4-β-硫酯-4-脱氧-4′-去甲表鬼臼毒素衍生物的合成及其抗肿瘤活性
作者：陈再新 马维勇 陈秀华 张椿年
单位：上海医药工业研究院，上海 200040
关键词：鬼臼毒素；衍生物；抗肿瘤活性
中国药物化学杂志000202 摘要 为考察4′-去甲鬼臼毒素C4位上联结碳原子对活性的影响，作者设计并合成C4位β构型的硫酯取代的衍生物18个.这类化合物在体外的抑制L1210细胞和KB细胞的药理实验中显示出一定的抗肿瘤活性，但均弱于etoposide.
Synthesis and Antitumor Activity of 4--Alky lthiocarbonyl-4Deoxy-4'-Deoxy -4'-Demethylepipodophyllotoxin
Chen Zaixin Ma Weiyong Chen Xiuhua Zhagn Chunnian
, 百拇医药
(Shanghai Institute of Pharmaceutical Industry ,Shanghai 200040)
Abstract Eighteen new 4--alkylthiocarbony -4-deoxy-4'-demethy lepipodophyllotoxin were synthesized adn screened in vitro against L1210 leukemia adn KBcells Most of them were less active than etoposide Fatty thioesters have higher activity than aromativ thioesters The carbon number of the main chain in fatty
Key words podophyllotoxin ;derivative ;antitumor activity
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鬼臼毒素(podophyllotoxin)是一种具有抗肿瘤活性的天然化合物.其半合成化合物依托泊苷(etoposide)和替尼泊苷(teniposide)在临床上广泛地应用于肿瘤的化疗〔1〕.但其疗效和毒副作用均有不足之处.为了寻找更为有效的鬼臼类抗肿瘤药物，药学工作者合成了大量的鬼臼毒素衍生物，并进行了构效关系研究〔2～6〕.本文作者曾报道C4为N取代的衍生物具有很高的生物活性〔7〕，根据生物电子等排原理，又设计并合成了C4位C取代的衍生物.本文报道4-β-硫酯-4-脱氧-4′-去甲表鬼臼毒素衍生物(Ⅲ)的合成及其体外抑制L1210细胞和KB细胞的活性.
1 合成路线及化合物表征
作者用4′-去甲表鬼臼毒素(1)为原料，合成中间体(2)和(3).在制备最终目标化合物(Ⅲ)的过程中，用二氯亚砜制备酰氯中间体，不经分离直接反应制得目标化合物18个.合成路线见图1，其理化数据见表1及表2.
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Fig.1 The route of synthesis of the title compounds(Ⅲ)
Tab.1 Physical data of the title compounds(Ⅲ)
Compd.
R
EI-MS m/z
mp/℃
〔α〕25D(DMF)
Yield/%
Ⅲ-1
—CH2CH3
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472(M+)
210～212
-23.5(c=0.2)
21.6
Ⅲ-2
—CH2CH2CH3
486(M+)
195～197
-57.6(c=0.2)
36.0
Ⅲ-3
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—CH(CH3)2
486(M+)
204～206
-98.3(c=0.2)
34.7
(to be continued)
Continued Tab.1
Compd.
R
EI-MS m/z
mp/℃
, 百拇医药
〔α〕25D(DMF)
Yield/%
Ⅲ-4
—(CH2)3CH3
500(M+)
189～192
-47.3(c=0.2)
41.0
Ⅲ-5
—(CH2)4CH3
, 百拇医药
514(M+)
270～273
-39.5(c=0.2)
35.1
Ⅲ-6
—CH2Ph
534(M+)
265～267
-105.6(c=0.2)
35.6
Ⅲ-7
, 百拇医药 520(M+)
235～238
-85.2(c=0.2)
46.2
Ⅲ-8
554(M+)
247～249
-112.9(c=0.2)
51.3
Ⅲ-9
554(M+)
214～217
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-164.7(c=0.2)
48.1
Ⅲ-10
588(M+)
221～224
-68.1(c=0.2)
36.2
Ⅲ-11
588(M+)
254～256
-70.5(c=0.2)
40.3
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Ⅲ-12
588(M+)
231～233
-88.3(c=0.2)
44.0
Ⅲ-13
600(M+)
209～212
-91.3(c=0.2)
38.5
Ⅲ-14
550(M+)
, 百拇医药
238～240
-115.6(c=0.2)
36.1
Ⅲ-15
550(M+)
224～226
-76.4(c=0.2)
33.9
Ⅲ-16
610(M+)
243～246
-168.4(c=0.2)
, 百拇医药
42.2
Ⅲ-17
660(M+)
230～233
-141.9(c=0.2)
44.6
Ⅲ-18
570(M+)
250～252
-60.4(c=0.2)
41.8
Tab.2 1H-NMR of the title compounds(Ⅲ)
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Compd.
