新型1, 3, 4-噻二唑衍生物的合成及抗肿瘤活性

引用本文: 刘婷婷, 万义超, 方浩. 新型1, 3, 4-噻二唑衍生物的合成及抗肿瘤活性[J]. 有机化学, 2015, 36(2): 417-424. doi: 10.6023/cjoc201507038 shu

Citation: Liu Tingting, Wan Yichao, Fang Hao. Synthesis and Antiproliferative Activity of Novel 1, 3, 4-Thiadiazole Derivatives[J]. Chinese Journal of Organic Chemistry, 2015, 36(2): 417-424. doi: 10.6023/cjoc201507038 shu

新型1, 3, 4-噻二唑衍生物的合成及抗肿瘤活性

1.
山东大学药学院济南 250012

通讯作者: 方浩, E-mail: haofangcn@sdu.edu.cn

摘要: 以取代的苯乙酸为起始原料, 通过成环、偶联、脱保护基并引入苯磺酰胺等反应得到了系列2, 5-二取代-1, 3, 4-噻二唑类化合物, 并利用¹H NMR, ¹³C NMR和HRMS对目标化合物进行了结构表征.用四甲基偶氮唑盐(MTT)法测试了目标化合物体外抑制前列腺癌细胞(PC-3)、乳腺癌细胞株(MDA-MB-231)和白血病细胞(K562)等肿瘤细胞的增殖活性.结果显示, 部分目标化合物具有较好的抗肿瘤细胞增殖活性, 其中(S)-N-(5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-基)-2-氨基-3-(4-溴苯基)丙酰胺(6a)和(S)-N-(5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-基)-2-氨基-3-苯基丙酰胺(6b)对K562细胞的活性与阳性对照药棉酚相当.

关键词:

噻二唑
/ 抗肿瘤
/ 合成

English

Synthesis and Antiproliferative Activity of Novel 1, 3, 4-Thiadiazole Derivatives

1.
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012

Corresponding author: Fang Hao, haofangcn@sdu.edu.cn

Received Date: 29 July 2015
Revised Date: 13 September 2015

Abstract: Twenty eight novel 1, 3, 4-thiadiazole derivatives were synthesized using different phenylacetic acids as the starting material, followed by the reaction of cyclization, coupling, deprotection, and finally introduced different substituted benzenesulfonamides. The structures of all target compounds were identified by ¹H NMR, ¹³C NMR and HRMS. The biological evaluation was performed on PC-3 (prostatic cancer cell), MDA-MB-231 (breast cancer cell) and K562 (chronic myelogenous leukemia cell) by 3-(4, 5-dimethylthigal-2-yl)-2, 5-(diphenyltetragalium) bromide (MTT) assay. The results suggested that some compounds exhibited good anti-proliferative activities against tumor cell lines. Especially, compounds 6a and 6b showed similar inhibitory activities against K562 cell compared with gossypol.

Key words:

杂环类化合物在生物活性化合物中发挥着重要作用.研究发现噻二唑类衍生物不仅具有杀虫、调节植物生长^{[1, 2]}等多种活性, 而且还能够发挥抗感染、抗炎^[3~5]、抗抑郁和抗癌^[6]等药理作用.在医药工业中, 噻二唑类化合物还是生产头孢唑啉、头孢卡奈、头孢西酮、唑酮头孢菌素、头孢帕罗、头孢菌素BL-S339、呋苄唑头孢菌素的重要中间体.特别是近年来许多研究发现2, 5-二取代-1, 3, 4-噻二唑类衍生物具有抗癌^{[9, 10, 11]}、抗糖尿病^[7]、抑制阿尔茨海默疾病^[8]和抗炎^{[12, 13]}等多种生物活性.因此针对2, 5-二取代-1, 3, 4-噻二唑化合物的研究已成为当前药学领域等研究的热点.我们以2, 5-二取代-1, 3, 4-噻二唑为母核, 结合文献报道^{[14, 15]}先后引入氨基酸和苯磺酰胺片断, 设计合成了一系列结构全新的目标化合物, 并考察了其抗肿瘤活性.合成路线设计见Scheme 1.

图图式1 目标化合物的合成 Figure 图式1. Synthetic route of the target compounds

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1 结果与讨论

1.1 目标化合物的合成

以取代的苯乙酸为起始原料, 与氨基硫脲在三氯氧磷的条件下得到2, 5-二取代-1, 3, 4-噻二唑中间体.随后与各种Boc保护氨基酸发生酰胺缩合反应得到目标化合物4a~4g, 目标化合物4a~4g在氯化氢饱和乙酸乙酯中脱去Boc保护基得到5a~5g, 部分脱保护基产物经Na₂CO₃碱化获得含有氨基的目标化合物6a~6c.若中间体5与不同取代苯磺酰氯反应可进一步得到目标化合物7a~7r.所有目标化合物结构均经¹H NMR, ¹³CNMR和HRMS确证.

1.2 目标化合物的抗肿瘤活性

以棉酚为阳性药, 用四甲基偶氮唑盐(MTT)法评价了目标化合物体外抗肿瘤活性.首先对所有目标化合物进行了体外抗肿瘤细胞增殖活性的初步测试, 结果表明:多数化合物抑制PC-3细胞效果较差而对K562的效果较好.分析目标化合物结构与K562抑制的关系可发现, 苯丙氨酸苯环上引入溴或苄氧基可使化合物活性降低, 抑制率下降(＜60%); Boc或苯磺酰基片断的引入也可使化合物活性降低, 大部分化合物抑制率＜60%;而在抑制率较好的化合物中(＞60%), 联苯基团的引入可使化合物活性提高, 抑制率提高.

