Syntheses and Antitumor Activities of Purine-sulfonamides Derivatives†

doi:10.7503/cjcu20131048

Abstract

Abstract:

As a new type of purine derivative, Roscovitine exhibits good antiproliferative activities to different types of tumor cell lines and currently has been investigated in Phase Ⅱ clinical trial. Previous structure-acti-vity relationship studies on Roscovitine suggested that the modification on C2, C6 and N9 positions of purine could significantly influence the antitumor acitivities. In this work, a biologically active fragment benzenesulfonamide was introduced to purine C2 position and totally 25 new purine-sulfonamides derivatives were synthesized and evaluated antiproliferative activities in some tumor cell lines by MTT assay. The results show that the substitutions on C2, N6 and N9 positions of purine have a great impact on antitumor activity. And introducing phenylsulfonyl piperazine on C2 position of purine could obviously enhance antiproliferative activities. Among them, compound 17d shows similar inhibitory activities against PC-3, HCT116 and K562 tumor cell lines compared with Roscovitine.

Key words: Purine derivative, Sulfonamide, Antitumor activity

CLC Number:

O625

TrendMD:

WANG Junhua, WANG Quande, DUN Yanyan, FANG Hao. Syntheses and Antitumor Activities of Purine-sulfonamides Derivatives^†[J]. Chem. J. Chinese Universities, 2014, 35(6): 1189.

Figures/Tables 8

References 21

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Compd.	m.p./℃	Yield(%)	Appearance	HRMS(calcd.)[M+H]⁺
5a	254(Dec.)	77	White solid	399.1034(399.1034)
5b	258(Dec.)	65	White solid	417.0940(417.0940)
5c	286(Dec.)	82	White solid	465.0955(465.0951)
8a	241—244	32	Light pink solid	459.1406(459.1409)
8b	215—218	24	White solid	491.1468(491.1472)
8c	245—246	60	Light yellow solid	468.1444(468.1449)
8d	206—208	5.5	White solid	453.1703(453.1703)
13a	86—90	39	Light yellow solid	506.2329(506.2333)
13b	80—83	42	Light yellow solid	526.1784(526.1786)
13c	108—111	59	White solid	528.1984(528.1988)
13d	86—88	65	Gray solid	560.2050(560.2050)
13e	226—228	28	Brick red solid	537.2023(537.2027)
13f	81—84	42	Light yellow solid	522.2279(522.2282)
13g	76—78	38	Light yellow solid	576.2000(576.1999)
17a	146—150	11	White solid	512.2803(512.2802)
17b	157—160	19	White solid	532.2254(532.2256)
17c	119—121	16	White solid	516.2548(516.2552)
17d	186—190	42	White solid	534.2454(534.2457)
17e	192—194	67	White solid	566.2520(566.2520)
17f	198—200	48	Yellow solid	543.2494(543.2496)
17g	148—150	15	White solid	528.2748(528.2751)
17h	167—168	59	White solid	582.2468(582.2469)
21a	256(Dec.)	78	White solid	532.2130(532.2137)
21b	275(Dec.)	47	White solid	550.2044(550.2043)
21c	228(Dec.)	91	White solid	544.2326(544.2337)

Compd.	m.p./℃	Yield(%)	Appearance	HRMS(calcd.)[M+H]⁺
5a	254(Dec.)	77	White solid	399.1034(399.1034)
5b	258(Dec.)	65	White solid	417.0940(417.0940)
5c	286(Dec.)	82	White solid	465.0955(465.0951)
8a	241—244	32	Light pink solid	459.1406(459.1409)
8b	215—218	24	White solid	491.1468(491.1472)
8c	245—246	60	Light yellow solid	468.1444(468.1449)
8d	206—208	5.5	White solid	453.1703(453.1703)
13a	86—90	39	Light yellow solid	506.2329(506.2333)
13b	80—83	42	Light yellow solid	526.1784(526.1786)
13c	108—111	59	White solid	528.1984(528.1988)
13d	86—88	65	Gray solid	560.2050(560.2050)
13e	226—228	28	Brick red solid	537.2023(537.2027)
13f	81—84	42	Light yellow solid	522.2279(522.2282)
13g	76—78	38	Light yellow solid	576.2000(576.1999)
17a	146—150	11	White solid	512.2803(512.2802)
17b	157—160	19	White solid	532.2254(532.2256)
17c	119—121	16	White solid	516.2548(516.2552)
17d	186—190	42	White solid	534.2454(534.2457)
17e	192—194	67	White solid	566.2520(566.2520)
17f	198—200	48	Yellow solid	543.2494(543.2496)
17g	148—150	15	White solid	528.2748(528.2751)
17h	167—168	59	White solid	582.2468(582.2469)
21a	256(Dec.)	78	White solid	532.2130(532.2137)
21b	275(Dec.)	47	White solid	550.2044(550.2043)
21c	228(Dec.)	91	White solid	544.2326(544.2337)

