CN107663182A - 一种谷氨酰胺代谢抑制剂化合物 - Google Patents
一种谷氨酰胺代谢抑制剂化合物 Download PDFInfo
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Abstract
本发明根据谷氨酰胺酶的变构位点的晶体结构，设计合成了一系列的新的对称和不对称的双杂环化合物,含3‑8个碳原子或含硫醚的长链和各类取代苯环，可有效结合谷氨酰胺酶的变构位点；实验结果表明这些化合物可直接结合谷氨酰胺酶和/或脱氢酶结合，并对于各类谷氨酰胺依赖的癌细胞，如肺癌、肝癌、泌尿系统肿瘤细胞的有很好的活性。并且谷氨酰胺酶的变构位点的抑制剂具有很好的选择性，对肿瘤细胞的活性增加(<100nM)，对正常细胞没有损伤(>10uM)；在多种皮下瘤模型中都有显著活性，并且没有毒性。
Description
技术领域
本发明属于生物医药领域，具体涉及到一种新结构谷氨酰胺代谢抑制剂化合物及其用途。
背景技术
肿瘤细胞基因突变，可造成葡萄糖有氧糖代谢途径的明显改变，即Warburg效应：葡萄糖代谢增加200倍，但产物乳酸被排出体外，不能进入线粒体三羧酸循环，则谷氨酰胺成为肿瘤细胞线粒体产生能量所依赖的原料，而谷氨酰胺酶是谷氨酰胺进入线粒体三羧酸循环必不可少的酶；谷氨酰胺缺乏或谷氨酰胺酶的抑制均能抑制肿瘤细胞的生长；同时线粒体中产生NAD(P)H是肿瘤生长的关键，此过程涉及的一系列关键代谢酶的抑制，如谷氨酰胺酶，谷氨酸脱氢酶(GDH)，琥珀酸脱氢酶和异柠檬酸脱氢酶，可以提高ROS对肿瘤细胞的杀伤力。
发明内容
根据谷氨酰胺酶的变构位点的晶体结构，我们设计合成了一系列的新的对称和不对称的双杂环化合物,含3-8个碳原子或含硫醚的长链和各类取代苯环，可有效结合谷氨酰胺酶的变构位点。实验结果表明这些化合物可直接结合谷氨酰胺酶和/或脱氢酶结合，并对于各类谷氨酰胺依赖的癌细胞，如肺癌、肝癌、泌尿系统肿瘤细胞的有很好的活性。并且谷氨酰胺酶的变构位点的抑制剂具有很好的选择性，对肿瘤细胞的活性增加(<100nM)，对正常细胞没有损伤(>10uM)。在多种皮下瘤模型中都有显著活性，并且没有毒性。
本发明发现了具有靶向性的高效低毒治疗癌症的新药药物，根据谷氨酰胺酶和BPTES化合物的晶体结构，我们改变了中间的硫醚结构，尝试不同构效关系，将噻二唑用其他杂环化合物替代，并对苯环增加吸电子基团或给电子基团以增加或减少化合物的氧化还原活性、优化化合物的药学性质、谷氨酰胺酶结合力、及化合物的抗肿瘤活性。设计合成的化合物具有靶向性，抑制线粒体功能，阻断肿瘤能量代谢，对谷氨酰胺依赖的肿瘤抑制能力非常强，并可通过药物联用取得很好的治疗效果。
该发明具体包括如下内容：一种新结构谷氨酰胺代谢抑制剂化合物，包括：
或者
或者
或者
或者：
或者：
或者：
其中R1、R2、R3、R4、R5、R6、R7、R8分别代表一个独立的取代基包含1～20个选自C、H、N、O、S、Si和卤素原子的原子；
所述的X或X＇为C、N、O、S、和Se原子中的一种；
所述X＂为S或者C原子；
所述Y为C、N、O、和S原子中的一种；
所述Z、Z＇、Z＂为C和N原子中的一种；
所述n或n＇为0～5的碳原子个数。
优选地，所述的谷氨酸代谢抑制剂化合物中的R1、R2、R3、R4、R5、R6、R7、R8为分别代表的独立的取代基包括：氢，芳香类杂环，取代烷基，酰胺，醚，脂类，卤素，硅烷类，硫醚，胺类，磷酸基团，亚砜类，磺酰基；
在同一个化学式中，所述的R1、R2、R3、R4、R5、R6、R7、R8中可以都为H原子，或者只有一个不为H原子或者任意组合。
优选地，所述的谷氨酸代谢抑制剂化合物中的n和n＇为0-2。
优选地，所述的谷氨酸代谢抑制剂化合物包括：
所述的R取代基包括芳香类杂环，取代烷基，酰胺，醚，脂类，卤素，硅烷类，硫醚，胺类，亚砜类，磺酰基。
一种药物组合物，包括上述任一所述的化合物及其药物活性上可接受的盐的化合物的药物组合物。
一种包括上述的化合物与FDA或cFDA批准的药物联用在对谷氨酰胺代谢有依赖性的癌症治疗中的用途，所述的癌症包括但不限于肺癌、肝癌、膀胱癌、肾癌、前列腺癌、血癌、胃癌、肠癌、脑瘤以及皮肤癌。