图 1 在10^-4 mol/L浓度下目标化合物对PC-3细胞株和K562细胞株的抑制作用 Figure 1. Inhibitions of all the target compounds to PC-3 and K562 cell lines at 10^-4 mol/L

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初筛时发现部分目标化合物4f、6a、6b、7j对K562细胞抑制率大于70%, 在此基础上继续深入评价上述活性化合物体外抑制肿瘤细胞PC-3, K562, MDA-MB-231增殖的活性(表 2).结果表明, 目标化合物6b和6a的活性结果显著优于化合物4f和7j.特别是目标化合物6b的抑制肿瘤细胞K562增殖活性(IC₅₀=9.80 μmol·L^-1)与阳性对照药棉酚(IC₅₀=8.28 μmol·L^-1)相当.

表 2 部分目标化合物的抑制活性 Table 2. Antiproliferative activities of representative compounds

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Compd.	IC₅₀/(μmol·L^-1)
Compd.	PC-3	K562	MDA-MB-231
4f	＞50	＞50	＞50
6a	13.90	11.33	16.73
6b	18.35	9.80	13.57
7j	＞50	＞50	＞50
棉酚	8.58	8.28	8.54

表 2 部分目标化合物的抑制活性
Table 2. Antiproliferative activities of representative compounds

2 结论

本文将苯丙氨酸和联苯结构引入1, 3, 4-噻二唑母核, 设计、合成了28个目标化合物.所有目标化合物结构均经¹H NMR, ¹³C NMR和HRMS确证.在活性评价中, 多数目标化合物对K562肿瘤细胞的抗增殖效果较好; 部分活性化合物还评价了其抑制PC-3和MDA-MB-231肿瘤细胞的增殖活性.其中, 活性目标化合物6b抑制K562肿瘤细胞增殖的活性与阳性对照药棉酚相当.上述研究为我们研究噻二唑类抗肿瘤药物提供了新的研究思路.

3 实验部分

3.1 仪器与试剂

合成所用实验中所使用的试剂均为市售分析纯或化学纯, 未经纯化直接使用.使用原料均为市售的国产试剂, 纯度为96%~98%.前列腺癌细胞PC-3、乳腺癌细胞株MDA-MB-231、白血病细胞K562和改良型RPMI1640培养基(美国Hyclone公司); 10% (体积分数)胎牛血清(美国Hyclone公司); 2.5 g/L胰蛋白酶(美国Gibco公司); RY-1型熔点仪(天津市分析仪器厂); Bruker-300 MHz核磁共振波谱仪; API 4000型电喷雾电离质谱测仪; Agilent 6520型高分辨电喷雾电离质谱仪; Thermo Varioskan Flash全波长多功能酶标仪; Thermo Forma3111型二氧化碳恒温培养箱; Olympus CKX31双目倒置显微镜.

3.2 化合物的合成

3.3 抗肿瘤活性实验

处于对数生长期的细胞用含10% (体积分数)小牛血清的RPMI1640培养液调整细胞数(贴壁细胞PC-3和MDA-MB-231先用2.5 g/L的胰蛋白酶消化后调整为5×10⁴ cell/mL的细胞悬液), 接种于96孔培养板中, 每孔加入100 μL细胞悬液, 然后于37 ℃, 5%二氧化碳条件下培养.待贴壁细胞贴壁后(悬浮细胞约静置2 h), 用完全培养基稀释药物至所需浓度, 每孔加入100 μL相应的含药(50 μmol/L)的培养基, 同时设立阴性对照组, 阳性对照组, 96孔细胞培养板置于37 ℃, 5% CO₂培养箱中培养48 h.然后每孔加入20 μL MTT (5 mg/mL), 于培养箱中继续培养4 h、弃去孔中液体, 每孔加入150 μL二甲基亚砜(DMSO)溶解, 于37 ℃恒温振摇5~10 min, 用酶标仪读出每孔的OD值(λ=57 0 nm), 计算抑制率, 计算公式如下:

抑制率(%)=(1-给药组吸光度值/空白组吸光度值)×100%.

初筛100 μmol/L时抑制率大于50%的样品, 重新设置浓度进行细筛并计算得IC₅₀.

辅助材料(Supporting Information) 所有化合物的¹H NMR、¹³C NMR和HRMS谱图.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.

3.2.1 中间体化合物3a~3d的合成

将联苯乙酸(10.62 g, 50 mmol)、2-氨基硫脲(4.56 g, 50 mmol)溶于三氯氧磷(10 mL), 油浴75 ℃反应0.5 h后, 加入110 mL水, 110 ℃回流反应4 h, 反应完毕, 用2 mol·L^-1 NaOH调pH至中性得固体过滤, 用乙醇重结晶得5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-胺(3b), 白色固体4.5 g, 产率33.7%. m.p. 240~242 ℃(文献值[3a]195~197 ℃); ¹H NMR (300 MHz, DMSO-d₆) δ: 7.67~7.62 (m, 4H), 7.48~7.43 (m, 2H), 7.38~7.33 (m, 3H), 7.04 (s, 1H).

5-(4-甲氧基苄基)-1, 3, 4-噻二唑-2-胺(3a):得红色固体1.2 g, 产率54%. m.p. 180~182 ℃(文献值[3b]229~231 ℃); ¹H NMR (300 MHz, DMSO-d₆) δ: 7.21~7.16 (m, 2H), 6.99 (s, 2H), 6.90~6.86 (m, 2H), 4.06 (s, 2H), 3.73 (s, 3H).