1H-NMR δ
Ⅲ-1
1.25～1.30(t,3H,SCH2CH3),2.89～2.95(m,2H,SCH2CH3),3.27～3.30(m,2H,H-2,3),3.79(s,6H,2×OCH3),3.86(d,1H,H-11α),4.07(d,1H,H-11β),4.39～4.46(m,2H,H-1,4),5.95(d,2H,OCH2O),6.13(s,2H,H-2′,6′),6.49(s,1H,H-8),7.12(s,1H,H-5)
Ⅲ-2
1.00(t,3H,SCH2CH2CH3),1.63(m,2H,SCH2CH2CH3),2.87(m,2H,SCH2CH2CH3),3.27(m,2H,H-2,3),3.77(s,6H,2×OCH3),3.88(d,1H,H-11α),4.06(d,1H,H-11β),4.40(m,1H,H-4),4.45(d,1H,H-1),5.93(d,2H,OCH2O),6.14(s,2H,H-2′,6′),6.48(s,1H,H-8),7.14(s,1H,H-5)
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Ⅲ-3
1.30～1.38(m,6H,2×CH3),3.22(dd,1H,H-2),3.27～3.38(m,1H,H-3),3.60～3.64(m,1H,CH at thioester),3.75(s,6H,2×OCH3),3.86(d,1H,H-11α),4.08(d,1H,H-11β),4.38～4.44(m,2H,H-1,4),5.93(d,2H,OCH2O),6.12(s,2H,H-2′,6′),6.57(s,1H,H-8),7.12(s,1H,H-5)
Ⅲ-4
0.95(t,3H,SCH2CH2CH2CH3),1.36～1.42(m,4H,SCH2CH2CH2CH3),2.87～2.92(m,2H,SCH2CH2CH2CH3),3.26～3.29(m,2H,H-2,3),3.75(s,6H,2×OCH3),3.84(d,1H,H-11α),4.06(d,1H,H-11β),4.39(m,1H,H-4),4.45(d,1H,H-1),5.93(d,2H,OCH2O),5.96(s,2H,H-2′,6′),6.48(s,1H,H-8),7.11(s,1H,H-5)
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(to be continued)
Continued Tab.2
Compd.
1H-NMR δ
Ⅲ-5
0.90〔t,3H,SCH2(CH2)3CH3〕,1.50～1.70〔m,6H,SCH2(CH2)3CH3〕,2.82～2.94〔m,2H,SCH2(CH2)3CH3〕,3.23～3.25(m,2H,H-2,3),3.75(s,6H,2×OCH3),3.84(d,1H,H-11α),4.06(d,1H,H-11β),4.00(m,1H,H-4),4.45(d,1H,H-1),5.94(d,2H,OCH2O),6.11(s,2H,H-2′,6′),6.48(s,1H,H-8),7.13(s,1H,H-5)
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Ⅲ-6
3.24～3.38(m,2H,H-2,3),3.66(s,6H,2×OCH3),3.85(d,1H,H-11α),4.14(d,1H,H-11β),4.18(d,2H,CH2 at thioester),4.38～4.45(m,2H,H-1,4),5.96(d,2H,OCH2O),6.19(s,2H,H-2′,6′),6.53(s,1H,H-8),6.99(s,1H,H-5),7.24～7.38(m,5H,Aromatic H at thioester)
Ⅲ-7
3.30～3.39(m,2H,H-2,3),3.66(s,6H,2×OCH3),3.85(d,1H,H-11α),4.18(d,1H,H-11β),4.38～4.42(m,1H,H-4),4.59(d,1H,H-1),5.96(d,2H,OCH2O),6.19(s,2H,H-2′,6′),6.53(s,1H,H-8),6.99(s,1H,H-5),7.26～7.43(m,5H,H at thioester)
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Ⅲ-8
3.31～3.35(m,1H,H-3),3.41～3.45(dd,1H,H-2),3.70(s,6H,2×OCH3),3.87(d,1H,H-11α),4.19(d,1H,H-11β),4.41～4.44(m,1H,H-4),4.57(d,1H,H-1),5.95(d,2H,OCH2O),6.11(s,2H,H-2′,6′),6.55(s,1H,H-8),7.13(s,1H,H-5),7.26～7.53(m,4H,H at thioester)
Ⅲ-9
3.29～3.41(m,2H,H-2,3),3.72(s,6H,2×OCH3),3.89(d,1H,H-11α),4.14(d,1H,H-11β),4.41～4.45(m,1H,H-4),4.57(d,1H,H-1),5.96(d,2H,OCH2O),6.16(s,2H,H-2′,6′),6.53(s,1H,H-8),7.13(s,1H,H-5),7.21～7.42(m,4H,Aromatic H at thioester)
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Ⅲ-10
