CN115403497B - 新型含有金刚烷骨架席夫碱衍生物的合成及抗肿瘤活性研究 - Google Patents
新型含有金刚烷骨架席夫碱衍生物的合成及抗肿瘤活性研究 Download PDFInfo
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- CN115403497B CN115403497B CN202211171610.9A CN202211171610A CN115403497B CN 115403497 B CN115403497 B CN 115403497B CN 202211171610 A CN202211171610 A CN 202211171610A CN 115403497 B CN115403497 B CN 115403497B
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- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical group C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 title claims abstract description 14
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- 238000003786 synthesis reaction Methods 0.000 title description 18
- 239000002246 antineoplastic agent Substances 0.000 claims abstract 2
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- -1 adamantane skeleton schiff base Chemical class 0.000 claims description 19
- 230000000840 anti-viral effect Effects 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
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- 229940124350 antibacterial drug Drugs 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 25
- IFOABTLXHWKNIJ-UHFFFAOYSA-N 5-(1-adamantyl)-2-hydroxybenzaldehyde Chemical compound C1=C(C=O)C(O)=CC=C1C1(C2)CC(C3)CC2CC3C1 IFOABTLXHWKNIJ-UHFFFAOYSA-N 0.000 abstract description 14
- 230000005764 inhibitory process Effects 0.000 abstract description 9
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- VQHPRVYDKRESCL-UHFFFAOYSA-N 1-bromoadamantane Chemical compound C1C(C2)CC3CC2CC1(Br)C3 VQHPRVYDKRESCL-UHFFFAOYSA-N 0.000 abstract description 3
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- PVRSIFAEUCUJPK-UHFFFAOYSA-N (4-methoxyphenyl)hydrazine Chemical compound COC1=CC=C(NN)C=C1 PVRSIFAEUCUJPK-UHFFFAOYSA-N 0.000 description 1
- QBTROWHSMGZXCV-RQURQNPSSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecoxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QBTROWHSMGZXCV-RQURQNPSSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C337/00—Derivatives of thiocarbonic acids containing functional groups covered by groups C07C333/00 or C07C335/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
