Heterocycle-containing tranylcypromine derivatives endowed with high anti-LSD1 activity

Figures & data

Figure 1. TCP-based LSD1 inhibitors disclosed by us.

Figure 2. Novel TCP-based analogs as LSD1 inhibitors 1 b-6.

Scheme 1. Synthesis of the N-(4-(2-aminocyclopropyl)phenyl)-(hetero)aryl-4- and 3-carboxamides 1 b-6. Reagents and conditions: (a) PyBop, Et₃N, dry DMF, N₂ atmosphere, overnight, rt. (b) 4 N HCl, dry dioxane/THF, overnight, rt.

Figure 3. Representative samples of thermal shifts by ThermoFAD assay (A) and FAD spectral bleaching (B) for selected compounds. LC305 is the code for the LSD1-CoREST complex.

Table 1. ThermoFAD assay and inhibition values (IC₅₀ values) of 1 b-6 vs LSD1-CoREST complex.

Lab code	compd	LSD1-CoREST
		Thermal shift, °C	IC50, μM^a
MC2652	1a	+ 6.5	0.190 ± 0.030
MC3993	1b	+ 8.0	0.149 ± 0.043
MC4014	2a	+ 7.0	2.001 ± 0.528
MC4032	2b	+ 8.0	0.110 ± 0.044
MC4022	3a	+ 6.5	2.343 ± 0.225
MC4024	3b	+ 8.0	0.221 ± 0.023
MC3995	4a	+ 6.5	1.077 ± 0.359
MC3994	4b	+ 8.0	0.015 ± 0.003
MC4030	5a	+ 5.0	0.341 ± 0.106
MC4025	5b	+ 7.5	0.005 ± 0.0008
MC4031	6a	+ 7.0	13.94 ± 3.06
MC4036	6b	+ 8.0	0.572 ± 0.157
	TCP	+ 6.5	40.82 ± 3.11

TCP and 1a were used as reference compounds.

^aEach IC₅₀ value is the mean ± SD from two experiments in duplicate.

Figure 4. Inhibition curves of 1 b-6 against LSD1-CoREST. Compound 1a has been reported for comparison purpose.

Table 2. Anti-MAO activities of 1 b-6.^a

Lab code	compd	IC50, μM		MAO Selectivity Index^b
		MAO-A	MAO-B
MC3993	1b	0.028 ± 0.002	0.327 ± 0.028	11.7
MC4014	2a	0.043 ± 0.004	0.073 ± 0.006	1.7
MC4032	2b	0.093 ± 0.008	0.888 ± 0.077	9.5
MC4022	3a	0.160 ± 0.014	0.093 ± 0.008	0.6
MC4024	3b	1.120 ± 0.097	0.519 ± 0.036	0.5
MC3995	4a	0.025 ± 0.002	0.032 ± 0.003	1.3
MC3994	4b	0.024 ± 0.002	0.366 ± 0.032	15.3
MC4030	5a	0.042 ± 0.004	0.067 ± 0.006	1.6
MC4025	5b	0.028 ± 0.002	0.820 ± 0.071	29.3
MC4031	6a	0.069 ± 0.006	0.358 ± 0.031	5.2
MC4036	6b	0.159 ± 0.014	10.42 ± 0.30	66
	clorgyline	0.005 ± 0.0009	63.41 ± 1.20	12,682
	R-(-)-deprenyl	68.73 ± 4.21	0.017 ± 0.002	0.0002

^aEach IC₅₀ value is the mean ± SD from three experiments (n = 3).

^bIC₅₀^MAO-B/IC₅₀^MAO-A.

Table 3. LSD1 selectivity over MAOs.

Lab code	compd	LSD1 selectivity vs MAO-A^a	LSD1 selectivity vs MAO-B^b
MC3993	1b	0.2	2.2
MC4032	2b	0.8	8.1
MC4024	3b	5.1	2.3
MC3994	4b	1.6	24.4
MC4025	5b	5.6	164.0
MC4036	6b	0.3	18.2

^aIC₅₀^MAO-A/IC₅₀^LSD1.

^bIC₅₀^MAO-B/IC₅₀^LSD1.

Table 4. Effects of 1a,b, 2 b, 3 b, 4 b, and 5a,b on cell viability in U937 cells after 48 and 72 h of treatment.

48 h
72 h

Table 5. Effects of 1a,b, 2 b, 3 b, 4 b, and 5a,b on cell viability in LNCaP cells after 48 and 72 h of treatment.

48 h
72 h

Table 6. IC₅₀ values of 1a,b, 2 b, 3 b, 4 b, and 5a,b in LNCaP cells. For comparison, the IC₅₀ (72 h) of the selective MAO-A inhibitor clorgyline has been added.

Compd	LNCaP cells, IC50 (μM)
	48 h	72 h
1a	34.1 ± 13.2	25.4 ± 3.2
1b	22.8 ± 5.1	9.9 ± 1.7
2b	27.6 ± 9.8	18.5 ± 2.7
3b	12.4 ± 6.1	13.4 ± 3.7
4b	25.7 ± 8.3	15.2 ± 3.5
5a	26.5 ± 4.8	17.9 ± 1.6
5b	32.1 ± 7.8	17.2 ± 3.5
clorgyline		63.7 ± 8.2^a

^aRef. 30.

Figure 5. Western blot analyses of the H3K4me2 levels in U937 cells (A) and of H3K4me2 and H3K9me2 levels in LNCaP cells (B).

Gaur S, Gross ME, Liao CP, et al. Effect of monoamine oxidase A (MAOA) inhibitors on androgen-sensitive and castration-resistant prostate cancer cells. Prostate 2019;79:667–77.

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