5-(4-氯)-1, 3, 4-噻二唑-2-胺(3c):得白色固体1.19 g, 产率50%. m.p. 195~197 ℃(文献值[3c]181~182 ℃); ¹H NMR (300 MHz, DMSO-d₆) δ: 7.41~7.35 (m, 2H), 7.31~7.29 (m, 2H), 7.04 (s, 2H), 4.15 (s, 2H).

5-(4-溴)-1, 3, 4-噻二唑-2-胺(3d):得白色固体1.69 g, 产率21%. m.p. 174~176 ℃(文献值[3c]200~202 ℃); ¹H NMR (400 MHz, DMSO-d₆) δ: 7.54~7.49 (m, 2H), 7.25~7.22 (m, 2H), 6.97 (s, 2H), 4.14 (s, 2H).

3.2.4 目标化合物7a~7q的合成

将4c (0.49 g, 1 mmol)溶于氯化氢饱和乙酸乙酯(10 mL)中, 室温搅拌过夜后, 过滤得到的白色固体5c未经纯化直接进行下一步反应.将5c (0.40 g, 1 mmol)溶于四氢呋喃(20 mL), 10 min后冰浴条件下加入三乙胺(0.84 mL, 6 mmol), 搅拌0.5 h后加入3-硝基-4-氯苯磺酰胺(0.38 g, 1.5 mmol), 反应过夜.次日蒸除溶剂后, 分别用1 mol·L^-1柠檬酸和饱和氯化钠洗2遍, 无水硫酸镁干燥后浓缩经柱层析[V(石油醚):V(乙酸乙酯)=2:1]纯化得(S)-2-(4-氯-3-硝基苯磺酰基)-N-(5-(4-甲氧基苄基)-1, 3, 4-噻二唑-2-基)-3-苯基丙酰胺(7a), 白色固体0.065 g, 产率34%. m.p. 232~234 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.68 (s, 1H), 9.01 (d, J=9.0 Hz, 1H), 8.04 (s, 1H), 7.73 (d, J=9.0 Hz, 2H), 7.26 (d, J=9.0 Hz, 2H), 7.12~7.10 (m, 5H), 6.93 (d, J=8.7 Hz, 2H), 4.35~4.26 (m, 3H), 3.74 (s, 3H), 2.99 (dd, J=13.8, 4.8 Hz, 1H), 2.74 (dd, J=13.8, 10.5 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 169.19, 164.68, 158.27, 157.88, 146.52, 140.39, 136.06, 132.82, 130.97, 129.86, 129.45, 129.36, 129.12, 127.94, 126.37, 123.49, 114.12, 57.55, 55.01, 37.45, 34.13; HRMS (AP-ESI) calcd for C₂₅H₂₁ClN₅O₆S₂ [M-H]^- 586.0622, found 586.0614.

(S)-2-(4-甲基苯磺酰基)-N-(5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-基)-3-(4-苄基苯基)丙酰胺(7b):得到白色固体0.08 g, 产率12%. m.p. 223~225 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.50 (s, 1H), 8.30 (d, J=9.1 Hz, 1H), 7.66~7.62 (m, 4H), 7.48~7.30 (m, 12H), 7.06 (d, J=8.2 Hz, 4H), 6.84 (d, J=8.6 Hz, 2H), 5.04 (s, 2H), 4.38 (s, 2H), 4.24~4.18 (m, 1H), 2.86 (dd, J=13.8, 5.4 Hz, 1H), 2.68 (dd, J=13.8, 9.24 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.11, 164.08, 158.64, 157.65, 142.77, 140.26, 139.44, 137.99, 137.63, 137.38, 130.73, 129.86, 129.49, 129.40, 128.88, 128.26, 128.12, 127.91, 127.55, 127.10, 126.80, 114.83, 69.61, 58.01, 37.50, 35.00, 21.20; HRMS (AP-ESI) calcd for C₃₈H₃₃N₄O₄S₂ [M-H]^- 673.1943, found 673.1952.

(S)-2-(4-硝基苯磺酰基)-N-(5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-基)-3-(4-苄基苯基)丙酰胺(7c):得到白色固体0.051 g, 产率16%. m.p. 222~224 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.74 (s, 1H), 8.95 (d, J=8.7 Hz, 1H), 8.16 (dd, J=6.9, 1.8 Hz, 1H), 7.68~7.4 (m, 6H), 7.47~7.03 (m, 10H), 7.05 (d, J=8.7 Hz, 2H), 6.75 (d, J=8.7 Hz, 2H), 4.96 (s, 2H), 4.38 (s, 2H), 4.30~4.22 (m, 1H), 2.92 (dd, J=13.8, 4.5 Hz, 1H), 2.63 (dd, J=13.8, 3.3 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.07, 164.32, 158.62, 157.68, 149.41, 146.55, 140.26, 139.42, 137.48, 137.29, 130.75, 129.84, 129.40, 128.84, 128.73, 128.29, 128.21, 128.16, 127.91, 127.55, 127.10, 124.48, 114.70, 69.61, 58.45, 37.20, 35.00; HRMS (AP-ESI) calcd for C₃₇H₃₀N₅O₆S₂ [M-H]^- 704.1638, found 704.1648.