- C07C337/06—Compounds containing any of the groups, e.g. thiosemicarbazides
- C07C337/08—Compounds containing any of the groups, e.g. thiosemicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. thiosemicarbazones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明研究一种含有金刚烷骨架席夫碱衍生物式（）的合成及抗肿瘤活性研究。
Description
技术领域
本发明涉及一种新型含有金刚烷骨架的席夫碱衍生物的合成及抗肿瘤的活性的研究。
背景技术
随着发病率和死亡率的增加，癌症是人们的主要死因，也是一个重大的公共卫生问题。肿瘤是由于身体内的局部组织细胞肿块异常，细胞增生所形成的新生物。根据2020年统计，全世界约有1930万新的癌症病例，此外，近1000万人死于癌症。其中，最常见的癌症是女性乳腺癌（226万例）、其次是肺癌（2.21万例）和前列腺癌（1.41万例）；最常见的癌症死亡原因是肺癌（179万人死亡）、肝癌（83万人）和胃癌（76.9万人）。目前，癌症的主要治疗方法包括手术治疗，放疗，化疗，靶向药物治疗，中药治疗。在早期，患者常采用的方法是手术切除，但是由于副作用比较大，有复发和转移的可能，所以在手术后可以采用化疗和放疗的方法。许多癌症和死亡病例可以通过降低风险因素的流行率来预防，同时提高临床护理服务的有效性，特别是对生活在农村地区和弱势群体的患者。
金刚烷是一种脂环烃，具有很好的脂溶性，最主要的性质在于金刚烷的骨架是无毒性的，所以可以利用这一性质来改变它的药理活性。早在1964年人们就发现，低浓度的金刚烷胺能够抑制甲型流感病毒，高浓度时抑制乙型流感病毒及其它病毒，具有抗病毒的作用。缩氨基硫脲是由氨基硫脲与适当的酮或醛通过缩合反应，研究发现缩氨基硫脲化合物不但具有抗病毒活性，还具有抗菌、抗肿瘤、抗麻风病、抗结核和抗疟疾等多种生物活性。总之，席夫碱衍生物可诱导溶酶体损伤，增加细胞内活性氧，导致细胞凋亡，这有助于其抗肿瘤氧化机制。
发明内容
1.本发明公开了一种含有金刚烷骨架席夫碱衍生物及其制备方法，使用CCK8法对细胞进行毒性试验，评价化合物对A549、HELA、MCF-7抗增殖效果。
2.本发明采用如下技术方案，含有金刚烷骨架席夫碱衍生物，结构为：
。
2.本发明中R为，R1,R2,R3是各自单独的H,F,OCH3或CH3。
3.在本发明中，以1-溴金刚烷为起始原料，在钯碳的催化下进行了付克烷基化反应，生成了1-（4-甲氧基-3-甲基苯基）金刚烷，随后，经过自由基取代、氧化反应和去甲基化反应得到5-（金刚烷-1-基）-2-羟基苯甲醛，结构式为：
。
4.本发明中，5-（金刚烷-1-基）-2-羟基苯甲醛与氨基硫脲通过缩合反应得到金刚
烷骨架席夫碱衍生物：式（）。
5.本发明中公开了上述席夫碱衍生物式（）在制备药物尤其是抗肿瘤方面的应
用。
6.本发明通过核磁共振，高分辨质谱，红外光谱等表征，结果充分证实了化合物的成功合成。
附图说明
图1为合成路线。
图2为合成路线的目标产物。
图3-6为化合物2、3、4、5的氢谱图和碳谱图。
图6-14为目标化合物6a-h氢谱图与碳谱图。
图15为目标化合物和5-氟尿嘧啶在20微摩浓度下对不同癌细胞的抑制率。
具体实施方式
实施例1，5-（金刚烷-1-基）-2-羟基苯甲醛的合成
（1）1-（4-甲氧基-3-甲基苯基）金刚烷的合成（化合物2）
取100ml单口瓶，在常温下依次加入1-溴金刚烷1g，无水碳酸钾0.321g，10%钯/碳0.742g，最后加入二甲基苯甲醚为溶剂，将整个反应体系转移到油浴锅中，温度调至173摄氏度，通入氮气隔绝空气，连接直行冷凝管，当开始滴定时，计时，反应12h。反应结束后，冷却至室温，使用二氯甲烷过滤，得到橙色滤液，将滤液浓缩，使用洗脱剂（V石油醚）经柱层析洗脱，洗脱过程中，由于柱层析无色，需要每50ml进行薄层层析并观察。洗脱后，去除其溶剂，由于二甲基苯甲醚沸点高，所以采用油泵将多余溶剂抽取出来。得到白色固体。收率：81%。1H NMR (400 MHz, Chloroform-d) δ 7.15 (s, 2H), 6.79 (d, J = 9.3 Hz, 1H),3.82 (s, 3H), 2.23 (s, 3H), 2.09 (s, 3H), 1.90 (s, 6H), 1.76 (s, 6H).13C NMR(101 MHz, Chloroform-d) δ 155.62, 143.35,127.40,125.90,122.80,109.61,55.33,43.47,36.90,35.49,29.10,16.49。
