Synthesis and Antitumor Activity of N9 Position Aromatic Substituted Purine-8-one Derivatives†

doi:10.7503/cjcu20180573

Abstract

Abstract:

A series of novel N9 position aromatic substituted purine-8-one derivatives was synthesized and the antitumor activities were evaluated in vitro. Chemical structures of target compounds were confirmed by means of nuclear magnetic resonance(NMR) and high resolution mass spectroscopy(HRMS). The antiproliferative acti-vities of target compounds were tested on a panel of tumor cell lines using thiazolyl blue tetrazolium bromide(MTT) assay. The results revealed that the substitutions on C2 and N9 position had great impacts on antitumor activities. Moreover, introducing aniline attached six-member ring on C2 position or p-CF₃ on N9 position could improve the antitumor activities. Importantly, the most potent compound 12c exhibited better inhibitory activities than R-Roscovitine against four tumor cell lines, including human leukemia cell lines(K562), human prostatic carcinoma cell lines(PC-3), human breast cancer cell lines(MDA-MB-231) and human colon cancer cell lines(HCT116).

Key words: Purine derivative, Synthesis, Antitumor activity

CLC Number:

O625

TrendMD:

LÜ Mingjun,LI Wen,YANG Xinying,FANG Hao. Synthesis and Antitumor Activity of N9 Position Aromatic Substituted Purine-8-one Derivatives^†[J]. Chem. J. Chinese Universities, 2019, 40(2): 254.

Figures/Tables 7

References 21

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Compd.	ESI-MS(calcd.), m/z[M+H]⁺	Compd.	ESI-MS(calcd.), m/z[M+H]⁺
2a	251.05(251.03)	3d	277.11(277.12)
2b	265.06(265.04)	3e	289.07(289.05)
2c	293.13(293.08)	6a	207.05(207.11)
2d	307.11(307.10)	6b	209.05(209.09)
2e	319.01(319.02)	6c	236.12(236.14)
3a	221.03(221.06)	7a	177.05(177.14)
3b	235.02(235.07)	7b	179.02(179.12)
3c	263.07(263.10)	7c	206.10(206.16)

Compd.	ESI-MS(calcd.), m/z[M+H]⁺	Compd.	ESI-MS(calcd.), m/z[M+H]⁺
2a	251.05(251.03)	3d	277.11(277.12)
2b	265.06(265.04)	3e	289.07(289.05)
2c	293.13(293.08)	6a	207.05(207.11)
2d	307.11(307.10)	6b	209.05(209.09)
2e	319.01(319.02)	6c	236.12(236.14)
3a	221.03(221.06)	7a	177.05(177.14)
3b	235.02(235.07)	7b	179.02(179.12)
3c	263.07(263.10)	7c	206.10(206.16)

Compd.	Appearance	Yield(%)	m.p./℃	ESI-MS(calcd.), m/z[M-H]^-	¹H NMR(400 MHz), δ
4a	Yellow solid	92	>280	245.09(245.02)	8.20(s, 1H, pyrimidine H), 7.49(d, J=7.3 Hz, 2H, PhH), 7.36(d, J=7.3 Hz, 2H, PhH), 2.43(s, 3H, CH₃)
4b	Yellow solid	98	>280	259.14(259.04)	8.20(s, 1H, pyrimidine H), 7.49(d, J=7.3 Hz, 2H, PhH), 7.36(d, J=7.3 Hz, 2H, PhH), 2.43(s, 3H, CH₃)
4c	Yellow solid	90	267—269	287.20(287.07)	11.83(s, 1H, NH), 8.24(s, 1H, pyrimidine H), 7.54—7.40(m, 4H, PhH), 2.99(Hept, J=6.8 Hz, 1H, CH), 1.26[d, J=6.9 Hz, 6H, (CH₃)₂]
4d	Gray solid	94	266—268	301.14(301.08)	10.37(s, 1H, NH), 8.25(s, 1H, pyrimidine H), 7.60(d, J=8.6 Hz, 2H, PhH), 7.54(d, J=8.7 Hz, 2H, PhH), 1.38[s, 9H, C(CH₃)₃]
4e	Gray solid	90	218—220	313.11(313.01)	9.64(s, 1H, NH), 8.29(s, 1H, pyrimidine H), 7.87(m, 4H, PhH)

