CN103980183A - 取代哌啶氨荒酸铋(ⅲ)配合物及其制备方法和在制备抗肿瘤药物中的应用 - Google Patents
取代哌啶氨荒酸铋(ⅲ)配合物及其制备方法和在制备抗肿瘤药物中的应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明涉及一种取代哌啶氨荒酸铋(Ⅲ)配合物，结构简式如下，该取代哌啶氨荒酸铋(Ⅲ)配合物具有良好的抗肿瘤活性，对胃癌、肺癌、肝癌、大肠癌、宫颈癌、卵巢癌、乳腺癌、白血病、结肠癌等恶性肿瘤具有显著的抑瘤活性，将其开发为新型抗肿瘤新药具有广泛的应用前景。。
Description
技术领域
本发明涉及抗肿瘤药物技术领域，具体涉及取代哌啶氨荒酸铋(Ⅲ)配合物及其制备方法和在制备抗肿瘤药物中的应用。
背景技术
恶性肿瘤(癌症)严重威胁着人类的健康和生命，每年死于癌症的病人约占总死亡人数的四分之一，且发病率呈逐年增长态势，癌症的防治成为医学和生命科学工作者主要研究的课题之一。我国癌症发病率十分惊人，已成为世界第二大癌症高发国，统计数据（WHOGLOBOCAN 2008）显示：中国所有的肿瘤新病例为280万，是美国新发肿瘤病例的2倍（美国为140万）；同年中国肿瘤死亡病例为196万，而美国的死亡病例为57万，二者的差距为3.4倍。由此可见，未来中国和全球的抗癌药物市场增长的潜力巨大，研发新一代抗癌药物必有庞大的市场。然而，目前用于癌症治疗的抗癌药物有几十种，但对多数常见实体瘤仍缺乏有效药物，且不少抗肿瘤药在临床应用过程中产生了不同程度的耐药性。因此，开发筛选高效低毒的抗肿瘤药物成为抗肿瘤新药研发最为重要的任务。
铋具有悠久的药用历史。铋属于周期表中第六周期第V A族重金属元素，位于金属和非金属交界处，具有特殊的理化性质。由于铋的无毒性、不致癌性，被称为绿色金属。经过多年的研究与发展，铋化合物已广泛的用于医学、化工以及生物等方面，其中应用最为广泛的领域是医药，如用于外科处理创伤和止血，作为杀灭幽门杆菌治疗胃溃疡和胃肠道紊乱的药物成分，另有研究发现铋的配合物能够抑制癌细胞的生长且无副作用。
香港大学孙红哲教授对铋制剂在医疗上的作用进行了深入研究。铋化合物在癌症治疗领域的应用不仅表现在具有抗癌活性上, 它们还可以减轻别的抗癌化疗药物所引起的毒副作用。动物实验表明, 硝酸铋和柠檬酸联用可以有效地缓解顺铂类药物在抗癌治疗过程中所引起的肾脏损害。最近研究发现, 铋剂可以抑制SARS冠状病毒的生长, 其过程可能同Bi(Ⅲ)抑制SARS病毒中的解旋酶(helicase)有关。铋可以和生物体内的多种分子结合。研究发现谷胱甘肽(GSH) 可以防止CBS 沉淀。铋也可以通过和转铁蛋白(transferrin) 结合来达到生物传输的目的。
2006年新加坡国立大学Edward R T Tiekink教授在美国申请了二烷基二硫代氨基甲酸铋化合物的专利（US 2006/0142621 A1），探讨了二烷基氨荒酸铋化合物的抗肿瘤活性。但存在结构单一，作用的抗肿瘤细胞株少，临床应用价值较低的问题，距临床应用还有较大距离。
发明内容
本发明的目的在于公开一种取代哌啶氨荒酸铋(Ⅲ)配合物及其制备方法和在制备抗肿瘤药物中的应用，取代哌啶氨荒酸铋(Ⅲ)配合物具有良好的抗肿瘤活性，对胃癌、肺癌、肝癌、大肠癌、宫颈癌、卵巢癌、乳腺癌、白血病、结肠癌等恶性肿瘤具有显著的抑瘤活性。
本发明为实现上述目的，所采用的技术方案是：取代哌啶氨荒酸铋(Ⅲ)配合物，结构简式如下：
,
当R2和R3为H时，R1为；
当R1和R3为H时，R2为；
当R1和R2为H时，R3为、或。
取代哌啶氨荒酸铋(Ⅲ)配合物的制备方法：
取 2-甲基哌啶和三乙胺加入无水甲醇，搅拌溶解后滴加CS2，得到反应液，取BiCl3和无水甲醇的混合溶液滴入上述反应液中，反应结束后进行抽滤、醇洗、干燥，固体物重结晶，得到2-甲基哌啶氨荒酸铋；