Compd.	¹H NMR, δ^a^,^b^,^c	¹³C NMR, δ^d^,^e
5a^a^,^d	4.53(br s, 2H, CH₂), 7.15—7.18(m, 2H, ArH), 7.25—7.30(m, 5H, ArH), 7.90—7.95(m, 3H, ArH, purine C8), 8.25(br s, 1H, NH), 11.08(br s, 1H, SO₂NH), 12.76(br s, 1H, purine C9)	163.78(d,J=249 Hz), 153.33, 152.43, 150.55, 139.54, 138.64, 138.21, 129.80(d, J=5.25 Hz), 128.15, 127.34, 126.71, 115.60(d, J=22.5 Hz), 42.80
5b^a^,^d	4.38(br s, 2H, CH₂), 6.98—7.08(m, 2H, ArH), 7.20—7.27(m, 5H, ArH), 7.41—7.48(m, 1H, ArH), 7.99(s, 1H, purine C8), 8.32(br s, 1H, NH), 11.72(br s, 1H, SO₂NH), 12.84(br s, 1H, purine C9)	158.72(dd,J=4.5, 252.75 Hz), 153.14, 152.40, 149.49, 139.67, 138.64, 133.34, 128.25, 127.68, 126.98, 112,72(d, J=24 Hz), 42.76
5c^a^,^d	4.49(br s, 2H, CH₂), 7.25—7.31(m, 7H, ArH), 7.89—7.99(m, 3H, ArH, purine C8), 8.35(br s, 1H, NH)	153.00, 152.84, 150.13, 141.68, 139.29, 129.19, 128.15, 127.32, 126.72, 120.54, 119.80(q, J=256.5 Hz), 111.54, 42.84
8a^b^,^d	1.36[d, J=6.3 Hz, 6H, (CH₃)₂], 4.47—4.53(m, 3H, CH, CH₂), 7.16(t, J=9.0 Hz, 2H, ArH), 7.20—7.29(m, 5H, ArH), 7.54—7.64(m, 1H, ArH), 8.21(s, 1H, purine C8), 8.46(br s, 1H, NH), 11.74(br s, 1H, SO₂NH)	158.87(d,J=255 Hz), 153.30, 152.63, 148.26, 139.12, 137.45, 134.91, 128.17, 127.52, 126.81, 118.94, 113.06(d, J=24 Hz), 113.05(t, J=11.25 Hz), 47.33, 42.73, 21.56
8b ^b^,^d	1.37[d, J=6.6 Hz, 6H, (CH₃)₂], 4.48—4.54(m, 3H, CH, CH₂), 7.18—7.28(m, 5H, ArH), 7.81(d, J=7.2 Hz, 2H, ArH), 8.05(s, 1H, purine C8), 8.10(d, J=7.2 Hz, 2H, ArH), 8.36(br s, 1H, NH), 11.39(br s, 1H, SO₂NH)	154.12, 151.77, 148.66, 145.29, 139.66, 137.74, 131.94(q, J=31.5 Hz), 128.11, 128.01, 127.25, 126.64, 125.92, 123.43(q, J=271.5 Hz), 115.53, 46.58, 42.71, 21.73
8c^b^,^d	1.41[d, J=6.3 Hz, 6H, (CH₃)₂], 4.50—4.52(m, 3H, CH, CH₂), 7.16—7.22(m, 5H, ArH), 8.05(s, 1H, purine C8), 8.09(d, J=7.2 Hz, 2H, ArH), 8.18(d, J=7.2 Hz, 2H, ArH), 8.36(br s, 1H, NH), 11.49(br s, 1H, SO₂NH)	154.14, 151.62, 149.08, 147.06, 139.51, 137.71, 128.29, 127.95, 126.93, 126.48, 123.97, 115.78, 46.39, 42.59, 21.85
8d ^c^,^d	1.51[d, J=6.6 Hz, 6H, (CH₃)₂], 3.80(s, 3H, OCH₃), 4.63(hept, J=6.6 Hz, 1H, CH), 4.72(br s, 2H, CH₂), 6.52(br s, 1H, NH), 6.81(d, J=9.0 Hz, 2H, ArH), 7.26—7.32(m, 5H, ArH), 7.61(s, 1H, purine C8), 8.01(d, J=9.0 Hz, 2H, ArH), 8.24(br s, 1H, SO₂NH)	162.03, 154.29, 151.94, 149.12, 139.94, 137.41, 132.69, 129.44, 128.01, 127.37, 126.50, 115.84, 113.61, 59.64, 46.24, 42.58, 21.88
Compd.	¹H NMR, δ^a^,^b^,^c	¹³C NMR, δ^d^,^e
13a ^a^,^e	1.42[d, J=6.6 Hz, 6H, (CH₃)₂], 2.37(s, 3H, CH₃), 2.75—2.78(m, 4H, piperazine), 3.74—3.82(m, 4H, piperazine), 4.50—4.52(m, 3H, CH, CH₂), 7.22—7.32(m, 5H, ArH), 7.42(d, J=7.8 Hz, 2H, ArH), 7.58(d, J=7.8 Hz, 2H, ArH), 7.86(s, 1H, purine C8), 8.11(br s, 1H, NH)	158.80, 152.94, 150.20, 143.77, 139.13, 133.86, 132.47, 129.70, 128.31, 127.82, 127.61, 126.91, 109.51, 47.47, 45.85, 44.42, 43.72, 22.12, 21.04
13b ^a^,^e	1.42[d, J=6.6 Hz, 6H, (CH₃)₂], 2.81—2.88(m, 4H, piperazine), 3.75—3.80(m, 4H, piperazine), 4.50—4.55(m, 3H, CH, CH₂), 7.21—7.32(m, 5H, ArH), 7.70(d, J=8.4 Hz, 2H, ArH), 7.72(d, J=8.4 Hz, 2H, ArH), 7.86(s, 1H, purine C8), 8.09(br s, 1H, NH)	158.74, 153.35, 150.50, 139.53, 139.08, 134.13, 133.89, 129.41, 129.15, 128.40, 127.60, 127.04, 111.01, 47.11, 45.79, 44.50, 43.77, 22.30
13c ^a^,^d	1.43[d, J=6.6 Hz, 6H, (CH₃)₂], 2.99—3.13(m, 4H, piperazine), 3.76—3.85(m, 4H, piperazine), 4.49—4.57(m, 3H, CH, CH₂), 7.18—7.35(m, 7H, ArH), 7.75—7.77(m, 1H, ArH), 7.87(s, 1H, purine C8), 8.11(br s, 1H, NH)	158.80(dd,J=3.75, 255 Hz), 157.34, 153.92, 150.21, 140.52, 136.21(t, J=11.25 Hz), 135.99, 127.90, 127.35, 126.37, 113.68(dd, J=3, 23.25 Hz), 113.35, 113.13, 45.67, 44.86, 43.40, 42.62, 21.97
