4.49 ± 1.20	23.3 ± 2.5	5.2	-39	-38
3ad	3-CN-C6H4	H	26.9 ± 0.6			-36

^aK_i values determined by Nikolovska-Coleska equation from IC₅₀ values.⁵⁰ Data represent the average of at least two independent assays; errors are standard deviations.

^bSelectivity is defined as the K_i (Bcl-x_L) divided by the K_i (Mcl-1). NA, no activity.