本发明提供了一类具有靶向性的广谱高效低毒治疗癌症新药药物，设计合成的化合物具有靶向性，抑制线粒体功能，阻断肿瘤能量代谢，对谷氨酰胺依赖的肿瘤抑制能力非常强，可用于多种癌症的治疗或手术后的预防。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动性的前提下，还可以根据这些附图获得其他的附图。
图1为分子互作仪检测化合物与谷氨酰胺酶和谷氨脱氢酶的结合效果图：
A.化合物8与GDH的结合(KD 700nM)
B.化合物1与KGA的结合(KD 120nM)
将KGA或GDH分子固定在ForteBio分子相互作用仪的传感器上，传感器浸没在化合物溶液里1分钟，检测化合物吸附上传感器的动力学常数(kon)；又将传感器浸泡在缓冲液中2分钟，检测化合物洗脱下传感器的动力学常数(koff)；从而计算化合物结合的平衡常数KD。
图1A、B中的三条曲线分别代表背景扣除后0.1μM，1μM，10μM三个浓度下的结合效果。
图2为GAC四聚体和BPTES结合图。
1、底物结合的活性位点；2、BPTES结合的变构位点。
具体实施方式
下面结合实施例对本发明做进一步的详细说明，以下实施例是对本发明的解释而本发明并不局限于以下实施例。
实施例
一、对称硒啉的合成
在50mL的烧瓶中加入硫醚二乙胺或者其他相应的二胺化合物，再加入二氯甲烷和TEA，搅拌冰浴条件下加入溶于二氯甲烷的2-(氯硒基)苯甲酰氯，或其它苯环取代的2-(氯硒基)苯甲酰氯。滴加完毕后撤去冰浴搅拌过夜。
后处理：抽滤得到白色固体，加水和甲醇搅拌1小时。抽滤，50℃烘箱烘干。硫醚乙烷硒啉(1)
HRMS(ESI):507(100％；M+Na+)；MS(507,505,503；M+Na+),LC:tR＝10min,XDB-C184.6mm×5μm，甲醇：水＝60:40，V＝1mL/min，λ＝254nm；1H NMR(500MHz,DMSO)δ8.05(d,J＝8Hz,2H),7.83(d,J＝7.7Hz,2H),7.64–7.39(m,4H),3.95(t,J＝7Hz,4H),2.8(t,J＝7Hz,4H)
硫醚二乙烷基(2,2’甲基)硒啉(2)
MS(ESI):535(100％:M+Na+),505,503.1H NMR(500MHz,DMSO)δ7.83(d,J＝7.7Hz,2H),7.4(d,J＝7.7Hz,2H),7.29(m,2H),3.95(t,J＝7Hz,4H),2.8(t,J＝7Hz,4H).2.34(s,6H)
硫醚乙烷基(2,2’-二甲基氨基)硒啉(3)
MS(ESI):593(100％:M+Na+),591,589.1H NMR(500MHz,DMSO)δ7.52(m,2H),7.40(,J＝7.7Hz,2H),7.01(,J＝7.7Hz,2H),3.95(t,J＝7Hz,4H),2.8(t,J＝7Hz,4H).3.1(s,12H)
硫醚乙烷基(4,4’-甲基)硒啉(4)
MS(ESI):535(100％:M+Na+),505,503.1H NMR(500MHz,DMSO)δ7.83(s,2H),7.5(m,4H),3.95(t,J＝7Hz,4H),2.8(t,J＝7Hz,4H).2.34(s,6H)
硫醚乙烷(4,4’-二甲基氨基)硒啉(5)
MS(ESI):593(100％:M+Na+),591,589.1H NMR(500MHz,DMSO)δ7.83(s,2H),7.5(m,4H),3.95(t,J＝7Hz,4H),2.8(t,J＝7Hz,4H).3.1(s,12H)硫醚乙烷基(3,3’-三氟甲基)硒啉(6)
MS(ESI):643(100％:M+Na+),641,639.1H NMR(500MHz,DMSO)δ7.96(d,J＝7.7Hz,2H),7.8(m,4H),3.95(t,J＝7Hz,4H),2.8(t,J＝7Hz,4H).硫醚乙烷基(5,5’-氟基)硒啉(7)
MS(ESI):543(100％:M+Na+),541,539.1H NMR(500MHz,DMSO)δ7.89(m,2H),7.53(d,J＝7.7Hz,2H),7.5(d,J＝7.7Hz,2H),3.95(t,J＝7Hz,4H),2.8(t,J＝7Hz,4H).