或者是：取3-哌啶甲酸乙酯和NaOH加入无水甲醇，搅拌溶解后滴加CS2，得到反应液，取BiCl3和无水甲醇的混合溶液滴入上述反应液中，反应结束后进行抽滤、醇洗、干燥，固体物在硅胶柱上分离得到3-乙氧羰基哌啶氨荒酸铋；
或者是：取4-（1-吡咯烷基）哌啶和NaOH加入无水甲醇，搅拌溶解后滴加CS2，得到反应液，取BiCl3和无水甲醇的混合溶液滴入上述反应液中，反应结束后进行抽滤、醇洗、干燥，固体物在硅胶柱上分离得到4-（1-吡咯烷基）哌啶氨荒酸铋；
或者是：取4-哌啶甲酸乙酯和NaOH加入无水甲醇，搅拌溶解后滴加CS2，得到反应液，取BiCl3和无水甲醇的混合溶液滴入上述反应液中，反应结束后进行抽滤、醇洗、干燥，固体物重结晶，得到4-乙氧羰基哌啶氨荒酸铋；
或者是：取4-苯基哌啶和NaOH加入无水甲醇，搅拌溶解后滴加CS2，得到反应液，取BiCl3和无水甲醇的混合溶液滴入上述反应液中，反应结束后进行抽滤、醇洗、干燥，固体物重结晶，得到4-苯基哌啶氨荒酸铋。
取代哌啶氨荒酸铋(Ⅲ)配合物对胃癌、肺癌、肝癌、大肠癌、宫颈癌、卵巢癌、乳腺癌、白血病、结肠癌等恶性肿瘤具有显著的抑瘤活性。
有益效果
本发明的取代哌啶氨荒酸铋(Ⅲ)配合物以及所述化合物的盐和水合物具有良好的抗肿瘤活性，制备方法简单易行，对胃癌、肺癌、肝癌、大肠癌、宫颈癌、卵巢癌、乳腺癌、白血病、结肠癌等恶性肿瘤具有显著的抑瘤活性，将其开发为新型抗肿瘤新药具有广泛的应用前景。
附图说明
图1-图3为实施例一的配合物（编号N056）对于肿瘤细胞体外生长抑制测试结果；
图4-图6为实施例三的配合物（编号N057）对于肿瘤细胞体外生长抑制测试结果；
图7为实施例一的配合物（编号N056）对实体肿瘤模型的生长抑制试验结果。
具体实施方式
以下通过具体实施例对本发明作出进一步说明，但不作为限制。
实施例一：2-甲基哌啶氨荒酸铋及其制备
在圆底烧瓶中加入0.496g(5mmol) 2-甲基哌啶，1.01 g(10 mmol)三乙胺，15 mL无水甲醇，磁力搅拌溶解后，0-5℃冷水浴，滴加0.76g(10mmol)CS2，磁力搅拌反应5 h。
将0.53g(1.7mmol)BiCl3溶于15 mL无水甲醇中，滴入上述反应液中，室温搅拌3 h，抽滤，无水甲醇洗，真空干燥。固体物用乙腈重结晶，得0.75 g黄色晶体，收率61.5%，熔点：194-195℃，编号为N056。
1HNMR(400 MHz, CDCl3), δ: 1.303～1.320 (9H, d, -CH3, J=6.8Hz), 1.627～1.715 (6H, m, Py-CH2，J=3.6-7.2Hz), 1.742～1.822 (6H, m, Py-CH2，J=4.4-7.6Hz), 2.163～2.213 (6H, m, Py-CH2，J=4.0-6.8Hz), 3.105～3.177(6H, q, N-CH2, J=7.2Hz), 4.978～5.122 (3H, m, N-CH, J=6.0-9.6Hz)。
分子式：C21H36N3S6Bi，元素分析结果(括号内为计算值％)：C 34.39 (34.46)，H 4.90(4.97)，N 5.66(5.74)。
实施例二： 3-乙氧羰基哌啶氨荒酸铋及其制备
在圆底烧瓶中加入0.786 g(5mmol)3-哌啶甲酸乙酯，0.25 g(6mmol)氢氧化钠，15 mL无水甲醇，磁力搅拌溶解后，0-5℃冷水浴，滴加0.76 g(10mmol) CS2，磁力搅拌反应5 h。
将0.53 g(1.7mmol)BiCl3溶于15 mL无水甲醇中，滴入上述反应液中，室温搅拌3 h，抽滤，无水甲醇洗，真空干燥。固体物在柱上纯化，洗脱剂：乙酸乙酯-石油醚= 1: 2，分离得到1.09 g黄色粉末固体，收率72.2 %，熔点：83-85℃。