13d ^a^,^d	1.43[d, J=6.6 Hz, 6H, (CH₃)₂], 2.79—3.03(m, 4H, piperazine), 3.71—3.89(m, 4H, piperazine), 4.45—4.61(m, 3H, CH, CH₂), 7.19—7.32(m, 5H, ArH), 7.90(s, 1H, purine C8), 7.94(d, J=7.8 Hz, 2H, ArH), 8.02(d, J=7.8 Hz, 2H, ArH), 8.10(br s, 1H, NH)	157.31, 153.85, 150.20, 140.50, 138.88, 135.99, 132.82(q, J=32.25 Hz), 128.47, 127.99, 127.37, 126.59(q, J=3.75 Hz), 126.40, 123.35(q, J=271.5 Hz), 113.45, 45.77, 45.45, 43.24, 42.65, 21.97
13e^a^,^e	1.42[d, J=6.6 Hz, 6H, (CH₃)₂], 2.87—2.93(m, 4H, piperazine), 3.76—3.80(m, 4H, piperazine), 4.48—4.55(m, 3H, CH, CH₂), 7.21—7.31(m, 5H, ArH), 7.85(s, 1H, purine C8), 7.98(d, J=8.4 Hz, 2H, ArH), 8.10(br s, 1H, NH), 8.41(d, J=8.4 Hz, 2H, ArH)	158.04, 154.34, 150.87, 150.22, 141.82, 139.21, 135.16, 128.89, 128.51, 127.51, 127.18, 124.31, 114.23, 46.42, 45.79, 44.45, 43.86, 22.48
13f ^a^,^e	1.42[d, J=6.6 Hz, 6H, (CH₃)₂], 2.75—2.78(m, 4H, piperazine), 3.75—3.80(m, 4H, piperazine), 4.49—4.52(m, 3H, CH, CH₂), 7.13(d, J=8.4 Hz, 2H, ArH), 7.21—7.33(m, 5H, ArH), 7.64(d, J=8.4 Hz, 2H, ArH), 7.86(s, 1H, purine C8), 8.12(br s, 1H, NH)	163.11, 158.73, 153.25, 150.31, 139.27, 133.92, 129.90, 128.30, 127.62, 127.02, 126.87, 114.24, 110.44, 55.62, 47.16, 45.87, 44.38, 43.72, 22.21
13g ^a^,^e	1.42[d,J=6.6 Hz, 6H, (CH₃)₂], 2.84—2.90(m, 4H, piperazine), 3.76—3.81(m, 4H, piperazine), 4.50—4.56(m, 3H, CH, CH₂), 7.19—7.32(m, 5H, ArH), 7.62(d, J=8.4 Hz, 2H, ArH), 7.86—7.88(m, 3H, purine C8, ArH), 8.10(br s, 1H, NH)	158.68, 153.30, 152.36, 150.30, 139.24, 134.04, 133.96, 129.88, 128.31, 127.59, 126.90, 120.89, 120.19(q, J=258 Hz), 110.60, 47.19, 45.81, 44.40, 43.72, 22.22
17a^c^,^e	0.96—1.01(m, 2H, cyclohexyl), 1.14—1.25(m, 3H, cyclohexyl), 1.51[d, J=6.6 Hz, 6H, (CH₃)₂], 1.57—1.79(m, 6H, cyclohexyl), 2.41(s, 3H, CH₃), 3.04—3.06(m, 4H, piperazine CH₂), 3.35(br s, 2H, CH₂), 3.90—3.92(m, 4H, piperazine CH₂), 4.62(hept, J=6.6 Hz, 1H, CH), 5.68(br s, 1H, NH), 7.30(d, J=8.4 Hz, 2H, ArH), 7.53(s, 1H, purine C8), 7.65(d, J=8.4 Hz, 2H, ArH)	158.30, 154.72, 150.65, 143.67, 134.70, 132.53, 129.65, 127.87, 114.02, 46.65, 46.33, 46.02, 43.85, 38.34, 31.00, 26.45, 25.94, 22.50, 21.50
17b ^a^,^e	0.88—0.90(m, 2H, cyclohexyl), 1.07—1.15(m, 3H, cyclohexyl), 1.46[d, J=6.6 Hz, 6H, (CH₃)₂], 1.57—1.68(m, 6H, cyclohexyl), 2.92—2.98(m, 4H, piperazine), 3.24(br s, 2H, CH₂), 3.78—3.88(m, 4H, piperazine), 4.57(hept, J=6.6 Hz, 1H, CH), 7.45(br s, 1H, NH), 7.71(d, J=8.4 Hz, 2H, ArH), 7.76(d, J=8.4 Hz, 2H, ArH), 7.87(s, 1H, purine C8)	158.22, 154.82, 150.63, 139.47, 134.81, 134.21, 129.37, 129.19, 114.25, 46.68, 46.33, 45.95, 43.84, 38.35, 31.01, 26.45, 25.94, 22.51
17c ^a^,^e	0.88—0.92(m, 2H, cyclohexyl), 1.12—1.19(m, 3H, cyclohexyl), 1.44[d, J=6.6 Hz, 6H, (CH₃)₂], 1.59—1.67(m, 6H, cyclohexyl), 2.91—2.97(m, 4H, piperazine), 3.22(br s, 2H, CH₂), 3.77—3.83(m, 4H, piperazine), 4.54(hept, J=6.6 Hz, 1H, CH), 7.44—7.48(m, 3H, NH, ArH), 7.81—7.84(m, 3H, ArH, purine C8)	165.28(d, J=253.5 Hz), 158.18, 154.74, 134.75, 131.82(d, J=3 Hz), 130.47(d, J=9 Hz), 116.33(d, J=22.5 Hz), 114.07, 46.65, 46.39, 45.97, 43.88, 38.36, 31.02, 26.46, 25.95, 22.50
17d^c^,^e	0.97—1.03(m, 2H, cyclohexyl), 1.15—1.22(m, 3H, cyclohexyl), 1.54[d, J=6.6 Hz, 6H, (CH₃)₂], 1.62—1.81(m, 6H, cyclohexyl), 3.29—3.34(m, 4H, piperazine), 3.37(br s, 2H, CH₂), 3.93—4.02(m, 4H, piperazine), 4.66(hept, J=6.6 Hz, 1H, CH), 6.22(br s, 1H, NH), 7.04(t, J=9.0 Hz, 2H, ArH), 7.50—7.54(m, 1H, ArH), 7.62(s, 1H, purine C8)	159.88(dd,J=3.75, 258 Hz), 154.25, 152.36, 150.53, 134.68(t, J=11.25 Hz), 115.05(t, J=16.5 Hz), 113.23(dd, J=3.75, 24 Hz), 112.54, 47.76, 46.80, 45.54, 44.09, 38.22, 31.01, 26.43, 25.92, 22.42