(S)-2-苯磺酰基-N-(5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-基)-3-(4-苄基苯基)丙酰胺(7d):得白色固体0.1 g, 收率15%. m.p. 224~226 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.56 (s, 1H), 8.45 (d, J=9.0 Hz, 1H), 7.68 (d, J=7.9 Hz, 4H), 7.50~7.24 (m, 16H), 7.07 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.5 Hz, 2H), 5.04 (s, 2H), 4.38 (s, 2H), 4.26~4.20 (m, 1H), 2.89 (dd, J=13.8, 5.4 Hz, 1H), 2.68 (dd, J=13.8, 9.4 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.19, 164.16, 158.66, 157.64, 140.99, 140.26, 139.43, 137.65, 137.48, 132.41, 130.74, 129.86, 129.41, 129.10, 128.88, 128.83, 128.26, 128.15, 127.91, 127.53, 127.10, 126.67, 114.88, 69.61, 58.09, 37.46, 35.01; HRMS (AP-ESI) calcd for C₃₇H₃₁N₄O₄S₂ [M-H]^- 659.1787, found 659.1771.

(S)-2-(4-硝基苯磺酰基)-N-(5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-基)-3-(4-溴苯基)丙酰胺(7e):得白色固体0.1 g, 产率29%. m.p. 246~248 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.78 (s, 1H), 9.01 (d, J=8.7 Hz, 1H), 8.17 (dd, J=6.9, 1.8 Hz, 2H), 7.68~7.64 (m, 6H), 7.49~7.34 (m, 5H), 7.28 (d, J=8.1 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 4.39 (s, 2H), 4.32~4.24 (m, 1H), 2.98 (dd, J=13.5, 3.9 Hz, 1H), 2.73 (dd, J=13.5, 1.8 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 169.83, 164.39, 158.65, 149.43, 146.47, 140.26, 139.42, 137.29, 136.21, 131.87, 131.35, 129.84, 129.40, 128.09, 127.91, 127.55, 127.10, 124.55, 120.54, 58.14, 37.26, 35.00. HRMS (AP-ESI) calcd for C₃₀H₂₃BrN₅O₅S₂ [M-H]^- 678.0304, found 678.0298.

(S)-2-(4-硝基苯磺酰基)-N-(5-([1, 1'-联苯] -4-基甲基)-1, 3, 4-噻二唑-2-基)-3-苯基丙酰胺(7f):得白色固体0.08 g, 产率83%. m.p. 242~244 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.70 (s, 1H), 8.95 (d, J=8.9 Hz, 1H), 8.13 (dd, J=7.0, 1.9 Hz, 2H), 7.71~7.63 (m, 6H), 7.49~7.44 (m, 2H), 7.40~7.35 (m, 3H), 7.14~7.09 (m, 5H), 4.36~4.02 (m, 3H), 2.98 (dd, J=13.6, 4.9 Hz, 1H), 2.75 (dd, J=13.6, 10.0 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 169.83, 164.31, 158.53, 149.55, 146.44, 140.27, 139.42, 137.26, 136.65, 129.82, 129.70, 129.40, 128.57, 128.18, 127.90, 127.55, 127.10, 126.98, 124.53, 58.09, 38.06, 34.98; HRMS (AP-ESI) calcd for C₃₀H₂₄N₅O₅S₂ [M-H]^- 598.1219, found 598.1222.

(S)-2-(4-甲基苯磺酰基)-N-(5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-基)-3-苯基丙酰胺(7g):得白色固体0.06 g, 产率11%. m.p. 222~224 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.51 (s, 1H), 8.34 (d, J=9.2 Hz, 1H), 7.67~7.65 (m, 4H), 7.48~7.34 (m, 7H), 7.40~7.35 (m, 3H), 7.23~7.14 (m, 5H), 7.07 (d, J=8.1 Hz, 2H), 4.38 (s, 2H), 4.30~4.24 (m, 1H), 2.93 (dd, J=13.6, 5.7 Hz, 1H), 2.75 (dd, J=13.6, 9.4 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 169.98, 164.09, 158.61, 142.86, 140.27, 139.44, 137.95, 137.37, 136.75, 129.86, 129.69, 129.53, 129.40, 128.58, 127.91, 127.55, 127.10, 127.03, 126.83, 57.77, 38.33, 35.00, 21.18; HRMS (AP-ESI) calcd for C₃₁H₂₇N₄O₃S₂ [M-H]^- 567.1525, found 567.1527.

(S)-2-苯磺酰基-N-(5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-基)-3-(4-溴苯基)丙酰胺(7h):得白色固体0.06 g, 产率10%. m.p. 244~246 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.63 (s, 1H), 8.52 (d, J=8.9 Hz, 1H), 7.68 (d, J=7.6 Hz, 4H), 7.46~7.26 (m, 12H), 7.11 (d, J=7.9 Hz, 2H), 4.39 (s, 2H), 4.25~4.24 (m, 1H), 2.93 (dd, J=13.6, 4.0 Hz, 1H), 2.70 (dd, J=13.6, 10.6 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 169.98, 164.25, 158.69, 140.91, 140.25, 139.43, 137.46, 136.30, 132.39, 131.90, 131.42, 129.86, 129.40, 129.11, 127.91, 127.54, 127.10, 126.58, 120.44, 57.78, 37.48, 35.02; HRMS (AP-ESI) calcd for C₃₀H₂₄BrN₄O₃S₂ [M-H]^- 633.0453, found 633.0435.