（2）1-（3-（溴甲基）-4-甲氧基苯基）金刚烷的合成（化合物3）
取100ml单口瓶，在常温下依次加入1-（4-甲氧基-3-甲基苯基）1g，N-溴代琥珀酰亚胺0.833g，过氧化苯甲酰10mg，最后加入10mlCCL4作为溶剂。将整个反应体系转移到80摄氏度油浴锅中，通入氮气隔绝空气，连接直行冷凝管，当开始滴定时，计时，反应12h。反应结束后，冷却至室温，使用CCL4过滤，得到淡黄色液体，将滤液浓缩，使用洗脱剂（V石油醚：V二氯甲烷=5：1）经柱层析洗脱，洗脱过程中，由于柱层析无色，需要每50ml进行薄层层析并观察。洗脱后，去除其溶剂，其残留物真空干燥一夜，得到淡黄色固体。收率：51%。.1H NMR(400 MHz, Chloroform-d) δ 7.30 (d, J = 8.9 Hz, 2H), 6.83 (d, J = 8.6 Hz, 1H),4.58 (s, 2H), 3.88 (s, 3H), 2.09 (s, 3H), 1.89 (s, 6H), 1.76 (d, J = 8.4 Hz,6H).13C NMR (101 MHz, Chloroform-d) δ 154.61, 143.83, 126.54, 125.41, 110.68,36.78,29.78,28.99。
（3）5-（金刚烷-1-基）-2-甲氧基苯甲醛的合成（化合物4）
取100ml单口瓶，在常温下依次加入1-（3-（溴甲基）-4-甲氧基苯基）金刚烷0.899g，N-甲基吗啉-N-氧化物1.9g，最后加入无水四氢呋喃为溶剂。将整个反应体系转移到66摄氏度油浴锅中，通入氮气隔绝空气，连接直行冷凝管，当开始滴定时，计时，反应4h。反应结束后，冷却至室温，加入10ml蒸馏水，用无水乙醚萃取多次，用无水硫酸镁干燥40min，干燥结束后抽滤，将滤液浓缩，使用洗脱剂（V石油醚：V二氯甲烷=1：1）经柱层析洗脱，洗脱后，去除其溶剂，其残留物真空干燥一夜，得到白色固体。收率：46%.1H NMR (400MHz, Chloroform-d) δ 10.47 (s,1H), 7.82 (s,1H), 7.55 (s, 1H), 6.94 (d, J =8.7 Hz, 1H), 3.91 (s, 3H), 2.10 (s, 3H), 1.89 (s, 6H), 1.76 (d, J = 10.2 Hz,6H).13C NMR (101 MHz, Chloroform-d) δ 190.07,159.94,143.87,132.63,124.83,124.37,111.43,55.69,43.16,36.67,35.70,28.89。
（4）5-（金刚烷-1-基）-2-羟基苯甲醛的合成（化合物5）
取100ml单口瓶，在常温下依次加入（金刚烷-1-基）-2-甲氧基苯甲醛0.1g，加入定量二氯甲烷将其溶解，最后加入1ml三溴化硼。将整个反应体系转移到-10摄氏度低温反应器中，计时，反应6h。反应结束后，加入10ml蒸馏水，用无水乙醚萃取多次，用无水硫酸镁干燥40min，干燥结束后抽滤，将滤液浓缩，使用洗脱剂（V石油醚：V二氯甲烷=1：1）经柱层析洗脱，洗脱后，去除其溶剂，其残留物真空干燥一夜得到淡黄色固体。收率：47%..1H NMR (400MHz, Chloroform-d) δ 10.84 (s, 1H), 9.89 (s, 1H), 7.57 (d, J = 8.7 Hz, 1H),7.47 (s, 1H), 6.94 (d, J = 8.9 Hz, 1H), 2.12 (s, 3H), 1.89 (s, 6H), 1.78 (d,J = 12.7 Hz, 6H).13C NMR (101 MHz, Chloroform-d) δ 196.82, 159.56, 143.12,129.65, 120.23, 117.20, 43.19,36.64,35.58。
实施例2：目标化合物6（a-h）的合成
（1）2-（5-（金刚烷-1-基）-2-羟基亚苄基）-N-（对甲苯基）肼-1-硫代氨基的合成（化合物6）