Compd.	¹H NMR, δ^a^,^b^,^c		¹³C NMR, δ^d^,^e
17e^c^,^e	0.97—1.01(m, 2H, cyclohexyl), 1.15—1.25(m, 3H, cyclohexyl), 1.51[d,J=6.6 Hz, 6H,(CH₃)₂], 1.57—1.79(m, 6H, cyclohexyl), 3.08—3.14(m, 4H, piperazine), 3.35(br s, 2H, CH₂), 3.92—3.96(m, 4H, piperazine), 4.61(hept, J=6.6 Hz, 1H, CH), 5.66(br s, 1H, NH), 7.52(s, 1H, purine C8), 7.79(d, J=8.4 Hz, 2H, ArH), 7.90(d, J=8.4 Hz, 2H, ArH)		158.19, 154.88, 150.69, 139.47, 134.88, 134.57(q, J=33 Hz), 128.27, 126.22(q, J=3.75 Hz), 123.20(q, J=271.5 Hz), 114.35, 46.71, 46.33, 45.98, 43.85, 38.35, 31.02, 26.45, 25.95, 22.51
17f ^c^,^e	0.94—0.99(m, 2H, cyclohexyl), 1.14—1.26(m, 3H, cyclohexyl), 1.51[d, J=6.6 Hz, 6H, (CH₃)₂], 1.53—1.77(m, 6H, cyclohexyl), 3.11—3.13(m, 4H, piperazine), 3.34(br s, 2H, CH₂), 3.93—3.97(m, 4H, piperazine), 4.61(hept, J=6.6 Hz, 1H, CH), 5.90(br s, 1H, NH), 7.51(s, 1H, purine C8), 7.95(d, J=9.0 Hz, 2H, ArH), 8.35(d, J=9.0 Hz, 2H, ArH)		158.11, 154.88, 150.60, 150.22, 141.87, 134.92, 128.91, 124.31, 114.38, 46.71, 46.33, 45.89, 43.87, 38.34, 31.00, 26.44, 25.94, 22.50
17g ^c^,^e	0.96—1.02(m, 2H, cyclohexyl), 1.16—1.22(m, 3H, cyclohexyl), 1.52[d, J=6.6 Hz, 6H, (CH₃)₂], 1.67—1.80(m, 6H, cyclohexyl), 3.01—3.11(m, 4H, piperazine), 3.37(br s, 2H, CH₂), 3.87(s, 3H, OCH₃), 3.88—3.99(m, 4H, piperazine), 4.63(hept, J=6.6 Hz, 1H, CH), 5.72(br s, 1H, NH), 6.99(d, J=7.8 Hz, 2H, ArH), 7.51(s, 1H, purine C8), 7.72(d, J=7.8 Hz, 2H, ArH)		163.07, 158.31, 154.80, 150.67, 134.75, 129.93, 127.15, 114.20, 55.59, 46.74, 46.29, 46.02, 43.84, 38.35, 31.00, 26.46, 25.95, 22.51
17h ^c^,^e	0.95—1.01(m, 2H, cyclohexyl), 1.14—1.24(m, 3H, cyclohexyl), 1.51[d, J=6.6 Hz, 6H, (CH₃)₂], 1.55—1.78(m, 6H, cyclohexyl), 3.07—3.13(m, 4H, piperazine), 3.35(br s, 2H, CH₂), 3.91—3.95(m, 4H, piperazine), 4.61(hept, J=6.6 Hz, 1H, CH), 5.68(br s, 1H, NH), 7.34(d, J=8.4 Hz, 2H, ArH), 7.51(s, 1H, purine C8), 7.82(d, J=8.4 Hz, 2H, ArH)		158.18, 154.81, 150.67, 139.45, 134.83, 134.14(q, J=33 Hz), 128.26, 126.22(q, J=3.75 Hz), 123.19(q, J=271.5 Hz), 114.25, 46.70, 46.35, 45.97, 43.85, 38.34, 31.01, 26.45, 25.94, 22.51
21a ^a^,^d	0.87—0.94(m, 2H, cyclohexyl), 1.15—1.25(m, 3H, cyclohexyl), 1.62—1.70(m, 6H, cyclohexyl), 2.85—3.05(m, 4H, piperazine), 3.24(br s, 2H, CH₂), 3.70—3.89(m, 4H, piperazine), 4.77(s, 2H, CH₂), 7.46—7.49(m, 3H, ArH, NH), 7.75(s, 1H, purine C8), 7.83(dd, J=7.2, 5.4 Hz, 2H, ArH), 13.12(br s, 1H, COOH)		169.49, 164.64(d, J=250.5 Hz), 157.83, 154.44, 150.71, 138.31, 131.23, 130.58(d, J=9.75 Hz), 116.59(d, J=22.5 Hz), 112.66, 45.79, 45.63, 43.35, 43.18, 37.57, 30.53, 26.08, 25.45
21b^a^,^d	0.85—0.98(m, 2H, cyclohexyl), 1.15—1.25(m, 3H, cyclohexyl), 1.62—1.71(m, 6H, cyclohexyl), 3.11—3.20(m, 4H, piperazine), 3.25(br s, 2H, CH₂), 3.74—3.94(m, 4H, piperazine), 4.79(s, 2H, CH₂), 7.33(t, J=9.0 Hz, 2H, ArH), 7.50(br s, 1H, NH), 7.70—7.86(m, 2H, ArH, purine C8), 13.12(br s, 1H, COOH)		169.51, 158.92(dd, J=3.75, 255 Hz), 157.87, 154.48, 150.78, 138.34, 136.26(t, J=10.5 Hz), 113.71(dd, J=3, 24 Hz), 113.33, 112.77, 45.81, 45.00, 43.44, 43.35, 37.62, 30.54, 26.08, 25.46
21c^a^,^d	0.86—0.94(m, 2H, cyclohexyl), 1.15—1.25(m, 3H, cyclohexyl), 1.61—1.67(m, 6H, cyclohexyl), 2.78—2.96(m, 4H, piperazine), 3.23(br s, 2H, CH₂), 3.72—3.81(m, 4H, piperazine), 3.83(s, 3H, OCH₃), 4.76(s, 2H, CH₂), 7.13(d, J=7.8 Hz, 2H, ArH), 7.47(br s, 1H, NH), 7.68(d, J=7.8 Hz, 2H, ArH), 7.73(s, 1H, purine C8), 13.06(br s, 1H, COOH)		169.50, 162.77, 157.79, 154.48, 150.83, 138.29, 129.74, 126.18, 114.50, 112.76, 55.62, 45.75, 45.61, 43.34, 43.21, 37.56, 30.54, 26.09, 25.47