3.35～3.37(m,2H,H-2,3),3.67(s,6H,2×OCH3),3.89(d,1H,H-11α),4.13(d,1H,H-11β),4.41～4.45(m,1H,H-4),4.56(d,1H,H-1),5.97(d,2H,OCH2O),6.16(s,2H,H-2′,6′),6.52(s,1H,H-8),7.00(s,1H,H-5),7.13～7.52(m,3H,Aromatic H at thioester)
Ⅲ-11
3.26～3.37(m,1H,H-3),3.42(dd,1H,H-2),3.74(s,6H,2×OCH3),3.88(d,1H,H-11α),4.09(d,1H,H-11β),4.38～4.44(m,1H,H-4),4.56(d,1H,H-1),5.96(d,2H,OCH2O),6.17(s,2H,H-2′,6′),6.50(s,1H,H-8),7.16(s,1H,H-5),7.22～7.43(m,3H,Aromatic H at thioester)
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Ⅲ-12
3.28～3.33(m,1H,H-3),3.47(dd,1H,H-2),3.77(s,6H,2×OCH3),3.87(d,1H,H-11α),4.24(d,1H,H-11β),4.40～4.44(m,1H,H-4),4.54(d,1H,H-1),5.96(d,2H,OCH2O),6.12(s,2H,H-2′,6′),6.55(s,1H,H-8),7.16(s,1H,H-5),7.19～7.48(m,3H,Aromatic H at thioester)
Ⅲ-13
3.28～3.35(m,1H,H-3),3.42(dd,1H,H-2),3.70(s,6H,2×OCH3),3.89(d,1H,H-11α),4.23(d,1H,H-11β),4.41～4.44(m,1H,H-4),4.59(d,1H,H-1),5.98(d,2H,OCH2O),6.18(s,2H,H-2′,6′),6.58(s,1H,H-8),7.00(s,1H,H-5),7.28～7.43(m,4H,Aromatic H at thioester)
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Ⅲ-14
3.31～3.39(m,2H,H-2,3),3.72(s,6H,2×OCH3),3.82(s,3H,OCH3 at thioester),3.86(d,1H,H-11α),4.13(d,1H,H-11β),4.38～4.20(m,1H,H-4),4.56(d,1H,H-1),5.95(d,2H,OCH2O),6.19(s,2H,H-2′,6′),6.52(s,1H,H-8),6.93(d,2H,Aromatic H at thioester),7.13(s,1H,H-5),7.26(d,2H,Aromatic H at thioester)
Ⅲ-15
3.29～3.41(m,2H,H-2,3),3.71(s,6H,2×OCH3),3.77(s,3H,OCH3 at thioester),3.90(d,1H,H-11α),4.15(d,1H,H-11β),4.41～4.44(m,1H,H-4),4.59(d,1H,H-1),5.42(s,1H,OH),5.96(d,2H,OCH2O),6.14(s,2H,H-2′,6′),6.53(s,1H,H-8),6.91～7.00(m,3H,H-4,5,6 at thioester),7.13(s,1H,H-5),7.30～7.34(m,1H,H-2 at thioester)
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Ⅲ-16
3.32～3.37(m,1H,H-3),3.47～3.52(dd,1H,H-2),3.75(s,6H,2×OCH3),3.89(d,1H,H-11α),4.10(d,1H,H-11β),4.41～4.55(m,1H,H-4),4.56(d,1H,H-1),5.97(d,2H,OCH2O),6.14(s,2H,H-2′,6′),6.53(s,1H,H-8),7.13(s,1H,H-5)
Ⅲ-17
3.35～3.38(m,1H,H-3),3.52(dd,1H,H-2),3.76(s,6H,2×OCH3),3.94(d,1H,H-11α),4.09(d,1H,H-11β),4.42～4.46(m,1H,H-4),4.55(d,1H,H-1),5.96(d,2H,OCH2O),6.16(s,2H,H-2′,6′),6.53(s,1H,H-8),7.14(s,1H,H-5)
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Ⅲ-18
3.35～3.39(m,1H,H-3),3.43(dd,1H,H-2),3.70(s,6H,2×OCH3),3.90(d,1H,H-11α),4.19(d,1H,H-11β),4.42～4.45(m,1H,H-4),4.63(d,1H,H-1),5.97(d,2H,OCH2O),6.23(s,2H,H-2′,6′),6.55(s,1H,H-8),7.14(s,1H,H-5),7.53～7.89(m,7H,Aromatic H at thioester)
2 合成实验
熔点用毛细管熔点仪测定，温度未校正.质谱由Varian MAT 212和计算机SS-MAT测定.核磁共振氢谱由Brucker AM-400测定，TMS为内标.旋光在Perkin-Elmer 214 MC旋光仪上测定，DMF为溶剂.柱色谱用硅胶H(薄层色谱用，青岛海洋化工厂)装柱.展开剂均为国产AR级试剂.