1HNMR(400 MHz, CDCl3), δ: 1.245～1.281 (9H, t, -CH3, J=7.2Hz), 1.662～1.754 (6H, m, Py-CH2, J=9.2Hz), 1.835～1.911 (3H, m, Py-CH，J=7.6Hz), 2.251～2.327 (3H, m, Py-CH，J=7.6Hz), 2.643～2.696 (3H, m, Py-CH，J=7.2Hz), 3.040～3.232 (6H, t t, N-CH2，J=10-12.8Hz), 4.119～4.172 (6H, q, O-CH2，J=6.8Hz), 4.982～5.218 (6H, d d, N-CH2, J=11.2-12.8Hz)。
分子式：C27H42N3O6S6Bi，元素分析结果(括号内为计算值％)：C 35.69 (35.79)，H 4.51(4.68)，N 4.56(4.64)。
实施例三：4-（1-吡咯烷基）哌啶氨荒酸铋及其制备
在圆底烧瓶中加入0.771 g(5 mmol) 4-（1-吡咯烷基）哌啶，0.25 g(6mmol)氢氧化钠，15 mL无水甲醇，磁力搅拌溶解后，0-5℃冷水浴，滴加0.76 g(10 mmol)CS2，磁力搅拌反应2 h，室温下再搅拌反应4 h。
将0.53 g (1.7 mmol) BiCl3溶于15 mL无水甲醇中，滴入上述反应液中，室温搅拌3 h，抽滤，无水甲醇洗，真空干燥。固体物在柱上纯化，洗脱剂：乙酸乙酯-石油醚 = 1: 3，分离得到0.86 g黄色粉末固体，收率57.5 %。熔点：138-140℃，编号为N057。
1HNMR(400 MHz, CDCl3), δ: 1.625～1.720 (6H, m, Py-CH2, J=3.6-10.8Hz), 1.777～1.891 (12H, t, Cy-CH2, J=4.0-8.4Hz), 1.964～2.005 (6H, d d, Py-CH2，J=3.2-10.4Hz), 2.335～2.392(3H, m, Py-CH-N, J=3.6-6.0Hz), 2.571～2.611(12H, t, Cy-CH2-N, J=3.6-8.4Hz), 3.285～3.352 (6H, m, Py-CH2-N, J=4.0-10.8Hz), 4.816～4.894 (6H, m, Py-CH2-N, J=3.6-10.4Hz)。
分子式：C30H51N6S6Bi，元素分析结果(括号内为计算值％)：C 40.09 (40.16)，H 5.60(5.74)，N 9.46(9.37)。
实施例四：4-乙氧羰基哌啶氨荒酸铋及其制备
在圆底烧瓶中加入0.786 g(5mmol)4-哌啶甲酸乙酯，0.25 g(6mmol)氢氧化钠，15 mL无水甲醇，磁力搅拌溶解后，0-5℃冷水浴，滴加0.76g(10 mmol) CS2，磁力搅拌反应5 h。
将0.53 g(1.7mmol)BiCl3溶于15 mL无水甲醇中，滴入上述反应液中，室温搅拌3 h，抽滤，无水甲醇洗，真空干燥。固体物用乙腈重结晶，得0.95 g黄色固体，收率62.9%，熔点：78-80℃。
1HNMR(400 MHz, CDCl3), δ: 1.233～1.282 (9H, t, -CH3, J=6.8Hz), 1.863～1.913(6H, m, Py-CH2，J=8.8Hz), 2.011～2.044(6H, m, Py-CH2, J=8.6Hz), 2.610～2.671(3H, m, Py-CH, J=8.6Hz), 3.386～3.446 (6H, q, N-CH2, J=10.4Hz), 4.130～4.184 (6H, q, O-CH2, J=7.2Hz), 4.742～4.822 (6H, q, N-CH2, J=10.8Hz)。
分子式：C27H42N3O6S6Bi，元素分析结果(括号内为计算值％)：C 35.69 (35.79)，H 4.51(4.68)，N 4.56(4.64)。