Compd.	¹H NMR, δ^a^,^b^,^c	¹³C NMR, δ^d^,^e
5a^a^,^d	4.53(br s, 2H, CH₂), 7.15—7.18(m, 2H, ArH), 7.25—7.30(m, 5H, ArH), 7.90—7.95(m, 3H, ArH, purine C8), 8.25(br s, 1H, NH), 11.08(br s, 1H, SO₂NH), 12.76(br s, 1H, purine C9)	163.78(d,J=249 Hz), 153.33, 152.43, 150.55, 139.54, 138.64, 138.21, 129.80(d, J=5.25 Hz), 128.15, 127.34, 126.71, 115.60(d, J=22.5 Hz), 42.80
5b^a^,^d	4.38(br s, 2H, CH₂), 6.98—7.08(m, 2H, ArH), 7.20—7.27(m, 5H, ArH), 7.41—7.48(m, 1H, ArH), 7.99(s, 1H, purine C8), 8.32(br s, 1H, NH), 11.72(br s, 1H, SO₂NH), 12.84(br s, 1H, purine C9)	158.72(dd,J=4.5, 252.75 Hz), 153.14, 152.40, 149.49, 139.67, 138.64, 133.34, 128.25, 127.68, 126.98, 112,72(d, J=24 Hz), 42.76
5c^a^,^d	4.49(br s, 2H, CH₂), 7.25—7.31(m, 7H, ArH), 7.89—7.99(m, 3H, ArH, purine C8), 8.35(br s, 1H, NH)	153.00, 152.84, 150.13, 141.68, 139.29, 129.19, 128.15, 127.32, 126.72, 120.54, 119.80(q, J=256.5 Hz), 111.54, 42.84
8a^b^,^d	1.36[d, J=6.3 Hz, 6H, (CH₃)₂], 4.47—4.53(m, 3H, CH, CH₂), 7.16(t, J=9.0 Hz, 2H, ArH), 7.20—7.29(m, 5H, ArH), 7.54—7.64(m, 1H, ArH), 8.21(s, 1H, purine C8), 8.46(br s, 1H, NH), 11.74(br s, 1H, SO₂NH)	158.87(d,J=255 Hz), 153.30, 152.63, 148.26, 139.12, 137.45, 134.91, 128.17, 127.52, 126.81, 118.94, 113.06(d, J=24 Hz), 113.05(t, J=11.25 Hz), 47.33, 42.73, 21.56
8b ^b^,^d	1.37[d, J=6.6 Hz, 6H, (CH₃)₂], 4.48—4.54(m, 3H, CH, CH₂), 7.18—7.28(m, 5H, ArH), 7.81(d, J=7.2 Hz, 2H, ArH), 8.05(s, 1H, purine C8), 8.10(d, J=7.2 Hz, 2H, ArH), 8.36(br s, 1H, NH), 11.39(br s, 1H, SO₂NH)	154.12, 151.77, 148.66, 145.29, 139.66, 137.74, 131.94(q, J=31.5 Hz), 128.11, 128.01, 127.25, 126.64, 125.92, 123.43(q, J=271.5 Hz), 115.53, 46.58, 42.71, 21.73
8c^b^,^d	1.41[d, J=6.3 Hz, 6H, (CH₃)₂], 4.50—4.52(m, 3H, CH, CH₂), 7.16—7.22(m, 5H, ArH), 8.05(s, 1H, purine C8), 8.09(d, J=7.2 Hz, 2H, ArH), 8.18(d, J=7.2 Hz, 2H, ArH), 8.36(br s, 1H, NH), 11.49(br s, 1H, SO₂NH)	154.14, 151.62, 149.08, 147.06, 139.51, 137.71, 128.29, 127.95, 126.93, 126.48, 123.97, 115.78, 46.39, 42.59, 21.85
8d ^c^,^d	1.51[d, J=6.6 Hz, 6H, (CH₃)₂], 3.80(s, 3H, OCH₃), 4.63(hept, J=6.6 Hz, 1H, CH), 4.72(br s, 2H, CH₂), 6.52(br s, 1H, NH), 6.81(d, J=9.0 Hz, 2H, ArH), 7.26—7.32(m, 5H, ArH), 7.61(s, 1H, purine C8), 8.01(d, J=9.0 Hz, 2H, ArH), 8.24(br s, 1H, SO₂NH)	162.03, 154.29, 151.94, 149.12, 139.94, 137.41, 132.69, 129.44, 128.01, 127.37, 126.50, 115.84, 113.61, 59.64, 46.24, 42.58, 21.88
Compd.	¹H NMR, δ^a^,^b^,^c	¹³C NMR, δ^d^,^e
13a ^a^,^e	1.42[d, J=6.6 Hz, 6H, (CH₃)₂], 2.37(s, 3H, CH₃), 2.75—2.78(m, 4H, piperazine), 3.74—3.82(m, 4H, piperazine), 4.50—4.52(m, 3H, CH, CH₂), 7.22—7.32(m, 5H, ArH), 7.42(d, J=7.8 Hz, 2H, ArH), 7.58(d, J=7.8 Hz, 2H, ArH), 7.86(s, 1H, purine C8), 8.11(br s, 1H, NH)	158.80, 152.94, 150.20, 143.77, 139.13, 133.86, 132.47, 129.70, 128.31, 127.82, 127.61, 126.91, 109.51, 47.47, 45.85, 44.42, 43.72, 22.12, 21.04