丙烷基硒啉(8)
MS(ESI):461(100％,M+Na+),459,457；m.p.:252.9-254.2℃；1H NMR(500MHz,CDCl3)δ8.08(d,J＝7.8Hz,2H),7.7-7.59(m,6H),3.8(t,J＝7Hz,4H),2.0(m,2H).
丙烷基(2,2’-二甲基氨基)硒啉(9)
MS(ESI):547(100％:M+Na+),545,543.1H NMR(500MHz,DMSO)δ7.52(m,2H),7.40(,J＝7.7Hz,2H),7.01(,J＝7.7Hz,2H),3.8(t,J＝7Hz,4H),3.1(s,12H),2.0(m,2H).
丙烷基(4,4’-二甲基氨基)硒啉(10)
MS(ESI):547(100％:M+Na+),545,543.1H NMR(500MHz,DMSO)δ7.83(s,2H),7.5(m,4H),3.95(t,J＝7Hz,4H),2.8(t,J＝7Hz,4H).3.1(s,12H)
二、对称苯并异噻唑的合成
在50mL的烧瓶中加入硫醚二乙胺或者其他相应的二胺化合物，再加入二氯甲烷和TEA，搅拌冰浴条件下加入溶于二氯甲烷的2-(氯硫基)苯甲酰氯，或其它苯环取代的2-(氯硫基)苯甲酰氯。滴加完毕后撤去冰浴搅拌过夜。
硫醚二乙烷基苯并异噻唑(11)
MS(ESI):343(M+H+)；1H NMR(500MHz,DMSO)δ8.02(d,J＝7.8Hz,2H),7.6–7.5(m,4H),7.4(d,J＝7.8Hz,2H),3.95(t,J＝7Hz,4H),2.8(t,J＝7Hz,4H)
己烷基苯并异噻唑(12)
MS(ESI):503(100％；M+H+)；m.p.:176.9-178.2℃；1H NMR(500MHz,CDCl3)δ8.05(d,J＝7.4Hz,2H),7.6-7.5(m,4H),7.40(m,2H),3.95(t,J＝7.2Hz,4H),1.75–1.70(m,4H),1.41–1.34(m,8H).
丙烷基苯并异噻唑(13)
MS(ESI):343(100％,M+H+)；1H NMR(500MHz,CDCl3)δ8.05(d,J＝7.4Hz,2H),7.6-7.5(m,4H),7.40(m,2H),3.8(t,J＝7Hz,4H),2.0(m,2H).