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标题化合物(Ⅲ)的制备通法：将化合物(3)100 mg(0.234 mmol)溶于5 mL的二氯甲烷中，加入5～6滴三乙胺.室温下慢慢滴加5～6滴二氯亚砜.搅拌反应30 min后，在低于30℃的温度下蒸干溶剂.再加入5 mL的二氯甲烷和5～6滴的吡啶.在搅拌下加入硫醇或硫酚(约6～7 mmol).继续搅拌反应4～10 h.用50 mL的二氯甲烷稀释.分别用冷的饱和碳酸氢钠溶液、水、饱和食盐水洗涤.无水硫酸钠干燥.柱色谱分离得白色固体.产率：20%～50%.
3 抗肿瘤活性实验
以etoposide为对照物，对表1中所列的化合物进行了体外L1210白血病细胞和KB细胞的生长抑制试验，结果见表3.该类化合物均表现出一定的抑瘤活性，但均弱于etoposide.和酯取代的化合物相似，脂肪硫酯的活性强于芳香硫酯的活性.但脂肪链的长短对活性没有影响.在芳香酯中，苯环上的取代基对化合物的活性无明显影响.Tab.3 Antitumor activities of the title compounds(Ⅲ)
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Compd.
L1210
KB
IC50/μg*mL-1
IC%/10 μg*mL-1
IC50/μg*mL-1
IC%/10 μg*mL-1
Ⅲ-1
4.11
74.19
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21.82
Ⅲ-2
3.16
91.13
6.91
58.18
Ⅲ-3
3.13
96.77
4.22
74.54
Ⅲ-4
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3.89
84.68
>10
45.45
Ⅲ-5
3.50
91.94
4.01
74.54
Ⅲ-6
4.34
65.32
>10
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9.09
Ⅲ-7
3.29
75.81
>10
12.73
Ⅲ-8
1.97
91.13
>10
25.45
Ⅲ-9
>10
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36.29
>10
16.36
Ⅲ-10
9.20
51.61
>10
9.09
Ⅲ-11
2.29
86.29
>10
9.09
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Ⅲ-12
5.40
65.32
>10
25.45
Ⅲ-13
4.34
85.48
>10
37.73
Ⅲ-14
>10
39.68
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>10
37.73
Ⅲ-15
>10
45.16
>10
7.27
Ⅲ-16
2.10
95.37
>10
21.83
Ⅲ-17
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2.69
87.04
>10
30.91
Ⅲ-18
>10
8.33
>10
18.18
etoposide
0.249
93.58
1.04
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80.00
参考文献
1，Issell BF.The podophyllotoxin derivatives VP-16-213 and VM-26.Cancer Chemother Pharmacol,1982，7(2-3)：73～80
2，王志光，马维勇，张椿年.4-烷硒基-4-脱氧-4′-去甲表鬼臼毒素衍生物的合成和抗肿瘤活性.化学学报，1993，51：933～936
3，王志光，马维勇，张椿年.4-巯基-4-脱氧-4′-去甲表鬼臼毒素衍生物的立体控制合成.化学学报，1992，50(7)：698～701
4，王志光，马维勇，李炳生，等.4-烷硫基-4-脱氧-4′-去甲表鬼臼毒素衍生物的合成和抗肿瘤活性.药学学报，1992，27(9)：656～661
5，尹述凡，庄武，马维勇，等.4-S-(5-酰胺基1,3,4-噻二唑-2-基)-4-脱氧-4′-去甲表鬼臼毒素衍生物的合成与抗肿瘤活性.药学学报，1993，28(10)：762～765
6，尹述凡，王志光，马维勇，等.4-O-卤代酰基-4′-去甲表鬼臼毒素类似物的合成和抗肿瘤活性.药学学报，1992，28(10)：758～761
7，王志光，尹述凡，马维勇，等.4-酰胺-4-脱氧-4′-去甲表鬼臼毒素衍生物的合成和抗肿瘤活性.药学学报，1993，28(6)：422～427
收稿日期:2000-01-28, 百拇医药
单位：上海医药工业研究院，上海 200040
关键词：鬼臼毒素；衍生物；抗肿瘤活性
中国药物化学杂志000202 摘要 为考察4′-去甲鬼臼毒素C4位上联结碳原子对活性的影响，作者设计并合成C4位β构型的硫酯取代的衍生物18个.这类化合物在体外的抑制L1210细胞和KB细胞的药理实验中显示出一定的抗肿瘤活性，但均弱于etoposide.