13b ^a^,^e	1.42[d, J=6.6 Hz, 6H, (CH₃)₂], 2.81—2.88(m, 4H, piperazine), 3.75—3.80(m, 4H, piperazine), 4.50—4.55(m, 3H, CH, CH₂), 7.21—7.32(m, 5H, ArH), 7.70(d, J=8.4 Hz, 2H, ArH), 7.72(d, J=8.4 Hz, 2H, ArH), 7.86(s, 1H, purine C8), 8.09(br s, 1H, NH)	158.74, 153.35, 150.50, 139.53, 139.08, 134.13, 133.89, 129.41, 129.15, 128.40, 127.60, 127.04, 111.01, 47.11, 45.79, 44.50, 43.77, 22.30
13c ^a^,^d	1.43[d, J=6.6 Hz, 6H, (CH₃)₂], 2.99—3.13(m, 4H, piperazine), 3.76—3.85(m, 4H, piperazine), 4.49—4.57(m, 3H, CH, CH₂), 7.18—7.35(m, 7H, ArH), 7.75—7.77(m, 1H, ArH), 7.87(s, 1H, purine C8), 8.11(br s, 1H, NH)	158.80(dd,J=3.75, 255 Hz), 157.34, 153.92, 150.21, 140.52, 136.21(t, J=11.25 Hz), 135.99, 127.90, 127.35, 126.37, 113.68(dd, J=3, 23.25 Hz), 113.35, 113.13, 45.67, 44.86, 43.40, 42.62, 21.97
13d ^a^,^d	1.43[d, J=6.6 Hz, 6H, (CH₃)₂], 2.79—3.03(m, 4H, piperazine), 3.71—3.89(m, 4H, piperazine), 4.45—4.61(m, 3H, CH, CH₂), 7.19—7.32(m, 5H, ArH), 7.90(s, 1H, purine C8), 7.94(d, J=7.8 Hz, 2H, ArH), 8.02(d, J=7.8 Hz, 2H, ArH), 8.10(br s, 1H, NH)	157.31, 153.85, 150.20, 140.50, 138.88, 135.99, 132.82(q, J=32.25 Hz), 128.47, 127.99, 127.37, 126.59(q, J=3.75 Hz), 126.40, 123.35(q, J=271.5 Hz), 113.45, 45.77, 45.45, 43.24, 42.65, 21.97
13e^a^,^e	1.42[d, J=6.6 Hz, 6H, (CH₃)₂], 2.87—2.93(m, 4H, piperazine), 3.76—3.80(m, 4H, piperazine), 4.48—4.55(m, 3H, CH, CH₂), 7.21—7.31(m, 5H, ArH), 7.85(s, 1H, purine C8), 7.98(d, J=8.4 Hz, 2H, ArH), 8.10(br s, 1H, NH), 8.41(d, J=8.4 Hz, 2H, ArH)	158.04, 154.34, 150.87, 150.22, 141.82, 139.21, 135.16, 128.89, 128.51, 127.51, 127.18, 124.31, 114.23, 46.42, 45.79, 44.45, 43.86, 22.48
13f ^a^,^e	1.42[d, J=6.6 Hz, 6H, (CH₃)₂], 2.75—2.78(m, 4H, piperazine), 3.75—3.80(m, 4H, piperazine), 4.49—4.52(m, 3H, CH, CH₂), 7.13(d, J=8.4 Hz, 2H, ArH), 7.21—7.33(m, 5H, ArH), 7.64(d, J=8.4 Hz, 2H, ArH), 7.86(s, 1H, purine C8), 8.12(br s, 1H, NH)	163.11, 158.73, 153.25, 150.31, 139.27, 133.92, 129.90, 128.30, 127.62, 127.02, 126.87, 114.24, 110.44, 55.62, 47.16, 45.87, 44.38, 43.72, 22.21
13g ^a^,^e	1.42[d,J=6.6 Hz, 6H, (CH₃)₂], 2.84—2.90(m, 4H, piperazine), 3.76—3.81(m, 4H, piperazine), 4.50—4.56(m, 3H, CH, CH₂), 7.19—7.32(m, 5H, ArH), 7.62(d, J=8.4 Hz, 2H, ArH), 7.86—7.88(m, 3H, purine C8, ArH), 8.10(br s, 1H, NH)	158.68, 153.30, 152.36, 150.30, 139.24, 134.04, 133.96, 129.88, 128.31, 127.59, 126.90, 120.89, 120.19(q, J=258 Hz), 110.60, 47.19, 45.81, 44.40, 43.72, 22.22