三、对称吲唑酮的合成
在50mL的烧瓶中加入硫醚二乙胺或者其他相应的二胺化合物，再加入二氯甲烷和TEA，搅拌冰浴条件下加入溶于二氯甲烷的邻溴甲基硝基苯，或其它苯环取代的邻溴甲基硝基苯。滴加完毕后撤去冰浴搅拌过夜。
硫醚二乙烷基吲唑-3-酮(14)
MS(355,M+H+)；1H NMR(500MHz,DMSO)δ7.87(d,J＝7.7Hz,2H),7.60(d,J＝7.7Hz,2H),7.10-7.0(m,4H),4.1(s,2H),3.95(t,J＝7Hz,4H),2.8(t,J＝7Hz,4H)
硫醚二乙烷基吲唑-1-甲基-3-酮(15)
MS(383,M+H+)；1H NMR(500MHz,DMSO)δ7.87(d,J＝7.7Hz,2H),7.60(d,J＝7.7Hz,2H),7.10-7.0(m,4H),3.95(t,J＝7Hz,4H),2.95(s,6H),2.8(t,J＝7Hz,4H)
硫醚二乙烷基吲唑-1-苯甲基-3-酮(16)
MS(535,M+H+)；1H NMR(500MHz,DMSO)δ7.87(d,J＝7.7Hz,2H),7.60(d,J＝7.7Hz,2H),7.3-7.2(m,10H),7.10-7.0(m,4H),4.4(s,4H),3.95(t,J＝7Hz,4H),2.8(t,J＝7Hz,4H)
己烷基二吲唑酮(17)
MS(ESI):351(100％；M+H+)；m.p.:176.9-178.2℃；1H NMR(500MHz,CDCl3)δ7.87(d,J＝7.7Hz,2H),7.60(d,J＝7.7Hz,2H),7.10-7.0(m,4H),4.1(s,2H)，3.95(t,J＝7.2Hz,4H),1.75–1.70(m,4H),1.41–1.34(m,4H).
己烷基二吲唑-1-甲基-3-酮(18)
MS(ESI):379(100％；M+H+)；m.p.:176.9-178.2℃；1H NMR(500MHz,CDCl3)δ7.87(d,J＝7.7Hz,2H),7.60(d,J＝7.7Hz,2H),7.10-7.0(m,4H),3.95(t,J＝7.2Hz,4H),2.95(s,6H),1.75–1.70(m,4H),1.41–1.34(m,8H).
四、对称异吲哚啉酮的合成
在50mL的烧瓶中加入硫醚二乙胺或者其他相应的二胺化合物，再加入二氯甲烷和TEA，搅拌冰浴条件下加入溶于二氯甲烷的2-(氯甲基)苯甲酰氯，或其它苯环取代的2-(氯甲基)苯甲酰氯。滴加完毕后撤去冰浴搅拌过夜。
硫醚二乙烷(2,2’甲基)异吲哚啉-1-酮(19)
MS(353,M+H+)；1H NMR(500MHz,DMSO)δ7.87(d,J＝7.7Hz,2H),7.6-7.4(m,4H),7.2(m,2H),4.6(s,4H)3.95(t,J＝7Hz,4H),2.8(t,J＝7Hz,4H)
己烷基异吲哚啉-1-酮(20)
MS(ESI):481(100％；M+H+)；1H NMR(500MHz,CDCl3)δ7.87(d,J＝7.7Hz,2H),7.6-7.4(m,4H),7.2(m,2H),4.6(s,4H)3.95(t,J＝7.2Hz,4H),1.75–1.70(m,4H),1.41–1.34(m,4H).
五、对称异恶唑酮的合成
在50mL的烧瓶中加入硫醚二乙基羟胺或者其他相应的二羟胺化合物，再加入二二氧六环，搅拌冰浴条件下加入邻羟基苯甲酸甲酯，或其它苯环取代的邻羟基苯甲酸甲酯。反应完成后，加入二氯亚砜。反应完成后，滴加三乙氨。完毕后撤去冰浴搅拌过夜。
硫醚二乙烷基二异恶唑-3-酮(21)
MS(357,M+H+)；1H NMR(500MHz,DMSO)δ7.87(d,J＝7.7Hz,2H),7.10(d,J＝7.7Hz,2H),7.5-7.2(m,4H),3.95(t,J＝7Hz,4H),2.8(t,J＝7Hz,4H)已烷二异恶唑-3-酮(22)
MS(ESI):353(100％；M+H+)；m.p.:176.9-178.2℃；1H NMR(500MHz,CDCl3)δ7.87(d,J＝7.7Hz,2H),7.60(d,J＝7.7Hz,2H),7.10-7.0(m,4H),3.95(t,J＝7.2Hz,4H),1.75–1.70(m,4H),1.41–1.34(m,4H).