Synthesis and Antitumor Activity of 4--Alky lthiocarbonyl-4Deoxy-4'-Deoxy -4'-Demethylepipodophyllotoxin
Chen Zaixin Ma Weiyong Chen Xiuhua Zhagn Chunnian
, 百拇医药
(Shanghai Institute of Pharmaceutical Industry ,Shanghai 200040)
Abstract Eighteen new 4--alkylthiocarbony -4-deoxy-4'-demethy lepipodophyllotoxin were synthesized adn screened in vitro against L1210 leukemia adn KBcells Most of them were less active than etoposide Fatty thioesters have higher activity than aromativ thioesters The carbon number of the main chain in fatty
Key words podophyllotoxin ;derivative ;antitumor activity
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鬼臼毒素(podophyllotoxin)是一种具有抗肿瘤活性的天然化合物.其半合成化合物依托泊苷(etoposide)和替尼泊苷(teniposide)在临床上广泛地应用于肿瘤的化疗〔1〕.但其疗效和毒副作用均有不足之处.为了寻找更为有效的鬼臼类抗肿瘤药物，药学工作者合成了大量的鬼臼毒素衍生物，并进行了构效关系研究〔2～6〕.本文作者曾报道C4为N取代的衍生物具有很高的生物活性〔7〕，根据生物电子等排原理，又设计并合成了C4位C取代的衍生物.本文报道4-β-硫酯-4-脱氧-4′-去甲表鬼臼毒素衍生物(Ⅲ)的合成及其体外抑制L1210细胞和KB细胞的活性.
1 合成路线及化合物表征
作者用4′-去甲表鬼臼毒素(1)为原料，合成中间体(2)和(3).在制备最终目标化合物(Ⅲ)的过程中，用二氯亚砜制备酰氯中间体，不经分离直接反应制得目标化合物18个.合成路线见图1，其理化数据见表1及表2.
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Fig.1 The route of synthesis of the title compounds(Ⅲ)
Tab.1 Physical data of the title compounds(Ⅲ)
Compd.
R
EI-MS m/z
mp/℃
〔α〕25D(DMF)
Yield/%
Ⅲ-1
—CH2CH3
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472(M+)
210～212
-23.5(c=0.2)
21.6
Ⅲ-2
—CH2CH2CH3
486(M+)
195～197
-57.6(c=0.2)
36.0
Ⅲ-3
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—CH(CH3)2
486(M+)
204～206
-98.3(c=0.2)
34.7
(to be continued)
Continued Tab.1
Compd.
R
EI-MS m/z
mp/℃
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〔α〕25D(DMF)
Yield/%
Ⅲ-4
—(CH2)3CH3
500(M+)
189～192
-47.3(c=0.2)
41.0
Ⅲ-5
—(CH2)4CH3
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514(M+)
270～273
-39.5(c=0.2)
35.1
Ⅲ-6
—CH2Ph
534(M+)
265～267
-105.6(c=0.2)
35.6
Ⅲ-7
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235～238
-85.2(c=0.2)
46.2
Ⅲ-8
554(M+)
247～249
-112.9(c=0.2)
51.3
Ⅲ-9
554(M+)
214～217
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-164.7(c=0.2)
48.1
Ⅲ-10
588(M+)
221～224
-68.1(c=0.2)
36.2
Ⅲ-11
588(M+)
254～256
-70.5(c=0.2)
40.3
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Ⅲ-12
588(M+)
231～233
-88.3(c=0.2)
44.0
Ⅲ-13
600(M+)
209～212
-91.3(c=0.2)
38.5
Ⅲ-14
550(M+)
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238～240
-115.6(c=0.2)
36.1
Ⅲ-15
550(M+)
224～226
-76.4(c=0.2)
33.9
Ⅲ-16
610(M+)
243～246
-168.4(c=0.2)
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42.2
Ⅲ-17
660(M+)
230～233
-141.9(c=0.2)
44.6
Ⅲ-18
570(M+)
250～252
-60.4(c=0.2)
41.8
Tab.2 1H-NMR of the title compounds(Ⅲ)
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Compd.