取100ml单口瓶，依次加入5-（-金刚烷-1-基）-2-羟基苯甲醛50mg，N-（对甲苯基）肼基硫代酰胺42mg，加入10ml无水乙醇为溶剂，最后加入5滴冰醋酸。将整个反应体系转移到80摄氏度油浴锅中，计时，反应6h。反应结束后，冷却至室温，会析出白色固体。用无水乙醇过滤，多次冲洗，再用二氯甲烷多次冲洗，将滤饼干燥过夜。得到白色固体。收率：77%。1HNMR (400 MHz, DMSO-d 6) δ 11.87 (s, 1H), 9.83 (s, 1H), 9.75 (s, 1H), 8.52 (s,1H), 7.74 (d, J = 20.2 Hz, 2H), 7.29 (d, J = 8.3 Hz, 4H), 6.84 (d, J = 8.6Hz, 1H), 2.03 (s, 3H), 1.84 (s, 6H), 1.71 (s, 6H).13C NMR (101 MHz, DMSO-d 6) δ177.00, 158.55, 156.10, 155.19, 142.48, 129.64,128.79,128.04,124.47,122.98,119.57,116.43,116.16,43.15,36.66,35.64,28.83。
（2）2-（5-（金刚烷-1-基）-2-羟基亚苄基）-N-（3-甲氧基苯基）肼-1-硫代氨基的合成（化合物7）
取100ml单口瓶，依次加入5-（-金刚烷-1-基）-2-羟基苯甲醛50mg，N-（3-甲氧基苯基）肼基硫代酰胺46mg，加入10ml无水乙醇为溶剂，最后加入5滴冰醋酸。将整个反应体系转移到80摄氏度油浴锅中，计时，反应6h。反应结束后，冷却至室温，会析出白色固体。用无水乙醇过滤，多次冲洗，再用二氯甲烷多次冲洗，将滤饼干燥过夜。得到白色固体。收率：76%1HNMR (400 MHz, DMSO-d 6) δ 11.88 (s, 1H), 9.87 (d, J = 24.2 Hz, 2H), 8.65 (s,1H), 8.53 (s, 1H), 7.74 (s, 1H), 7.29 (d, J = 11.0 Hz, 1H), 7.12 (d, J = 13.2Hz, 2H), 6.96 (s, 1H), 6.86 (d, J = 8.6 Hz, 1H), 3.90 (s, 3H), 2.04 (s, 3H),1.86 (s, 6H), 1.72 (s, 6H).13C NMR (101 MHz, DMSO-d 6) δ 174.25, 155.33,150.52, 142.37, 141.09, 128.93, 128.30, 125.27, 122.28, 120.34,116.58,111.55,56.44,43.20,36.64,35.56,28.81。
（3）2-（5-（金刚烷-1-基）-2-羟基亚苄基）-N-（4-甲氧基苯基）肼-1-硫代氨基的合成（化合物8）
取100ml单口瓶，依次加入5-（-金刚烷-1-基）-2-羟基苯甲醛50mg，N-（4-甲氧基苯基）肼硫代酰胺42mg，加入10ml无水乙醇为溶剂，最后加入5滴冰醋酸。将整个反应体系转移到80摄氏度油浴锅中，计时，反应6h。反应结束后，冷却至室温，会析出白色固体。用无水乙醇过滤，多次冲洗，再用二氯甲烷多次冲洗，将滤饼干燥过夜。得到白色固体。收率：85%。1HNMR (400 MHz, DMSO-d 6) δ 11.60 (s, 1H), 9.86 (s, 1H), 9.71 (s, 1H), 8.49 (s,1H), 7.74 (s, 1H), 7.40 (d, J = 7.4 Hz, 2H), 7.25 (s, 1H), 6.94 (s, 2H), 6.85(s, 1H), 3.76 (s, 3H), 2.03 (s, 3H), 1.85 (s, 6H), 1.71 (s, 6H).13C NMR (101MHz, DMSO-d 6) δ 176.71, 157.46, 155.05, 142.47, 132.70, 128.56, 128.03,123.50, 119.68, 116.38, 113.83, 55.75, 43.15, 36.67, 35.66, 28.84。
（4）2-（5-（金刚烷-1-基）-2-羟基亚苄基）-N-（2-甲氧基苯基）肼-1-硫代氨基的合成（化合物9）
取100ml单口瓶，依次加入5-（-金刚烷-1-基）-2-羟基苯甲醛50mg，N-（2-甲氧基苯基）肼基硫代酰胺46mg，加入10ml无水乙醇为溶剂，最后加入5滴冰醋酸。将整个反应体系转移到80摄氏度油浴锅中，计时，反应6h。反应结束后，冷却至室温，会析出白色固体。用无水乙醇过滤，多次冲洗，再用二氯甲烷多次冲洗，将滤饼干燥过夜。得到白色固体。收率：87%。1H NMR (400 MHz, DMSO-d 6) δ 11.64 (s, 1H), 9.90 (s, 1H), 9.74 (s, 1H), 8.49(s, 1H), 7.74 (s, 1H), 7.42 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 8.6 Hz, 1H),7.17 (d, J = 7.9 Hz, 2H), 6.84 (d, J = 8.6 Hz, 1H), 2.31 (s, 3H), 2.03 (s,3H), 1.85 (s, 6H), 1.71 (s, 6H).13C NMR (101 MHz, DMSO-d 6) δ 176.40, 155.08,142.46, 137.22, 134.87, 129.06, 128.59, 126.17, 123.54, 119.65, 116.40,43.16,36.68,35.66,28.85,21.05。