六、不对称化合物的合成
在50mL的烧瓶中加入BOC保护的1,6-己二胺或者单边端位胺化合物，再加入二氯甲烷和TEA，搅拌冰浴条件下加入溶于二氯甲烷的2-氯羰基苯基硒氯或其它苯环取代的2-(氯硫基)苯甲酰氯、2-(氯甲基)苯甲酰氯、邻溴甲基硝基苯。滴加完毕后撤去冰浴搅拌过夜。抽滤得到白色固体，纯化。
己二氨基N-Boc基硒啉(23)
MS(ESI):421.1，100％:M+Na；1H NMR(500MHz,CDCl3)δ8.00(d,J＝8.4Hz,1H),7.65(d,J＝8.0Hz,1H),7.54(dd,J＝15.2,1.3Hz,1H),7.40–7.35(m,1H),4.74(s,1H),3.81(t,J＝7.1Hz,2H),3.06(d,J＝6.1Hz,2H),1.71–1.63(m,2H),1.41(d,J＝17.0Hz,11H),1.33(dt,J＝14.6,5.8Hz,4H).
硫醚二乙烷基N-Boc基硒啉(24)
MS(ESI):425，100％:M+Na+
硫醚二乙烷基苯并异噻唑基硒啉(25)
MS(ESI):459，100％:M+Na+
硫醚二乙烷基基吲唑酮硒啉(26)
MS(ESI):442，100％:M+Na+
4-四氮唑乙酰胺已烷二苯并异噻唑(27)
MS(ESI):514，100％:M+H+
2-四氮唑乙酰胺已烷二苯并异噻唑(28)
MS(ESI):514，100％:M+H+
4-四氮唑乙酰胺硫醚硒琳(29)
MS(ESI):632，100％:M+Na+
2-四氮唑乙酰胺硫醚硒琳(30)
MS(ESI):632，100％:M+Na+
4-四氮唑乙酰胺已烷二苯并异噻唑(31)
MS(ESI):510，100％:M+H+
2-四氮唑乙酰胺已烷二苯并异噻唑(32)
MS(ESI):510，100％:M+H+
4-四氮唑乙酰胺已烷硒琳(33)
MS(ESI):628，100％:M+Na+
2-四氮唑乙酰胺已烷硒琳(34)
MS(ESI):628，100％:M+Na+
硫醚二乙烷基苯并异噻唑基(2－甲基)硒啉(35)
MS(ESI):473，100％:M+Na+
硫醚二乙烷基异吲哚啉酮基硒啉(36)
MS(ESI):441，100％:M+Na+
硫醚二乙烷基苯并异噻唑基(1－二甲胺基)硒啉(37)
MS(ESI):502，100％:M+Na+
硫醚二乙烷基苯并异噻唑基(4－甲基)硒啉(38)
MS(ESI):473，100％:M+Na+
硫醚二乙烷基苯并异噻唑基(4－二甲胺基)硒啉(39)
MS(ESI):502，100％:M+Na+
苯乙酰胺哒嗪基硫醚二乙烷基硒啉(40)
MS(ESI):521，100％:M+Na+
己烷基苯并异噻唑基硒啉(41)
MS(ESI):503，100％:M+Na+
苯乙酰胺噻二唑基己烷硒啉(42)
MS(ESI):523，100％:M+Na+
苯乙酰胺哒嗪基己烷基硒啉(43)
MS(ESI):432，100％:M+H+
2.分子互作仪检测化合物与谷氨酰胺酶(KGA)或谷氨酰胺脱氢酶(GDH)的结合:KGA酶固定在ForteBio的芯片上，注射化合物溶液(0-1000nM)，观察化合物与酶的结合。GDH酶固定在ForteBio的芯片上，注射化合物溶液(0-1000nM)，观察化合物与酶的结合；具体效果见图1A、B。
3.化合物对KGA和GDH活性通过测定NAD(P)H还原EZMTT产生450nm吸光度来测定。100ul反应缓冲液中加终浓度0-26uM抑制剂，1nM KGA,20mM谷氨酰胺,反应2小时后加8nMGDH，100uM NADP+，25℃温和震荡反应30min。30min后，加入等体积的包含EZMTT检测试剂，混匀5min后，测定450nm吸光度值。
化合物对GDH抑制性实验方法参照GDH活性实验。100ul反应缓冲液中加终浓度0-26uM抑制剂，4nM GDH，加入终浓度50uM NADP+，20mM谷氨酰胺的缓冲液，25℃温和震荡反应60min。
4.抑制肿瘤细胞生长：各类肿瘤细胞(1000个每孔)加化合物在CO2培养箱中培养生长3天后，加细胞生长检测试剂(EZMTT)，检测细胞活性。化合物对肺癌，肝癌，泌尿系统肿瘤都有很好的抑制作用，并对正常细胞毒性很小。