Compd.	Appearance	Yield(%)	m.p./℃	ESI-MS(calcd.), m/z[M-H]^-	¹H NMR(400 MHz), δ
4a	Yellow solid	92	>280	245.09(245.02)	8.20(s, 1H, pyrimidine H), 7.49(d, J=7.3 Hz, 2H, PhH), 7.36(d, J=7.3 Hz, 2H, PhH), 2.43(s, 3H, CH₃)
4b	Yellow solid	98	>280	259.14(259.04)	8.20(s, 1H, pyrimidine H), 7.49(d, J=7.3 Hz, 2H, PhH), 7.36(d, J=7.3 Hz, 2H, PhH), 2.43(s, 3H, CH₃)
4c	Yellow solid	90	267—269	287.20(287.07)	11.83(s, 1H, NH), 8.24(s, 1H, pyrimidine H), 7.54—7.40(m, 4H, PhH), 2.99(Hept, J=6.8 Hz, 1H, CH), 1.26[d, J=6.9 Hz, 6H, (CH₃)₂]
4d	Gray solid	94	266—268	301.14(301.08)	10.37(s, 1H, NH), 8.25(s, 1H, pyrimidine H), 7.60(d, J=8.6 Hz, 2H, PhH), 7.54(d, J=8.7 Hz, 2H, PhH), 1.38[s, 9H, C(CH₃)₃]
4e	Gray solid	90	218—220	313.11(313.01)	9.64(s, 1H, NH), 8.29(s, 1H, pyrimidine H), 7.87(m, 4H, PhH)

Compd.	Appearance	Yield(%)	m.p./℃	HRMS(calcd.), m/z[M+H]⁺
8a	Gray solid	54	>280	387.1941(387.1928)
8b	Gray solid	58	>280	389.1730(389.1721)
8c	Gray solid	46	244—246	416.2205(416.2193)
8d	Yellowsolid	51	>280	346.1675(346.1662)
8f	Yellow solid	37	>280	382.0984(382.0968)
9a	Gray solid	40	245—247	401.2095(401.2084)
9b	Yellow solid	58	270—272	403.1889(403.1877)
9c	Gray solid	28	246—248	430.2364(430.2350)
9d	White solid	53	276—278	360.1836(360.1819)
9e	Gray solid	40	264—266	361.1769(361.1771)
9f	White solid	33	>280	396.1148(396.1125)
10a	Gray solid	42	252—254	429.2401(429.2397)
10b	White solid	63	259—261	431.2209(431.2190)
10c	Gray solid	51	>280	458.2681(458.2663)
10d	White solid	43	260—262	388.2145(388.2132)
10e	Gray solid	51	242—244	389.2086(389.2084)
10f	White solid	28	>280	424.1456(424.1438)
11a	Gray solid	59	>280	443.2556(443.2554)
11b	White solid	54	>280	445.2369(445.2347)
11c	Gray solid	41	260—262	472.2836(472.2819)
11d	White solid	50	254—256	402.2301(402.2288)
11e	Gray solid	53	264—266	403.2241(403.2241)
11f	White solid	15	>280	438.1616(438.1594)
12a	Gray solid	40	>280	455.1811(455.1802)
12b	Gray solid	45	>280	457.1604(457.1594)
12c	Gray solid	29	>280	484.2090(484.2067)
12d	White solid	36	>280	414.1535(414.1536)
12e	Gray solid	48	>280	415.1490(415.1489)
12f	White solid	56	>280	450.0863(450.0842)