(S)-2-(3-硝基-4-氯苯磺酰基)-N-(5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-基)-3-苯基丙酰胺(7i):得白色固体0.1 g, 产率16%. m.p. 218~220 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.74 (s, 1H), 9.02 (d, J=8.9 Hz, 1H), 8.04 (s, 1H), 7.71~7.64 (m, 6H), 7.49~7.34 (m, 5H), 7.13~7.09 (m, 5H), 4.39~4.4.30 (m, 3H), 2.98 (dd, J=13.6, 4.6 Hz, 1H), 2.74 (dd, J=13.6, 10.3 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 169.78, 164.32, 158.55, 147.06, 140.93, 140.28, 139.43, 137.28, 136.59, 133.34, 131.51, 129.88, 129.65, 129.40, 128.47, 127.90, 127.55, 127.09, 126.91, 124.03, 58.10, 38.00, 35.06; HRMS (AP-ESI) calcd for C₃₀H₂₃ClN₅O₅S₂ [M-H]^- 632.0829, found 632.0813.

(S)-2-(3-硝基-4-氯苯磺酰基)-N-(5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-基)-3-(4-溴苯基)丙酰胺(7j):得白色固体0.05 g, 产率11%. m.p. 224~25 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.75 (s, 1H), 8.09 (d, J=1.8 Hz, 1H), 7.74~7.64 (m, 6H), 7.49~7.31 (m, 7H), 7.11 (d, J=8.2 Hz, 2H), 4.40 (s, 2H), 4.30 (s, 1H), 2.98 (dd, J=13.8, 4.0 Hz, 1H), 2.70 (dd, J=13.8, 10.8 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 164.40, 147.07, 140.87, 140.27, 139.42, 137.29, 136.08, 133.33, 131.83, 131.41, 131.34, 129.88, 129.41, 127.91, 127.55, 127.10, 124.04, 120.53, 57.91, 37.24, 35.04 (s); HRMS (AP-ESI) calcd for C₃₀H₂₂BrClN₅O₅S₂ [M-H]^- 709.9934, found 709.9918.

(S)-2-(4-甲基苯磺酰基)-N-(5-([1, 1'-联苯]-4-基甲基-1, 3, 4-噻二唑-2-基)-3-(4-溴苯基)丙酰胺(7k):得白色固体0.09 g, 产率14%. m.p. 234~236 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.58 (s, 1H), 8.38 (d, J=9.1Hz, 1H), 7.67~7.65 (m, 4H), 7.48~7.41 (m, 4H), 7.38~7.33 (m, 5H), 7.09 (t, J=17.9, 8.8 Hz, 4H), 4.40 (s, 2H), 4.24~4.18 (m, 1H), 2.91 (dd, J=13.6, 4.6 Hz, 1H), 2.69 (dd, J=13.6, 10.2 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 169.99, 164.18, 158.71, 142.84, 140.26, 139.44, 137.88, 137.37, 136.30, 131.89, 131.33, 129.86, 129.49, 129.40, 127.90, 127.55, 127.10, 126.68, 120.40, 57.71, 37.49, 35.02, 21.31; HRMS (AP-ESI) calcd for C₃₁H₂₆BrN₄O₃S₂ [M-H]^- 647.0609, found 647.0634.

(S)-2-苯磺酰基-N-(5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-基)-3-苯基丙酰胺(7l):得白色固体0.05 g, 产率9%. m.p. 266~268 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.57 (s, 1H), 8.47 (d, J=9.1 Hz, 1H), 7.67~7.61 (m, 4H), 7.51~7.28 (m, 10H), 7.22~7.14 (m, 5H), 4.38 (s, 2H), 4.33~4.27 (m, 1H), 2.96 (dd, J=13.6, 5.6 Hz, 1H), 2.75 (dd, J=13.6, 9.4 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.08, 164.16, 158.64, 140.95, 140.26, 139.43, 137.47, 136.75, 132.49, 129.85, 129.68, 129.41, 129.14, 128.59, 127.91, 127.53, 127.11, 126.68, 57.84, 38.27, 35.00; HRMS (AP-ESI) calcd for C₃₀H₂₅N₄O₃S₂ [M-H]^- 553.1368, found 553.1366.

(S)-2-(3-硝基-4-氯苯磺酰基)-N-(5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-基)-3-(4-苄基苯基)丙酰胺(7m):得到白色固体0.11 g, 收率15%. m.p. 236~238 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.72 (s, 1H), 8.99 (d, J=8.8 Hz, 1H), 8.09 (d, J=1.5 Hz, 1H), 7.74~7.64 (m, 6H), 7.48~7.33 (m, 10H), 7.06 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.4 Hz, 2H), 5.00 (s, 2H), 4.40 (s, 2H), 4.31~4.26 (m, 1H), 2.92 (dd, J=13.8, 4.4 Hz, 1H), 2.67 (dd, J=13.8, 10.4 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 169.88, 164.33, 158.54, 157.65, 147.01, 141.02, 140.27, 139.43, 137.54, 137.29, 133.30, 131.53, 130.71, 129.88, 129.77, 129.40, 128.86, 128.57, 128.27, 128.18, 127.90, 127.55, 127.09, 124.08, 114.61, 69.55, 58.29, 37.19, 35.06; HRMS (AP-ESI) calcd for C₃₇H₂₉ClN₅O₆S₂ [M-H]^- 738.1248, found 738.1264.