1H-NMR δ
Ⅲ-1
1.25～1.30(t,3H,SCH2CH3),2.89～2.95(m,2H,SCH2CH3),3.27～3.30(m,2H,H-2,3),3.79(s,6H,2×OCH3),3.86(d,1H,H-11α),4.07(d,1H,H-11β),4.39～4.46(m,2H,H-1,4),5.95(d,2H,OCH2O),6.13(s,2H,H-2′,6′),6.49(s,1H,H-8),7.12(s,1H,H-5)
Ⅲ-2
1.00(t,3H,SCH2CH2CH3),1.63(m,2H,SCH2CH2CH3),2.87(m,2H,SCH2CH2CH3),3.27(m,2H,H-2,3),3.77(s,6H,2×OCH3),3.88(d,1H,H-11α),4.06(d,1H,H-11β),4.40(m,1H,H-4),4.45(d,1H,H-1),5.93(d,2H,OCH2O),6.14(s,2H,H-2′,6′),6.48(s,1H,H-8),7.14(s,1H,H-5)
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Ⅲ-3
1.30～1.38(m,6H,2×CH3),3.22(dd,1H,H-2),3.27～3.38(m,1H,H-3),3.60～3.64(m,1H,CH at thioester),3.75(s,6H,2×OCH3),3.86(d,1H,H-11α),4.08(d,1H,H-11β),4.38～4.44(m,2H,H-1,4),5.93(d,2H,OCH2O),6.12(s,2H,H-2′,6′),6.57(s,1H,H-8),7.12(s,1H,H-5)
Ⅲ-4
0.95(t,3H,SCH2CH2CH2CH3),1.36～1.42(m,4H,SCH2CH2CH2CH3),2.87～2.92(m,2H,SCH2CH2CH2CH3),3.26～3.29(m,2H,H-2,3),3.75(s,6H,2×OCH3),3.84(d,1H,H-11α),4.06(d,1H,H-11β),4.39(m,1H,H-4),4.45(d,1H,H-1),5.93(d,2H,OCH2O),5.96(s,2H,H-2′,6′),6.48(s,1H,H-8),7.11(s,1H,H-5)
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(to be continued)
Continued Tab.2
Compd.
1H-NMR δ
Ⅲ-5
0.90〔t,3H,SCH2(CH2)3CH3〕,1.50～1.70〔m,6H,SCH2(CH2)3CH3〕,2.82～2.94〔m,2H,SCH2(CH2)3CH3〕,3.23～3.25(m,2H,H-2,3),3.75(s,6H,2×OCH3),3.84(d,1H,H-11α),4.06(d,1H,H-11β),4.00(m,1H,H-4),4.45(d,1H,H-1),5.94(d,2H,OCH2O),6.11(s,2H,H-2′,6′),6.48(s,1H,H-8),7.13(s,1H,H-5)
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Ⅲ-6
3.24～3.38(m,2H,H-2,3),3.66(s,6H,2×OCH3),3.85(d,1H,H-11α),4.14(d,1H,H-11β),4.18(d,2H,CH2 at thioester),4.38～4.45(m,2H,H-1,4),5.96(d,2H,OCH2O),6.19(s,2H,H-2′,6′),6.53(s,1H,H-8),6.99(s,1H,H-5),7.24～7.38(m,5H,Aromatic H at thioester)
Ⅲ-7
3.30～3.39(m,2H,H-2,3),3.66(s,6H,2×OCH3),3.85(d,1H,H-11α),4.18(d,1H,H-11β),4.38～4.42(m,1H,H-4),4.59(d,1H,H-1),5.96(d,2H,OCH2O),6.19(s,2H,H-2′,6′),6.53(s,1H,H-8),6.99(s,1H,H-5),7.26～7.43(m,5H,H at thioester)
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Ⅲ-8
3.31～3.35(m,1H,H-3),3.41～3.45(dd,1H,H-2),3.70(s,6H,2×OCH3),3.87(d,1H,H-11α),4.19(d,1H,H-11β),4.41～4.44(m,1H,H-4),4.57(d,1H,H-1),5.95(d,2H,OCH2O),6.11(s,2H,H-2′,6′),6.55(s,1H,H-8),7.13(s,1H,H-5),7.26～7.53(m,4H,H at thioester)
Ⅲ-9
3.29～3.41(m,2H,H-2,3),3.72(s,6H,2×OCH3),3.89(d,1H,H-11α),4.14(d,1H,H-11β),4.41～4.45(m,1H,H-4),4.57(d,1H,H-1),5.96(d,2H,OCH2O),6.16(s,2H,H-2′,6′),6.53(s,1H,H-8),7.13(s,1H,H-5),7.21～7.42(m,4H,Aromatic H at thioester)
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Ⅲ-10
