Synthesis and anticancer and lipophilic properties of 10-dialkylaminobutynyl derivatives of 1,8- and 2,7-diazaphenothiazines

Figures & data

Scheme 1. Synthesis of 10-dialkylaminobutynyl 1,8- and 2,7-diazaphenothiazines (3–9)AB and the structures of promazine and prothipendyl.

Table 1. Anticancer activities IC₅₀ (μg/ml) of 10-substituted 1,8-diazaphenothiazines (2–9)a and 2,7-diazaphenothiazines (2–9)B.

	Anticancer activity IC50 (μg/ml)
No.	SNB-19	C-32	T47D
2A	>50	>50	>50
3A	>50	26.6 ± 1.1	>50
4A	>50	26.1 ± 6.1	>50
5A	36.1 ± 7.7	37.0 ± 2.3	>50
6A	31.9 ± 9.9	35.4 ± 7.4	45.0 ± 4.3
7A	>50	>50	>50
8A	>50	>50	>50
9A	33.1 ± 2.9	27.5 ± 2.8	45.8 ± 4.9
2B	>50	>50	>50
3B	36.2 ± 3.3	29.2 ± 2.7	>50
4B	39.0 ± 3.5	25.0 ± 7.8	40.5 ± 9.7
5B	36.9 ± 1.9	35.1 ± 1.8	34.1 ± 3.2
6B	35.6 ± 3.1	24.8 ± 1.7	41.1 ± 4.9
7B	42.4 ± 5.1	40.6 ± 3.9	>50
8B	21.2 ± 2.3	35.0 ± 2.6	9.6 ± 2.2
9B	35.1 ± 4.6	36.1 ± 4.1	46.4 ± 4.4
Prothipendyl	36.6 ± 9.1	28.1 ± 6.8	32.3 ± 6.2
Cisplatin	7.7  ± 1.5	7.8 ± 1.3	46.9 ± 2.7

Table 2. The influence of compound 8B on expression of genes encoding TP53, CDKN1A, BCL-2, BAX in glioblastoma SNB-19, melanoma C-32 and ductal carcinoma T47D cells.

		number of mRNA copies/μg total RNA
Gene		SNB-19	C-32	T47D
TP53	Control	1218 ± 284	944 ± 171	100745 ± 30542
	8B	20209 ± 697	475 ± 129	110117 ± 18230
CDKN1A	Control	3184 ± 301	1304 ± 246	17642 ± 2327
	8B	5850 ± 422	1206 ± 351	31258 ± 1265
BCL-2	Control	2795 ± 410	13413 ± 3549	1080 ± 34
	8B	6949 ± 668	17203 ± 964	298 ± 11
BAX	Control	29678 ± 5198	2452 ± 563	26727 ± 4060
	8B	55650 ± 10542	1528 ± 429	20850 ± 5979
BCL-2/BAX	Control	0.09	5.47	0.02
	8B	0.12	11.26	0.04

Table 3. The R_M0, logP_TLC values and b (slope) and r (correlation coefficient) of the equation R_M = R_M0 + bC for diazaphenothiazines (2–9)A,B.

No	−b	RM0	r	logPTLC	No	−b	RM0	r	logPTLC
2A	0.0293	1.997	0.994	2.18652	2B	0.024	1.454	0.984	1.654
3A	0.016	0.704	0.989	0.920	3B	0.017	0.753	0.991	0.968
4A	0.016	0.746	0.996	0.961	4B	0.018	0.824	0.994	1.037
5A	0.022	1.023	0.988	1.232	5B	0.019	1.317	0.989	1.520
6A	0.021	1.143	0.989	1.350	6B	0.025	1.325	0.985	1.528
7A	0.019	1.313	0.996	1.516	7B	0.020	1.431	0.989	1.632
8A	0.029	2.027	0.997	2.215	8B	0.025	2.047	0.993	2.235
9A	0.033	2.261	0.987	2.447	9B	0.032	2.464	0.981	2.644

Table 4. The correlation between the anticancer activities IC₅₀ and the logP values for diazaphenothiazines (2–9)A,B.

No	Cell line	Equation	r
(3–9)A	SNB-19	IC50 = −109.0logP^2 + 353.9logP − 50.9	0.141
(3–9)B	SNB-19	IC50 = −4.462logP^2 + 8.889logP + 33.70	0.552
(3–9)A	C-32	IC50 = −114.1logP^2 + 535.5logP − 415.6	0.539
(3–9)B	C-32	IC50 = −5.736logP^2 + 25.84logP + 6.931	0.625
(3–9)A	T47D	IC50 = 227.4logP^2 − 822.6logP + 783.6	0.531
(3–9)B	T47D	IC50 = 22.87logP^2 − 97.18logP + 134.2	0.615

Vaštag D, Perišić-Janjić N, Tomić J, Petrović S. Evaluation of the lipophilicity and prediction of biological activity of some N-cyclohexyl-N-substituted-2-phenylacetamide derivatives using RP-TLC. J Planar Chromatog 2011;24:435–40

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