17a^c^,^e	0.96—1.01(m, 2H, cyclohexyl), 1.14—1.25(m, 3H, cyclohexyl), 1.51[d, J=6.6 Hz, 6H, (CH₃)₂], 1.57—1.79(m, 6H, cyclohexyl), 2.41(s, 3H, CH₃), 3.04—3.06(m, 4H, piperazine CH₂), 3.35(br s, 2H, CH₂), 3.90—3.92(m, 4H, piperazine CH₂), 4.62(hept, J=6.6 Hz, 1H, CH), 5.68(br s, 1H, NH), 7.30(d, J=8.4 Hz, 2H, ArH), 7.53(s, 1H, purine C8), 7.65(d, J=8.4 Hz, 2H, ArH)	158.30, 154.72, 150.65, 143.67, 134.70, 132.53, 129.65, 127.87, 114.02, 46.65, 46.33, 46.02, 43.85, 38.34, 31.00, 26.45, 25.94, 22.50, 21.50
17b ^a^,^e	0.88—0.90(m, 2H, cyclohexyl), 1.07—1.15(m, 3H, cyclohexyl), 1.46[d, J=6.6 Hz, 6H, (CH₃)₂], 1.57—1.68(m, 6H, cyclohexyl), 2.92—2.98(m, 4H, piperazine), 3.24(br s, 2H, CH₂), 3.78—3.88(m, 4H, piperazine), 4.57(hept, J=6.6 Hz, 1H, CH), 7.45(br s, 1H, NH), 7.71(d, J=8.4 Hz, 2H, ArH), 7.76(d, J=8.4 Hz, 2H, ArH), 7.87(s, 1H, purine C8)	158.22, 154.82, 150.63, 139.47, 134.81, 134.21, 129.37, 129.19, 114.25, 46.68, 46.33, 45.95, 43.84, 38.35, 31.01, 26.45, 25.94, 22.51
17c ^a^,^e	0.88—0.92(m, 2H, cyclohexyl), 1.12—1.19(m, 3H, cyclohexyl), 1.44[d, J=6.6 Hz, 6H, (CH₃)₂], 1.59—1.67(m, 6H, cyclohexyl), 2.91—2.97(m, 4H, piperazine), 3.22(br s, 2H, CH₂), 3.77—3.83(m, 4H, piperazine), 4.54(hept, J=6.6 Hz, 1H, CH), 7.44—7.48(m, 3H, NH, ArH), 7.81—7.84(m, 3H, ArH, purine C8)	165.28(d, J=253.5 Hz), 158.18, 154.74, 134.75, 131.82(d, J=3 Hz), 130.47(d, J=9 Hz), 116.33(d, J=22.5 Hz), 114.07, 46.65, 46.39, 45.97, 43.88, 38.36, 31.02, 26.46, 25.95, 22.50
17d^c^,^e	0.97—1.03(m, 2H, cyclohexyl), 1.15—1.22(m, 3H, cyclohexyl), 1.54[d, J=6.6 Hz, 6H, (CH₃)₂], 1.62—1.81(m, 6H, cyclohexyl), 3.29—3.34(m, 4H, piperazine), 3.37(br s, 2H, CH₂), 3.93—4.02(m, 4H, piperazine), 4.66(hept, J=6.6 Hz, 1H, CH), 6.22(br s, 1H, NH), 7.04(t, J=9.0 Hz, 2H, ArH), 7.50—7.54(m, 1H, ArH), 7.62(s, 1H, purine C8)	159.88(dd,J=3.75, 258 Hz), 154.25, 152.36, 150.53, 134.68(t, J=11.25 Hz), 115.05(t, J=16.5 Hz), 113.23(dd, J=3.75, 24 Hz), 112.54, 47.76, 46.80, 45.54, 44.09, 38.22, 31.01, 26.43, 25.92, 22.42
Compd.	¹H NMR, δ^a^,^b^,^c		¹³C NMR, δ^d^,^e
17e^c^,^e	0.97—1.01(m, 2H, cyclohexyl), 1.15—1.25(m, 3H, cyclohexyl), 1.51[d,J=6.6 Hz, 6H,(CH₃)₂], 1.57—1.79(m, 6H, cyclohexyl), 3.08—3.14(m, 4H, piperazine), 3.35(br s, 2H, CH₂), 3.92—3.96(m, 4H, piperazine), 4.61(hept, J=6.6 Hz, 1H, CH), 5.66(br s, 1H, NH), 7.52(s, 1H, purine C8), 7.79(d, J=8.4 Hz, 2H, ArH), 7.90(d, J=8.4 Hz, 2H, ArH)		158.19, 154.88, 150.69, 139.47, 134.88, 134.57(q, J=33 Hz), 128.27, 126.22(q, J=3.75 Hz), 123.20(q, J=271.5 Hz), 114.35, 46.71, 46.33, 45.98, 43.85, 38.35, 31.02, 26.45, 25.95, 22.51
17f ^c^,^e	0.94—0.99(m, 2H, cyclohexyl), 1.14—1.26(m, 3H, cyclohexyl), 1.51[d, J=6.6 Hz, 6H, (CH₃)₂], 1.53—1.77(m, 6H, cyclohexyl), 3.11—3.13(m, 4H, piperazine), 3.34(br s, 2H, CH₂), 3.93—3.97(m, 4H, piperazine), 4.61(hept, J=6.6 Hz, 1H, CH), 5.90(br s, 1H, NH), 7.51(s, 1H, purine C8), 7.95(d, J=9.0 Hz, 2H, ArH), 8.35(d, J=9.0 Hz, 2H, ArH)		158.11, 154.88, 150.60, 150.22, 141.87, 134.92, 128.91, 124.31, 114.38, 46.71, 46.33, 45.89, 43.87, 38.34, 31.00, 26.44, 25.94, 22.50