3.35～3.37(m,2H,H-2,3),3.67(s,6H,2×OCH3),3.89(d,1H,H-11α),4.13(d,1H,H-11β),4.41～4.45(m,1H,H-4),4.56(d,1H,H-1),5.97(d,2H,OCH2O),6.16(s,2H,H-2′,6′),6.52(s,1H,H-8),7.00(s,1H,H-5),7.13～7.52(m,3H,Aromatic H at thioester)
Ⅲ-11
3.26～3.37(m,1H,H-3),3.42(dd,1H,H-2),3.74(s,6H,2×OCH3),3.88(d,1H,H-11α),4.09(d,1H,H-11β),4.38～4.44(m,1H,H-4),4.56(d,1H,H-1),5.96(d,2H,OCH2O),6.17(s,2H,H-2′,6′),6.50(s,1H,H-8),7.16(s,1H,H-5),7.22～7.43(m,3H,Aromatic H at thioester)
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Ⅲ-12
3.28～3.33(m,1H,H-3),3.47(dd,1H,H-2),3.77(s,6H,2×OCH3),3.87(d,1H,H-11α),4.24(d,1H,H-11β),4.40～4.44(m,1H,H-4),4.54(d,1H,H-1),5.96(d,2H,OCH2O),6.12(s,2H,H-2′,6′),6.55(s,1H,H-8),7.16(s,1H,H-5),7.19～7.48(m,3H,Aromatic H at thioester)
Ⅲ-13
3.28～3.35(m,1H,H-3),3.42(dd,1H,H-2),3.70(s,6H,2×OCH3),3.89(d,1H,H-11α),4.23(d,1H,H-11β),4.41～4.44(m,1H,H-4),4.59(d,1H,H-1),5.98(d,2H,OCH2O),6.18(s,2H,H-2′,6′),6.58(s,1H,H-8),7.00(s,1H,H-5),7.28～7.43(m,4H,Aromatic H at thioester)
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Ⅲ-14
3.31～3.39(m,2H,H-2,3),3.72(s,6H,2×OCH3),3.82(s,3H,OCH3 at thioester),3.86(d,1H,H-11α),4.13(d,1H,H-11β),4.38～4.20(m,1H,H-4),4.56(d,1H,H-1),5.95(d,2H,OCH2O),6.19(s,2H,H-2′,6′),6.52(s,1H,H-8),6.93(d,2H,Aromatic H at thioester),7.13(s,1H,H-5),7.26(d,2H,Aromatic H at thioester)
Ⅲ-15
3.29～3.41(m,2H,H-2,3),3.71(s,6H,2×OCH3),3.77(s,3H,OCH3 at thioester),3.90(d,1H,H-11α),4.15(d,1H,H-11β),4.41～4.44(m,1H,H-4),4.59(d,1H,H-1),5.42(s,1H,OH),5.96(d,2H,OCH2O),6.14(s,2H,H-2′,6′),6.53(s,1H,H-8),6.91～7.00(m,3H,H-4,5,6 at thioester),7.13(s,1H,H-5),7.30～7.34(m,1H,H-2 at thioester)
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Ⅲ-16
3.32～3.37(m,1H,H-3),3.47～3.52(dd,1H,H-2),3.75(s,6H,2×OCH3),3.89(d,1H,H-11α),4.10(d,1H,H-11β),4.41～4.55(m,1H,H-4),4.56(d,1H,H-1),5.97(d,2H,OCH2O),6.14(s,2H,H-2′,6′),6.53(s,1H,H-8),7.13(s,1H,H-5)
Ⅲ-17
3.35～3.38(m,1H,H-3),3.52(dd,1H,H-2),3.76(s,6H,2×OCH3),3.94(d,1H,H-11α),4.09(d,1H,H-11β),4.42～4.46(m,1H,H-4),4.55(d,1H,H-1),5.96(d,2H,OCH2O),6.16(s,2H,H-2′,6′),6.53(s,1H,H-8),7.14(s,1H,H-5)
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Ⅲ-18
3.35～3.39(m,1H,H-3),3.43(dd,1H,H-2),3.70(s,6H,2×OCH3),3.90(d,1H,H-11α),4.19(d,1H,H-11β),4.42～4.45(m,1H,H-4),4.63(d,1H,H-1),5.97(d,2H,OCH2O),6.23(s,2H,H-2′,6′),6.55(s,1H,H-8),7.14(s,1H,H-5),7.53～7.89(m,7H,Aromatic H at thioester)
2 合成实验
熔点用毛细管熔点仪测定，温度未校正.质谱由Varian MAT 212和计算机SS-MAT测定.核磁共振氢谱由Brucker AM-400测定，TMS为内标.旋光在Perkin-Elmer 214 MC旋光仪上测定，DMF为溶剂.柱色谱用硅胶H(薄层色谱用，青岛海洋化工厂)装柱.展开剂均为国产AR级试剂.