（5）2-（5-（金刚烷-1-基）-2-羟基亚苄基）-N-苯肼-1-硫代酰胺的合成（化合物10）
取100ml单口瓶，依次加入5-（-金刚烷-1-基）-2-羟基苯甲醛50mg，苯胺39mg，加入10ml无水乙醇为溶剂，最后加入5滴冰醋酸。将整个反应体系转移到80摄氏度油浴锅中，计时，反应6h。反应结束后，冷却至室温，会析出白色固体。用无水乙醇过滤，多次冲洗，再用二氯甲烷多次冲洗，将滤饼干燥过夜。得到白色固体。收率：78%。1H NMR (400 MHz, DMSO-d 6)δ 11.69 (s, 1H), 9.98 (s, 1H), 9.74 (s, 1H), 8.50 (s, 1H), 7.75 (s, 1H), 7.57(d, J = 7.8 Hz, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.27 (d, J = 6.0 Hz, 1H), 7.20(s, 1H), 6.84 (d, J = 8.6 Hz, 1H), 2.04 (s, 3H), 1.85 (s, 6H), 1.71 (s, 6H).13C NMR (101 MHz, DMSO-d 6) δ 176.31, 155.11, 142.47, 139.80, 128.59, 126.18,125.67, 123.52, 119.63, 116.40, 43.15, 36.67, 35.66, 28.84。
（6）2-（5-（金刚烷-1-基）-2-羟基亚苄基）-N-（3-氟苯基）肼-1-硫代氨基的合成（化合物11）
取100ml单口瓶，依次加入5-（-金刚烷-1-基）-2-羟基苯甲醛103mg，N-（3-氟苯基）肼基硫代酰胺89mg，加入10ml无水乙醇为溶剂，最后加入5滴冰醋酸。将整个反应体系转移到80摄氏度油浴锅中，计时，反应6h。反应结束后，冷却至室温，会析出白色固体。用无水乙醇过滤，多次冲洗，再用二氯甲烷多次冲洗，将滤饼干燥过夜。得到白色固体。收率50%。.1HNMR (400 MHz, DMSO-d 6) δ 11.82 (s, 1H), 10.07 (s, 1H), 9.76 (s, 1H), 8.52 (s,1H), 7.75 (s, 1H), 7.62 (s, 1H), 7.42 (s, 2H), 7.26 (s, 1H), 7.01 (s, 1H),6.83 (s, 1H), 2.04 (s, 3H), 1.85 (s, 6H), 1.71 (s, 6H).13C NMR (101 MHz, DMSO-d 6) δ 176.04, 163.26, 160.85, 155.20, 142.90, 142.48, 141.51, 129.98, 128.80,123.57, 121.53, 119.52, 116.43, 112.58，112.33,112.13,111.92,43.15,36.68,35.67,28.85。
（7）2-（5-（金刚烷-1-基）-2-羟基亚苄基）-N-（2-氟苯基）肼-1-硫代氨基的合成（化合物12）
取100ml单口瓶，依次加入5-（-金刚烷-1-基）-2-羟基苯甲醛100mg，N-（4-氟苯基）肼基硫代酰胺86mg，加入10ml无水乙醇为溶剂，最后加入5滴冰醋酸。将整个反应体系转移到80摄氏度油浴锅中，计时，反应6h。反应结束后，冷却至室温，会析出白色固体。用无水乙醇过滤，多次冲洗，再用二氯甲烷多次冲洗，将滤饼干燥过夜。得到白色固体。收率75%。1HNMR (400 MHz, DMSO-d 6) δ 11.72 (s, 1H), 9.96 (s, 1H), 9.75 (s, 1H), 8.49 (s,1H), 7.75 (s, 1H), 7.28 (d, J = 8.1 Hz, 3H), 7.17 (d, J = 7.9 Hz, 1H), 6.83(d, J = 8.6 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 3.76 (s, 3H), 2.04 (s, 3H),1.86 (s, 6H), 1.72 (s, 6H).13C NMR (101 MHz, DMSO-d 6) δ 176.01, 159.58,155.12, 142.46, 140.88, 129.31, 128.65, 123.57, 119.61, 117.82, 116.42,111.41,111.12,55.60,43.16,36.68,35.66,28.86。