实施例五：4-苯基哌啶氨荒酸铋及其制备
在圆底烧瓶中加入0.806 g(5mmol)4-苯基哌啶，0.25 g(6mmol)氢氧化钠，15 mL无水甲醇，磁力搅拌溶解后，0-5℃冷水浴，滴加0.76g(10 mmol) CS2，磁力搅拌反应5 h。
将0.53 g(1.7mmol)BiCl3溶于15 mL无水甲醇中，滴入上述反应液中，室温搅拌3 h，抽滤，无水甲醇洗，真空干燥。固体物用乙腈重结晶，得1.35 g鲜黄色晶体，收率88.2%，熔点：127-129℃。
1HNMR(400 MHz, CDCl3), δ: 1.822～1.927 (6H, m, Py-CH2, J=3.6-9.6Hz), 1.954～2.032(6H, m, Py-CH2, J=3.6-9.4Hz), 2.812～2.882 (3H, m, Ph-CH，J=3.6-8.4Hz), 3.100～3.170 (6H, m, N-CH2, J=2.4-10.8Hz), 5.211～5.273 (6H, m, N-CH2，J=3.6-10.2Hz), 7.210～7.246 (9H, t, Ph-H, J=8.4Hz), 7.302～7.339 (6H, t, Ph-H, J=8.0Hz)。
分子式：C36H42N3S6Bi，元素分析结果(括号内为计算值％)：C 47.05 (47.09)，H 4.50(4.62)，N 4.49(4.58)。
抗肿瘤活性测定
一、体外抗肿瘤活性研究
1. 细胞株和培养
将癌症细胞白血病细胞株(HL-60)、肺癌细胞株(A-549)、肝癌细胞株(BEL-7402)、大肠癌细胞株(SW-1116)、宫颈癌细胞株(HELA)、卵巢癌细胞株(3AO)、乳腺癌细胞株(MCF-7)、胃癌细胞株(MKN-28)等癌症细胞培养于10%灭活胎牛血清，100U/mL青霉素，100 μg/mL链霉素的RPMI1640或DMEM培养基中，于37 ℃的10% CO2培养箱及饱和湿度条件下培养。对于正常培养，贴壁细胞均用1倍浓度的胰蛋白酶-EDTA中进行胰蛋白酶消化脱壁后，按1: 5～1: 20的比率将细胞每3～4天传代一次（当细胞在培养皿中所覆盖面积为80-90%时）。
2. 药物抗肿瘤活性测定
实验前一天，所述细胞在1倍浓度胰蛋白酶-EDTA溶液中进行胰蛋白酶消化约5分钟（在37℃培养箱中），悬浮于10 mL的DMEM或RPMI培养液中，然后接种到96孔板。细胞按密度为1～2×104/孔接种到标准DMEM或RPMI培养基中，体积为50 μL 。
第二天，用标准DMEM培养液制备受试金属配合物的一系列2x浓度稀释贮液（0.003μM～60μM）。将50 μL稀释贮液加入到相对应平板孔中，测试平板中的细胞所接受的受试配合物最终浓度为（0.0015μM～30μM）一系列9个不同的剂量组，每组3个平行孔。因此2种化合物（例如X和Y)可以在一个板中同时进行试验（表1）。除了试验化合物之外，每个板还包括阳性对照（0.5 μM 阿霉素）和阴性对照（DMSO）。
表1：试验中96孔板与受测化合物终浓度的测试方案
96孔板培养板置37 ℃ 培养箱中培养48小时后，弃去上清液，加入200 μL/孔新鲜配置的含有20μL的0.5 mg/mL MTT溶液（0.5%MTT）的无血清培养液，37℃ 继续培养5小时。弃去上清液，加入150μL DMSO，震荡混匀后，在酶联免疫检测仪OD 490 nm处测量各孔的吸光值，计算细胞生长抑制率，公式为：细胞生长抑制率 =[（阴性对照组OD值—实验组OD值）/ 阴性对照组OD值] ×100%。并由细胞生长抑制率与对应浓度，通过软件计算出IC50值（半数抑制率IC50，细胞生长抑制率为50%的药物浓度）。对于每一种化合物，这种测定都另外重复两次，一旦完成三次测定，就用原始数据计算出IC50值。
3.实验结果