(S)-2-苯磺酰基-N-(5-(4-氯苄基)-1, 3, 4-噻二唑-2-基)-3-苯基丙酰胺(7n):得白色固体0.15 g, 收率29%. m.p. 254~256 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.59 (s, 1H), 8.50 (d, J=12.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.36~7.14 (m, 10H), 4.34~4.26 (m, 3H), 2.91~2.72 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 169.56, 163.18, 158.13, 140.43, 136.73, 136.22, 131.95, 131.68, 130.65, 129.16, 128.63, 128.07, 126.58, 126.16, 57.30, 37.75, 34.03; HRMS (AP-ESI) calcd for C₂₄H₂₀ClN₄O₃S₂ [M-H]^-511.0665, found 511.0659.

(S)-2-(4-甲氧基苯磺酰基)-N-(5-(4-溴苄基)-1, 3, 4-噻二唑-2-基)-3-苯基丙酰胺(7o):得白色固体0.14 g, 收率24%. m.p. 224~226 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.53 (s, 1H), 8.30 (d, J=12.0 Hz, 1H), 7.57~7.54 (m, 2H), 7.45~7.42 (m, 2H), 7.30~7.14 (m, 7H), 6.81~6.77 (m, 2H), 4.35~4.21 (m, 3H), 3.64 (s, 3H), 2.92 (dd, J=16.0, 8.0 Hz, 1H), 2.74~2.87 (m, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 169.57, 162.98, 161.88, 158.10, 137.02, 136.24, 136.24, 131.92, 131.55, 131.03, 129.17, 128.50, 128.06, 126.54, 120.15, 113.76, 57.18, 55.38, 37.82 m, 34.06; HRMS (AP-ESI) calcd for C₂₅H₂₂N₄O₄S₂ [M-H]^- 587.0245, found 587.0243.

(S)-2-(3-硝基-4-氯苯磺酰基)-N-5-(4-氯苄基)-1, 3, 4-噻二唑-2-基)-3-苯基丙酰胺(7p):得白色固体0.15 g, 产率25%. m.p. 241~243℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.74 (s, 1H), 9.02 (d, J=8.0 Hz, 1H), 8.26 (s, 1H), 7.71 (s, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 7.14~7.09 (m, 5H), 4.36 (s, 3H), 2.99 (dd, J=12.0, 4.0 Hz, 1H), 2.75 (t, J=8.0 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 169.23, 163.34, 158.01, 146.54, 140.40, 136.56, 136.06, 132.84, 131.69, 131.69, 130.99, 130.68, 129.34, 129.13, 128.64, 127.96, 126.40, 123.50, 57.53, 37.46, 34.07; HRMS (AP-ESI) calcd for C₂₄H₁₈Cl₂N₅O₅S₂ [M-H]^- 590.0126, found 590.0120.

(S)-2-(4-甲氧基苯磺酰基)-N-(5-(4-甲氧基苄基)-1, 3, 4-噻二唑-2-基)-3-苯基丙酰胺(7q):得白色固体0.13 g, 产率24%. m.p. 218~220℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.46 (s, 1H), .26 (d, J=8.0 Hz, 1H), 7.47 (d, J=12.0 Hz, 2H), 7.25~7.14 (m, 7H), 6.93 (d, J=8.0 Hz, 2H), 6.81 (d, J=8.0 Hz, 2H), 4.25 (s, 3H), 3.75 (s, 3H), 3.67 (s, 3H), 2.92 (dd, J=12.0, 4.0 Hz, 1H), 2.75 (t, J=12.0, 8.0 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 169.53, 164.41, 161.89, 158.26, 157.98, 136.25, 131.93, 129.85, 129.50, 129.16, 128.49, 128.05, 126.53, 114.11, 113.76, 57.19, 55.39, 55.02, 37.82, 34.07; HRMS (AP-ESI) calcd for C₂₆H₂₅N₄O₅S₂ [M-H]^- 537.1266, found 537.1274.

3.2.3 目标化合物6a~6c的合成

将4c (0.49 g, 1 mmol)溶于氯化氢饱和乙酸乙酯(10 mL)中, 室温搅拌过夜后, 将白色固体过滤后加入饱和碳酸钠液搅拌, 2 h后用乙酸乙酯提取.提取液经干燥后蒸除除乙酸乙酯, 得(S)-N-(5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-基)-2-氨基-3-(4-溴苯基)丙酰胺(6a)白色固体0.3 g, 产率61%. m.p. 237~240 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.67~7.63 (m, 4H), 7.48~7.34 (m, 7H), 7.18 (d, J=8.0 Hz, 2H), 5.79 (s, 3H), 4.37 (s, 2H), 3.72 (t, J=4.0 Hz, 1H), 2.97 (dd, J=12.0, 4.0 Hz, 1H), 2.76 (dd, J=12.0, 8.0 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 173.95, 163.36, 160.62, 140.27, 139.32, 137.92, 137.62, 132.06, 131.41, 129.86, 129.39, 127.88, 127.49, 127.08, 119.96, 56.74, 35.21, 14.56; HRMS (AP-ESI) calcd for C₂₄H₂₂BrN₄OS [M+H]⁺ 495.0677, found 495.0688.

(S)-N-(5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-基)-2-氨基-3-苯基丙酰胺(6b):得白色固体0.4 g, 产率96%. m.p. 188~190 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.67~7.63 (m, 4H), 7.48~7.36 (m, 5H), 7.25~7.18 (m, 5H), 5.76 (s, 3H), 4.37 (s, 2H), 3.75 (t, J=4.0 Hz, 1H), 3.01 (dd, J=12.0, 4.0 Hz, 1H), 2.78 (dd, J=12.0, 8.0 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 174.13, 163.33, 160.59, 140.27, 139.32, 138.38, 137.62, 129.86, 129.75, 129.39, 128.60, 127.88, 127.49, 127.09, 126.75, 56.94, 35.21; HRMS (AP-ESI) calcd for C₂₄H₂₃N₄OS [M+H]⁺ 415.1593, found 415.1603.