17g ^c^,^e	0.96—1.02(m, 2H, cyclohexyl), 1.16—1.22(m, 3H, cyclohexyl), 1.52[d, J=6.6 Hz, 6H, (CH₃)₂], 1.67—1.80(m, 6H, cyclohexyl), 3.01—3.11(m, 4H, piperazine), 3.37(br s, 2H, CH₂), 3.87(s, 3H, OCH₃), 3.88—3.99(m, 4H, piperazine), 4.63(hept, J=6.6 Hz, 1H, CH), 5.72(br s, 1H, NH), 6.99(d, J=7.8 Hz, 2H, ArH), 7.51(s, 1H, purine C8), 7.72(d, J=7.8 Hz, 2H, ArH)		163.07, 158.31, 154.80, 150.67, 134.75, 129.93, 127.15, 114.20, 55.59, 46.74, 46.29, 46.02, 43.84, 38.35, 31.00, 26.46, 25.95, 22.51
17h ^c^,^e	0.95—1.01(m, 2H, cyclohexyl), 1.14—1.24(m, 3H, cyclohexyl), 1.51[d, J=6.6 Hz, 6H, (CH₃)₂], 1.55—1.78(m, 6H, cyclohexyl), 3.07—3.13(m, 4H, piperazine), 3.35(br s, 2H, CH₂), 3.91—3.95(m, 4H, piperazine), 4.61(hept, J=6.6 Hz, 1H, CH), 5.68(br s, 1H, NH), 7.34(d, J=8.4 Hz, 2H, ArH), 7.51(s, 1H, purine C8), 7.82(d, J=8.4 Hz, 2H, ArH)		158.18, 154.81, 150.67, 139.45, 134.83, 134.14(q, J=33 Hz), 128.26, 126.22(q, J=3.75 Hz), 123.19(q, J=271.5 Hz), 114.25, 46.70, 46.35, 45.97, 43.85, 38.34, 31.01, 26.45, 25.94, 22.51
21a ^a^,^d	0.87—0.94(m, 2H, cyclohexyl), 1.15—1.25(m, 3H, cyclohexyl), 1.62—1.70(m, 6H, cyclohexyl), 2.85—3.05(m, 4H, piperazine), 3.24(br s, 2H, CH₂), 3.70—3.89(m, 4H, piperazine), 4.77(s, 2H, CH₂), 7.46—7.49(m, 3H, ArH, NH), 7.75(s, 1H, purine C8), 7.83(dd, J=7.2, 5.4 Hz, 2H, ArH), 13.12(br s, 1H, COOH)		169.49, 164.64(d, J=250.5 Hz), 157.83, 154.44, 150.71, 138.31, 131.23, 130.58(d, J=9.75 Hz), 116.59(d, J=22.5 Hz), 112.66, 45.79, 45.63, 43.35, 43.18, 37.57, 30.53, 26.08, 25.45
21b^a^,^d	0.85—0.98(m, 2H, cyclohexyl), 1.15—1.25(m, 3H, cyclohexyl), 1.62—1.71(m, 6H, cyclohexyl), 3.11—3.20(m, 4H, piperazine), 3.25(br s, 2H, CH₂), 3.74—3.94(m, 4H, piperazine), 4.79(s, 2H, CH₂), 7.33(t, J=9.0 Hz, 2H, ArH), 7.50(br s, 1H, NH), 7.70—7.86(m, 2H, ArH, purine C8), 13.12(br s, 1H, COOH)		169.51, 158.92(dd, J=3.75, 255 Hz), 157.87, 154.48, 150.78, 138.34, 136.26(t, J=10.5 Hz), 113.71(dd, J=3, 24 Hz), 113.33, 112.77, 45.81, 45.00, 43.44, 43.35, 37.62, 30.54, 26.08, 25.46
21c^a^,^d	0.86—0.94(m, 2H, cyclohexyl), 1.15—1.25(m, 3H, cyclohexyl), 1.61—1.67(m, 6H, cyclohexyl), 2.78—2.96(m, 4H, piperazine), 3.23(br s, 2H, CH₂), 3.72—3.81(m, 4H, piperazine), 3.83(s, 3H, OCH₃), 4.76(s, 2H, CH₂), 7.13(d, J=7.8 Hz, 2H, ArH), 7.47(br s, 1H, NH), 7.68(d, J=7.8 Hz, 2H, ArH), 7.73(s, 1H, purine C8), 13.06(br s, 1H, COOH)		169.50, 162.77, 157.79, 154.48, 150.83, 138.29, 129.74, 126.18, 114.50, 112.76, 55.62, 45.75, 45.61, 43.34, 43.21, 37.56, 30.54, 26.09, 25.47

Compd.	IC₅₀/(μmol·L^-1)			Compd.	IC₅₀/(μmol·L^-1)
Compd.	PC-3		HCT116	K562	PC-3	HCT116	K562
13d	23.4	> 50	> 100	17d	19.1	27.3	33.1
13g	39.7	> 50	> 100	Roscovitine	12.1	21.2	26.6
17c	> 50	26.7	47.6