Synthesis and Antitumor Activity of Novel Pyrimidine Monocyclic Nonclassical Antifolates

doi:10.6023/cjoc202007006

Abstract

Regarding the nonclassical antifolates 6-(4'-methylphenethyl)-5-chloroacetyl-5,6,7,8-tetrahydropyrido[3,2-d]pyri- midine (wm-8.2) as the lead compound, in order to improve molecular flexibility and simplify molecular structure, two series of compounds were designed and synthesized according to the 6-H and 6-methyl group. And the effects of carbon chain length and aromatic heterocyclic side chain on antitumor activity were investgated. Besides, the activities of key intermediates with molecular skeleton of folic acid inhibitor were measured to study the effect of the chloroacetyl group at N(5) position. Structures of 36 target compounds and key intermediates were confirmed by ¹H NMR, ¹³C NMR and MS. The biological activity results showed that 6-methyl-2,4-diamino-5-(N-(4-methylphenyl)propyl-N-(2-chloroacetyl))aminopyrimidine (6b-3), which had three-carbon bridge and p-methylbenzene ring side chain, exhibited the best inhibition activities against HL-60, A549 and HCT116 cells with IC₅₀ values as 0.25, 0.83 and 0.63 μmol?L ^–1 respectively. 6-Methyl-2,4-diamino-5-(N-(4-methylphenyl)- propyl)aminopyrimidine (5b-3), the key intermediate of 6b-3, showed excellent dihydrofolate reductase inhibitory activity. Molecular docking studies further explored the structure-activity relationship and possible causes of the difference inhibitory activity against dihydrofolate reductase.

Key words: nonclassical antifolate, novel pyrimidine monocyclic derivative, antitumor activity, dihydrofolate reductase inhibitory activity, molecular docking

Cite this article

Jing Cong, Fang Fang, Liangmin Xue, Meng Wang, Chao Tian, Xiaowei Wang, Junyi Liu, Zhili Zhang. Synthesis and Antitumor Activity of Novel Pyrimidine Monocyclic Nonclassical Antifolates[J]. Chinese Journal of Organic Chemistry, 2021, 41(2): 776-787.

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Compd.	n	IC₅₀/(μmol?L^–1)^a
Compd.	n	A549	HCT-116	HL-60
6a-1	1	10.44±3.29	3.72±0.08	5.24±0.34
6a-2	2	2.93±0.35	2.37±0.03	1.25±0.25
6a-3	3	2.62±0.42	0.98±0.34	0.60±0.01
6a-4	4	2.42±0.32	2.16±0.20	3.24±0.02
6b-1	1	18.35±2.45	3.88±0.24	1.65±0.23
6b-2	2	2.18±0.34	1.47±0.23	0.54±0.03
6b-3	3	0.83±0.13	0.63±0.08	0.25±0.08
6b-4	4	2.42±0.32	1.19±0.20	0.84±0.10
6a-5	2	8.24±2.45	1.57±0.35	0.92±0.23
6a-6	3	3.20±0.35	1.04±0.09	1.03±0.34
6b-5	2	2.34±0.23	0.99±0.39	1.43±0.43
6b-6	3	2.31±0.23	0.86±0.16	1.12±0.22
6a-7	1	29.98±0.97	9.32±0.93	10.99±0.99
6a-8	1	31.26±0.86	14.23±1.32	19.44±2.14
6a-9	1	48.46±3.21	9.83±0.92	34.24±2.15
6b-7	1	19.33±3.45	3.23±0.23	8.17±0.1
6b-8	1	26.42±2.26	10.33±0.89	8.93±0.94
6b-9	1	43.41±4.49	4.24±0.99	14.98±2.88
5a-1	1	>100	>100	74.10±2.14
5a-2	2	28.04±0.42	>100	17.37±0.98
5a-3	3	18.51±0.44	29.40±3.87	12.68±0.97
5a-4	4	16.64±1.61	>100	15.95±0.35
5b-1	1	61.26±1.72	>100	14.59±1.12
5b-2	2	3.64±0.58	10.23+0.55	3.31±0.02
5b-3	3	4.00±0.33	14.18±1.69	3.72±0.82
5b-4	4	7.10±1.04	>100	6.83±0.98
5a-5	2	19.24±0.98	34.26±1.24	38.24±0.23
5a-6	3	20.24±0.25	36.24±3.52	23.25±0.72
5b-5	2	10.24±0.24	19.43±0.48	13.53±0.92
5b-6	3	6.24±0.22	15.42±0.29	10.09±0.94
5a-7	1	18.42±0.24	25.26±0.92	32.42±2.58
5a-8	1	29.35±0.24	33.35±0.75	12.45±1.31
5a-9	1	23.25±2.34	28.45±2.32	23.12±2.15
5b-7	1	34.24±2.59	20.24±0.14	8.18±0.18
5b-8	1	43.25±0.33	36.25±0.96	14.24±0.34
5b-9	1	38.24±0.97	21.82±0.88	9.44±0.02
MTX		9.04±0.46	7.12±0.58	0.04±0.01
wm-8.2		0.28±0.03	0.82±0.02	1.08±0.03