经MTT法测定不同浓度的编号N056、N057等对于肿瘤细胞生长活性影响，结果如图1-图6所示。编号N056、N057等对各种肿瘤细胞体外生长抑制活性IC50值如下表所示（表2）。
表2．配合物对肿瘤细胞体外生长抑制活性
二、体内抗肿瘤活性研究
1. 实验材料
1.1. 实验动物与瘤株
8-12周龄健康Balb/c小鼠，雌雄各半（体重22-25g），每个笼子装5只小鼠，置于清洁动物饲养间，自由摄食饮水。
使用小鼠结肠癌细胞C26在Balb/c小鼠两侧皮下造异源实体肿瘤模型。
1.2. 测试药物
所有配合物都配制在20% DMSO载体溶液中，对编号N056，浓度为4 mg/mL。
2. 实验步骤
2.1. 动物造模与分组
在小鼠两侧前掖下通过皮下注射5×106个培养细胞建立了C26实体瘤模型，待80%肿瘤体积大于80 mm3时，将所有小鼠随机分成实施例处理组和载体对照组。
2.2. 给药方法
所有所述配合物都以腹腔注射给药，30 mg/kg/天，对照组接受无药载体注射，一周5天持续3周，休息一周，或直到小鼠不得不由于大肿瘤而处死。
2.3. 肿瘤测量
游标卡尺测量肿瘤的两个轴（mm)(L，最长轴；W，最短轴）。用公式：肿瘤体积 V=0.5×L×W2来估算肿瘤体积V（立方毫米，mm3)。在药物治疗的同时每天进行肿瘤测量，在治疗结束后一周3-4次。
2.4. 抗肿瘤效果的评价
抗肿瘤活性通过绘制肿瘤生长曲线以及计算最大肿瘤生长抑制率（最大抑瘤率，MTGI)进行评价：最大肿瘤生长抑制（MTGI）=[（载体对照组平均肿瘤体积—给药组平均肿瘤体积）/载体对照组平均肿瘤体积]×100%。
2.5. 实验结果
结果经统计分析，编号N056的最大抑瘤率为38%，p<0.05。经one-way ANOVA分析后所绘出的肿瘤生长曲线如图7。
3.结论
实验数据显示，金属配合物对胃癌、肺癌、肝癌、大肠癌、宫颈癌、卵巢癌、乳腺癌、白血病、结肠癌等恶性肿瘤具有显著的抑瘤活性，将其开发为新型抗肿瘤新药具有广泛的应用前景。
Claims (4)
1.取代哌啶氨荒酸铋(Ⅲ)配合物，其特征在于：结构简式如下：
,
当R2和R3为H时，R1为；
当R1和R3为H时，R2为；
当R1和R2为H时，R3为、或。
2.如权利要求1所述的取代哌啶氨荒酸铋(Ⅲ)配合物的制备方法，其特征在于：
取 2-甲基哌啶和三乙胺加入无水甲醇，搅拌溶解后滴加CS2，得到反应液，取BiCl3和无水甲醇的混合溶液滴入上述反应液中，反应结束后进行抽滤、醇洗、干燥，固体物重结晶，得到2-甲基哌啶氨荒酸铋；
或者是：取3-哌啶甲酸乙酯和NaOH加入无水甲醇，搅拌溶解后滴加CS2，得到反应液，取BiCl3和无水甲醇的混合溶液滴入上述反应液中，反应结束后进行抽滤、醇洗、干燥，固体物在硅胶柱上分离得到3-乙氧羰基哌啶氨荒酸铋；
或者是：取4-（1-吡咯烷基）哌啶和NaOH加入无水甲醇，搅拌溶解后滴加CS2，得到反应液，取BiCl3和无水甲醇的混合溶液滴入上述反应液中，反应结束后进行抽滤、醇洗、干燥，固体物在硅胶柱上分离得到4-（1-吡咯烷基）哌啶氨荒酸铋；
或者是：取4-哌啶甲酸乙酯和NaOH加入无水甲醇，搅拌溶解后滴加CS2，得到反应液，取BiCl3和无水甲醇的混合溶液滴入上述反应液中，反应结束后进行抽滤、醇洗、干燥，固体物重结晶，得到4-乙氧羰基哌啶氨荒酸铋；
或者是：取4-苯基哌啶和NaOH加入无水甲醇，搅拌溶解后滴加CS2，得到反应液，取BiCl3和无水甲醇的混合溶液滴入上述反应液中，反应结束后进行抽滤、醇洗、干燥，固体物重结晶，得到4-苯基哌啶氨荒酸铋。
3.如权利要求1所述的取代哌啶氨荒酸铋(Ⅲ)配合物以及所述化合物的盐和水合物在制备抗肿瘤药物中的应用。
4.如权利要求3所述的取代哌啶氨荒酸铋(Ⅲ)配合物以及所述化合物的盐和水合物在制备抗肿瘤药物中的应用，其特征在于：所述的肿瘤为胃癌、肺癌、肝癌、大肠癌、宫颈癌、卵巢癌、乳腺癌、白血病或者结肠癌。