(S)-叔丁基(1-((5-(4-溴苯基)-1, 3, 4-噻二唑-2-基)氨基)-3-(4-((4-硝基苄基)氧基)苯基)-1-氧代丙-2-基)氨基甲酸酯(6c):得白色固体, 产率100%. m.p. 216~219 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.96 (s, 1H), 8.26 (d, J=8.0 Hz, 2H), 7.93 (d, J=8.0 Hz, 2H), 7.73~7.69 (m, 4H), 7.38 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 2H), 6.97 (d, J=8.0 Hz, 2H), 5.25 (s, 2H), 4.46~4.36 (m, 1H), 3.00 (dd, J=16.0, 4.0 Hz, 1H), 2.82~2.76 (m, 1H), 1.32~1.16 (m, 9H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 172.11, 161.41, 159.07, 157.13, 155.94, 147.44, 145.66, 132.78, 132.78, 130.90, 130.44, 129.85, 129.29, 128.61, 124.40, 124.04, 115.01, 78.86, 68.45, 56.86, 36.43, 28.60; HRMS (AP-ESI) calcd for C₂₉H₂₉BrN₅O₆S [M+H]⁺ 654.1022, found 654.1014.

3.2.5 目标化合物7r的合成

将7ba (0.1 g, 0.14 mmol)于50 mL茄形瓶中, 加入3 mL二氯甲烷与2.5 mL三氟乙酸, 室温搅拌过夜.反应结束后蒸除溶剂, 然后用1 mol·L^-1氢氧化钠溶液调pH至碱性, 经乙酸乙酯提取除杂质后, 水层析出白色固体得(S)-2-(3-硝基-4-氯苯磺酰基)-N-(5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-基)-3-(4-羟基苯基)丙酰胺(7r) 0.03 mg, 产率34%. m.p. 222~224 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.66 (s, 1H), 9.16~8.90 (m, 2H), 8.13 (s, 1H), 7.10~7.63 (m, 5H), 7.49~7.34 (m, 5H), 6.93 (d, J=7.8 Hz, 2H), 6.53 (d, J=8.1 Hz, 2H), 4.38 (s, 2H), 4.25 (s, 1H), 2.87 (dd, J=13.8, 4.8 Hz, 1H), 2.66 (dd, J=13.8, 9.9 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 173.94, 172.96, 158.82, 155.64, 146.15, 141.77, 139.95, 138.46, 137.95, 132.02, 131.33, 130.05, 129.22, 128.85, 128.45, 127.96, 127.23, 126.75, 126.53, 123.86, 114.61, 60.65, 34.93, 23.32; HRMS (AP-ESI) calcd for C₃₀H₂₃ClN₅O₆S₂ [M-H]^- 648.0778, found 648.0777.

3.2.2 目标化合物4a~4g的合成

将Boc-苯丙氨酸(0.58 g, 2.2 mmol)溶于30 mL二氯甲烷中, 冰浴下加入N, N-二异丙基乙胺(DIEA) (0.7 mL, 4 mmol), 待液体澄清后加入2-(7-偶氮苯并三氮唑)-N, N, N', N'-四甲基脲六氟磷酸酯(HATU) (0.99 g, 2.6 mmol), 搅拌0.5 h后加入3a (0.44 g, 2 mmol), 常温反应过夜.次日减压蒸除二氯甲烷, 用乙酸乙酯萃取, 萃取液分别用1M柠檬酸和饱和氯化钠洗2遍, 无水硫酸镁干燥, 蒸除溶剂后用乙醇与水重结晶得(S)-叔丁基(1-{[5-(4-甲氧基苄基)-1, 3, 4-噻二唑-2-基]氨基}-1-氧代-3-苯基丙-2-基)氨基甲酸酯(4a), 白色固体0.5 g, 产率53%. m.p. 154~156 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.64 (s, 1H), 7.33~7.07 (m, 8H), 6.92 (d, J=8.0 Hz, 2H), 4.42 (s, 1H), 4.27 (s, 2H), 3.74 (s, 3H), 3.00 (dd, J=16.0, 4.0 Hz, 1H), 2.82~2.76 (m, 1H), 1.29~1.08 (m, 9H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 171.28, 164.40, 158.50, 158.25, 155.36, 137.41, 129.88, 129.63, 129.22, 128.04, 126.40, 114.13, 78.29, 55.99, 55.02, 36.72, 34.14, 28.06; HRMS (AP-ESI) calcd for C₂₄H₂₉N₄O₄S [M+H]⁺469.1910, found 469.1903.

(S)-叔丁基(1-{[5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-基]氨基}-1-氧代-3-(4-苄基苯基)丙-2-基)氨基甲酸酯(4b):得白色固体1.0 g, 产率100%. m.p. 210~212 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.68 (s, 1H), 7.67~7.63 (m, 4H), 7.48~6.93 (m, 13H), 6.93 (d, J=8.4 Hz, 2H), 5.05 (s, 1H), 4.40~4.36 (m, 3H), 2.94~2.88 (m, 1H), 2.76~2.68 (m, 1H), 1.29~1.18 (m, 9H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.41, 163.51, 158.63, 157.04, 155.40, 139.73, 138.88, 137.14, 136.92, 130.27, 129.54, 129.37, 128.87, 128.34, 127.70, 127.57, 127.37, 127.02, 126.57, 114.40, 78.29, 69.12, 56.32, 35.91, 34.54, 28.08; HRMS (AP-ESI) calcd for C₃₆H₃₇N₄O₄S [M+H]⁺621.2536, found 621.2529.