1μM新化合物对KGA、GDH、癌细胞株及正常细胞生长的抑制率
此外，需要说明的是，本说明书中所描述的具体实施例，其化合物名称等可以不同。凡依本发明专利构思所述的特征及原理所做的等效或简单变化，均包括于本发明专利的保护范围内。本发明所属技术领域的技术人员可以对所描述的具体实施例做各种各样的修改或补充或采用类似的方式替代，只要不偏离本发明的结构或者超越本权利要求书所定义的范围，均应属于本发明的保护范围。
Claims (7)
1.一种谷氨酰胺代谢抑制剂化合物，其特征在于：所述的谷氨酰胺代谢抑制剂化合物的结构式包括：
或者
或者
或者
或者：
或者：
或者：
其中R1、R2、R3、R4、R5、R6、R7、R8分别代表一个独立的取代基包含1～20个选自C、H、N、O、S、Si和卤素原子的原子；
所述的X或X＇分别为C、N、O、S、和Se原子中的一种；
所述X＂为S或者C原子；
所述Y为C、N、O、和S原子中的一种；
所述Z、Z＇、Z＂分别为C和N原子中的一种；
所述n或n＇分别为0～5的碳原子个数。
2.根据权利要求1所述的谷氨酰胺代谢抑制剂化合物，其特征在于：所述的R1、R2、R3、R4、R5、R6、R7、R8为分别代表的独立的取代基包括：氢，芳香类杂环，取代烷基，酰胺，醚，脂类，卤素，硅烷类，硫醚，胺类，磷酸基团，亚砜类或者磺酰基。
3.根据权利要求1所述的新结构谷氨酰胺代谢抑制剂化合物，其特征在于：所述的n和n＇分别为0～2。
4.根据权利要求1所述的新结构谷氨酰胺代谢抑制剂化合物，其特征在于：所述的化合物包括：
所述的R取代基包括芳香类杂环，取代烷基，酰胺，醚，脂类，卤素，硅烷类，硫醚，胺类，亚砜类或者磺酰基。
5.一种药物组合物，其特征在于：包括如权利要求1～4中任一所述的化合物及其药物活性上可接受的盐的化合物的药物组合物。
6.一种包括权利要求1～4中任一所述的化合物与FDA或cFDA批准的药物联用在对谷氨酰胺代谢有依赖性的癌症治疗中的用途。
7.根据权利要求6所述的药物组合物在对谷氨酰胺代谢有依赖性的癌症治疗中的用途，其特征在于所述的癌症包括肺癌、肝癌、膀胱癌、肾癌、前列腺癌、血癌、胃癌、肠癌、脑瘤以及皮肤癌。
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| CN110396089A (zh) * | 2018-04-24 | 2019-11-01 | 杭州健昵福生物科技有限公司 | 靶向肾型谷氨酰胺酶变构位点的化合物及应用 |
| CN112760359A (zh) * | 2019-11-04 | 2021-05-07 | 南京盛德生物科技研究院有限公司 | 基于人突变蛋白为基础的gdh抑制剂高通量筛选方法 |
| CN115286625A (zh) * | 2022-06-23 | 2022-11-04 | 浙江工业大学 | 谷氨酰胺酶别构位点共价抑制剂及其制备方法与应用 |
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| CN110396089A (zh) * | 2018-04-24 | 2019-11-01 | 杭州健昵福生物科技有限公司 | 靶向肾型谷氨酰胺酶变构位点的化合物及应用 |
| CN109223778A (zh) * | 2018-11-16 | 2019-01-18 | 上海市肺科医院 | C24h24n6o2s3在制备抗结核菌药物中的用途 |
| CN109223778B (zh) * | 2018-11-16 | 2021-07-27 | 上海市肺科医院 | C24h24n6o2s3在制备抗结核菌药物中的用途 |
| CN112760359A (zh) * | 2019-11-04 | 2021-05-07 | 南京盛德生物科技研究院有限公司 | 基于人突变蛋白为基础的gdh抑制剂高通量筛选方法 |
| CN115286625A (zh) * | 2022-06-23 | 2022-11-04 | 浙江工业大学 | 谷氨酰胺酶别构位点共价抑制剂及其制备方法与应用 |
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