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| CN104876893A (zh) * | 2015-05-25 | 2015-09-02 | 南阳师范学院 | 一类取代高哌嗪氨荒酸铋配合物、配合物的可药用盐以及配合物的制备方法和抗肿瘤应用 |
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| US20060142621A1 (en) * | 2003-01-29 | 2006-06-29 | Tiekink Edward R T | Bismuth dithiocarbamate compounds and uses thereof |
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| ANTONIO COSTANTINO FABRETTI,等: "Synthesis and spectroscopic characterization of arsenic(III), antimony(III), bismuth(III), tin(II) and lead(II) dithiocarbamate adducts", 《POLYHEDRON》, vol. 5, no. 3, 31 December 1986 (1986-12-31), pages 871 - 875 * |
| AYSEGUL EFENDIOGLU,等: "Bi(III)4-methylpiperidinedithiocarbamate coprecipitation procedure for separation-pre-concentration of trace metal ions in water samples by flame atomic absorption spectrometric determination", 《JOURNAL OF HAZARDOUS MATERIALS》, vol. 149, no. 1, 27 March 2007 (2007-03-27), pages 160 - 165, XP022235141, DOI: doi:10.1016/j.jhazmat.2007.03.065 * |
| CARLO PRETI,等: "Preparation and study of some antimony and bismuth tris(dithiocarbamate) and five-coordinate monohalobis(dithiocarbamate) derivatives", 《JOURNAL OF MOLECULAR STRUCTURE》, vol. 53, no. 1, 31 December 1979 (1979-12-31), pages 35 - 44 * |
| MANOUSSAKIS, G. E.,等: "Bis(N,N-disubstituted dithiocarbamate)bismuth(III) tetrafluoroborates", 《JOURNAL OF INORGANIC AND NUCLEAR CHEMISTRY》, vol. 37, no. 11, 31 December 1975 (1975-12-31), pages 2330 - 2333 * |
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| CN104876893A (zh) * | 2015-05-25 | 2015-09-02 | 南阳师范学院 | 一类取代高哌嗪氨荒酸铋配合物、配合物的可药用盐以及配合物的制备方法和抗肿瘤应用 |
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