(S)-叔丁基(1-{[5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-基]氨基}-1-氧代-3-(4-溴苯基)丙-2-基)氨基甲酸酯(4c):得白色固体1.5 g, 产率100%. m.p. 212~214 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.71 (s, 1H), 7.67~7.64 (m, 4H), 7.50~7.42 (m, 6H), 7.38~7.28 (m, 7H), 4.41 (s, 3H), 3.00~2.94 (m, 1H), 2.79~2.72 (m, 1H), 1.29~1.15 (m, 9H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.07, 163.57, 158.62, 155.39, 139.73, 138.88, 136.96, 136.90, 131.50, 130.93, 129.36, 128.86, 127.37, 127.02, 126.57, 119.68, 78.36, 56.01, 36.04, 34.54, 28.03; HRMS (AP-ESI) calcd for C₂₉H₃₀BrN₄O₃S [M+H]⁺595.1202, found 595.1212.

(S)-叔丁基(1-((5-([1, 1'-联苯]-4-基甲基)-1, 3, 4-噻二唑-2-基)氨基)-1-氧代-3-苯基丙-2-基)氨基甲酸酯(4d):得白色固体0.40 g, 产率49%. m.p. 190~192 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.69 (s, 1H), 7.67~7.64 (m, 4H), 7.66~7.42 (m, 4H), 7.38~7.19 (m, 7H), 4.41~4.37 (m, 3H), 2.82~2.76 (m, 1H), 2.51~7.49 (m, 1H), 1.29~1.18 (m, 9H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.85, 164.05, 159.16, 155.90, 140.25, 139.41, 137.93, 137.43, 129.89, 129.74, 129.38, 128.56, 127.89, 127.54, 127.09, 126.93, 78.82, 56.57, 37.26, 35.07, 28.58; HRMS (AP-ESI) calcd for C₂₉H₃₁N₄O₃S [M+H]⁺ 515.2117, found 515.2112.

(S)-叔丁基(1-((5-(4-氯)-1, 3, 4-噻二唑-2-基)氨基)-1-氧代-3-苯基丙-2-基)氨基甲酸酯(4e):得白色固体0.5 g, 收率53%. m.p. 186~188 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 2.72 (s, 1H), 7.61~7.18 (m, 10H), 4.45~6.35 (m, 3H), 3.00 (dd, J=12.0, 4.0 Hz), 2.82 (dd, J=12.0, 4.0 Hz), 1.32~1.14 (m, 9H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 171.34, 163.06, 158.66, 155.38, 137.40, 136.69, 131.67, 130.68, 129.22, 128.63, 128.04, 126.40, 78.30, 56.05, 36.72, 34.10, 28.06; HRMS (AP-ESI) calcd for C₂₃H₂₆ClN₄O₃S [M+H]⁺ 473. 1414, found 473. 1410.

(S)-叔丁基(1-((5-(4-溴)-1, 3, 4-噻二唑-2-基)氨基)-1-氧代-3-苯基丙-2-基)氨基甲酸酯(4f):得白色固体2.0 g, 收率100%. m.p. 170~172 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.70 (s, 1H), 7.55~7.45 (m, 2H), 7.35~7.18 (m, 8H), 4.45 (s, 1H), 4.35 (d, J=8.0 Hz, 2H), 3.02 (dd, J=16.0, 4.0 Hz, 1H), 2.84~2.78 (m, 1H), 1.30~1.08 (m, 9H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 171.35, 162.96, 158.66, 155.38, 137.41, 137.12, 131.56, 131.06, 129.22, 128.04, 126.41, 120.14, 78.30, 56.05, 36.71, 34.15, 28.06; HRMS (AP-ESI) calcd for C₂₃H₂₆BrN₄O₃S [M+H]⁺ 519. 0889, found 519.0903.

(S)-叔丁基(3-(4-溴苯基)-1-((5-(4-溴苯基)-1, 3, 4-噻二唑-2-基)氨基)-1-氧代丙-2-基)氨基甲酸酯(4g):得白色固体2.0 g, 产率100%, m. p. 200~202 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.99 (s, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.75 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 2H), 4.48~4.43 (m, 1H), 3.05~3.01 (m, 1H), 2.85~2.79 (m, 1H), 1.32 (s, 9H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.78, 161.48, 159.04, 155.94, 137.42, 132.79, 132.04, 131.48, 129.83, 129.30, 124.42, 120.24, 78.94, 56.46, 36.58, 28.57; HRMS (AP-ESI) calcd for C₂₂H₂₃Br₂N₄O₃S [M+H]⁺ 582.9837, found 582.9830.

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图式1 目标化合物的合成

Scheme 1 Synthetic route of the target compounds

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图 1 在10^-4 mol/L浓度下目标化合物对PC-3细胞株和K562细胞株的抑制作用

Figure 1 Inhibitions of all the target compounds to PC-3 and K562 cell lines at 10^-4 mol/L

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表 2 部分目标化合物的抑制活性

Table 2. Antiproliferative activities of representative compounds

Compd.	IC₅₀/(μmol·L^-1)
Compd.	PC-3	K562	MDA-MB-231
4f	＞50	＞50	＞50
6a	13.90	11.33	16.73
6b	18.35	9.80	13.57
7j	＞50	＞50	＞50
棉酚	8.58	8.28	8.54

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