Compd.	n	IC₅₀/(μmol?L^–1)^a
Compd.	n	A549	HCT-116	HL-60
6a-1	1	10.44±3.29	3.72±0.08	5.24±0.34
6a-2	2	2.93±0.35	2.37±0.03	1.25±0.25
6a-3	3	2.62±0.42	0.98±0.34	0.60±0.01
6a-4	4	2.42±0.32	2.16±0.20	3.24±0.02
6b-1	1	18.35±2.45	3.88±0.24	1.65±0.23
6b-2	2	2.18±0.34	1.47±0.23	0.54±0.03
6b-3	3	0.83±0.13	0.63±0.08	0.25±0.08
6b-4	4	2.42±0.32	1.19±0.20	0.84±0.10
6a-5	2	8.24±2.45	1.57±0.35	0.92±0.23
6a-6	3	3.20±0.35	1.04±0.09	1.03±0.34
6b-5	2	2.34±0.23	0.99±0.39	1.43±0.43
6b-6	3	2.31±0.23	0.86±0.16	1.12±0.22
6a-7	1	29.98±0.97	9.32±0.93	10.99±0.99
6a-8	1	31.26±0.86	14.23±1.32	19.44±2.14
6a-9	1	48.46±3.21	9.83±0.92	34.24±2.15
6b-7	1	19.33±3.45	3.23±0.23	8.17±0.1
6b-8	1	26.42±2.26	10.33±0.89	8.93±0.94
6b-9	1	43.41±4.49	4.24±0.99	14.98±2.88
5a-1	1	>100	>100	74.10±2.14
5a-2	2	28.04±0.42	>100	17.37±0.98
5a-3	3	18.51±0.44	29.40±3.87	12.68±0.97
5a-4	4	16.64±1.61	>100	15.95±0.35
5b-1	1	61.26±1.72	>100	14.59±1.12
5b-2	2	3.64±0.58	10.23+0.55	3.31±0.02
5b-3	3	4.00±0.33	14.18±1.69	3.72±0.82
5b-4	4	7.10±1.04	>100	6.83±0.98
5a-5	2	19.24±0.98	34.26±1.24	38.24±0.23
5a-6	3	20.24±0.25	36.24±3.52	23.25±0.72
5b-5	2	10.24±0.24	19.43±0.48	13.53±0.92
5b-6	3	6.24±0.22	15.42±0.29	10.09±0.94
5a-7	1	18.42±0.24	25.26±0.92	32.42±2.58
5a-8	1	29.35±0.24	33.35±0.75	12.45±1.31
5a-9	1	23.25±2.34	28.45±2.32	23.12±2.15
5b-7	1	34.24±2.59	20.24±0.14	8.18±0.18
5b-8	1	43.25±0.33	36.25±0.96	14.24±0.34
5b-9	1	38.24±0.97	21.82±0.88	9.44±0.02
MTX		9.04±0.46	7.12±0.58	0.04±0.01
wm-8.2		0.28±0.03	0.82±0.02	1.08±0.03

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