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标题化合物(Ⅲ)的制备通法：将化合物(3)100 mg(0.234 mmol)溶于5 mL的二氯甲烷中，加入5～6滴三乙胺.室温下慢慢滴加5～6滴二氯亚砜.搅拌反应30 min后，在低于30℃的温度下蒸干溶剂.再加入5 mL的二氯甲烷和5～6滴的吡啶.在搅拌下加入硫醇或硫酚(约6～7 mmol).继续搅拌反应4～10 h.用50 mL的二氯甲烷稀释.分别用冷的饱和碳酸氢钠溶液、水、饱和食盐水洗涤.无水硫酸钠干燥.柱色谱分离得白色固体.产率：20%～50%.
3 抗肿瘤活性实验
以etoposide为对照物，对表1中所列的化合物进行了体外L1210白血病细胞和KB细胞的生长抑制试验，结果见表3.该类化合物均表现出一定的抑瘤活性，但均弱于etoposide.和酯取代的化合物相似，脂肪硫酯的活性强于芳香硫酯的活性.但脂肪链的长短对活性没有影响.在芳香酯中，苯环上的取代基对化合物的活性无明显影响.Tab.3 Antitumor activities of the title compounds(Ⅲ)
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Compd.
L1210
KB
IC50/μg*mL-1
IC%/10 μg*mL-1
IC50/μg*mL-1
IC%/10 μg*mL-1
Ⅲ-1
4.11
74.19
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21.82
Ⅲ-2
3.16
91.13
6.91
58.18
Ⅲ-3
3.13
96.77
4.22
74.54
Ⅲ-4
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3.89
84.68
>10
45.45
Ⅲ-5
3.50
91.94
4.01
74.54
Ⅲ-6
4.34
65.32
>10
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9.09
Ⅲ-7
3.29
75.81
>10
12.73
Ⅲ-8
1.97
91.13
>10
25.45
Ⅲ-9
>10
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36.29
>10
16.36
Ⅲ-10
9.20
51.61
>10
9.09
Ⅲ-11
2.29
86.29
>10
9.09
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Ⅲ-12
5.40
65.32
>10
25.45
Ⅲ-13
4.34
85.48
>10
37.73
Ⅲ-14
>10
39.68
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>10
37.73
Ⅲ-15
>10
45.16
>10
7.27
Ⅲ-16
2.10
95.37
>10
21.83
Ⅲ-17
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2.69
87.04
>10
30.91
Ⅲ-18
>10
8.33
>10
18.18
etoposide
0.249
93.58
1.04
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80.00
参考文献
1，Issell BF.The podophyllotoxin derivatives VP-16-213 and VM-26.Cancer Chemother Pharmacol,1982，7(2-3)：73～80
2，王志光，马维勇，张椿年.4-烷硒基-4-脱氧-4′-去甲表鬼臼毒素衍生物的合成和抗肿瘤活性.化学学报，1993，51：933～936
3，王志光，马维勇，张椿年.4-巯基-4-脱氧-4′-去甲表鬼臼毒素衍生物的立体控制合成.化学学报，1992，50(7)：698～701
4，王志光，马维勇，李炳生，等.4-烷硫基-4-脱氧-4′-去甲表鬼臼毒素衍生物的合成和抗肿瘤活性.药学学报，1992，27(9)：656～661
5，尹述凡，庄武，马维勇，等.4-S-(5-酰胺基1,3,4-噻二唑-2-基)-4-脱氧-4′-去甲表鬼臼毒素衍生物的合成与抗肿瘤活性.药学学报，1993，28(10)：762～765
6，尹述凡，王志光，马维勇，等.4-O-卤代酰基-4′-去甲表鬼臼毒素类似物的合成和抗肿瘤活性.药学学报，1992，28(10)：758～761
7，王志光，尹述凡，马维勇，等.4-酰胺-4-脱氧-4′-去甲表鬼臼毒素衍生物的合成和抗肿瘤活性.药学学报，1993，28(6)：422～427
收稿日期:2000-01-28, 百拇医药