（8）2-（5-（金刚烷-1-基）-2-羟基亚苄基）-N-（4-氟苯基）肼-1-硫代氨基的合成（化合物13）
取100ml单口瓶，依次加入5-（-金刚烷-1-基）-2-羟基苯甲醛85mg，N-（4-氟苯基）肼基硫代酰胺80mg，加入10ml无水乙醇为溶剂，最后加入5滴冰醋酸。将整个反应体系转移到80摄氏度油浴锅中，计时，反应6h。反应结束后，冷却至室温，会析出白色固体。用无水乙醇过滤，多次冲洗，再用二氯甲烷多次冲洗，将滤饼干燥过夜。得到白色固体。收率79%1HNMR (400 MHz, DMSO-d 6) δ 11.71 (s, 1H), 9.98 (s, 1H), 9.73 (s, 1H), 8.51 (s,1H), 7.75 (s, 1H), 7.54 (s, 2H), 7.23 (d, J = 25.5 Hz, 3H), 6.85 (s, 1H),2.03 (s, 3H), 1.85 (s, 6H), 1.71 (s, 6H).13C NMR (101 MHz, DMSO-d 6) δ 176.68,161.34, 158.93, 155.12, 142.48, 136.15, 128.69, 123.51, 119.60,116.40,115.30,115.08,43.15,36.67,35.66,28.84。
实施例3：体外细胞毒性评价结果
1.本发明对目标化合物6a-h进行了CCK-8实验测试，对HELA,A549,MCF-7,和HEK-293进行表达，目标化合物6a-h和5-氟尿嘧啶在20μM浓度下测试。由图可以看出，化合物6g对HELA抑制效果最好，抑制率为91.18%，而5-氟尿嘧啶对HELA细胞的抑制率为25.56%；化合物6g对MCF-7抑制效果最好，抑制率为76.48%，5-氟尿嘧啶对MCF-7细胞的抑制率为48.69%；化合物6f对A549抑制效果最好，但是其它化合物对A549抑制效果均不好，抑制率为61.36%，而5-氟尿嘧啶对HELA细胞的抑制率为0%。
2.本发明计算出对化合物6a-h在320μM、160μM、80μM、40μM、20μM、10μM、5μM、2.5μM浓度下对A549、HELA、MCF- 7细胞的IC50值，其中，化合物6a、6f、6g对HELA细胞、MCF-7的IC50值较低。
表1目标化合物6a-h对不同细胞的IC50值
| IC(μM) | IC(μM) | |
| HELA | MCF-7 | |
| 6a | 28.25 | 20.60 |
| 6b | >30 | >30 |
| 6c | >30 | >30 |
| 6d | >30 | >30 |
| 6e | >30 | >30 |
| 6f | 19.82 | 28.42 |
| 6g | 12.71 | 17.07 |
| 6h | >30 | >30 |
Claims (3)
1.一种含金刚烷骨架席夫碱类衍生物(Ⅰ)，其特征在于，分子化学结构如下，
式(Ⅰ)中，R选自：
2.根据权利要求1所述含有金刚烷骨架席夫碱类衍生物式(Ⅰ)的合成路线，其特征在于，合成路线：
3.根据权利要求1所述含有金刚烷骨架席夫碱类衍生物式(Ⅰ)在制备抗病毒、抗菌、抗肿瘤药物中的应用。
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| CN102070463A (zh) * | 2009-06-11 | 2011-05-25 | 辽宁利锋科技开发有限公司 | 具有金刚烷结构药物美金刚胺及其衍生物和类似物抗肿瘤新适应症的应用 |
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| CN102070463A (zh) * | 2009-06-11 | 2011-05-25 | 辽宁利锋科技开发有限公司 | 具有金刚烷结构药物美金刚胺及其衍生物和类似物抗肿瘤新适应症的应用 |
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| 金刚烷席夫碱类衍生物的设计合成及其初步抗肿瘤活性研究;宫旭阳等;长春工业大学学报;第43卷(第3期);P207-211 * |
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