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"A Sweet Combination": Developing Saccharin and Acesulfame K Structures for Selectively Targeting the Tumor-Associated Carbonic Anhydrases IX and XII.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-12-18 , DOI: 10.1021/acs.jmedchem.9b01669 Silvia Bua 1 , Carrie Lomelino 2 , Akilah B Murray 2 , Sameh M Osman 3 , Zeid A ALOthman 3 , Murat Bozdag 1 , Hatem A Abdel-Aziz 4 , Wagdy M Eldehna 5 , Robert McKenna 2 , Alessio Nocentini 1 , Claudiu T Supuran 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-12-18 , DOI: 10.1021/acs.jmedchem.9b01669 Silvia Bua 1 , Carrie Lomelino 2 , Akilah B Murray 2 , Sameh M Osman 3 , Zeid A ALOthman 3 , Murat Bozdag 1 , Hatem A Abdel-Aziz 4 , Wagdy M Eldehna 5 , Robert McKenna 2 , Alessio Nocentini 1 , Claudiu T Supuran 1
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The sweeteners saccharin (SAC) and acesulfame K (ACE) recently entered the topic of anticancer human carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, as they showed to selectively inhibit the tumor-associated CAs IX/XII over ubiquitous CAs. A drug design strategy is here reported, which took SAC and ACE as leads and produced a series of 2H-benzo[e][1,2,4]thiadiazin-3(4H)-one-1,1-dioxides (BTD). Many derivatives showed greater potency (KIs-CA IX 19.1-408.5 nM) and selectivity (II/IX SI 2-76) than the leads (KIs-CA IX 103, 2400 nM; II/IX-SI 56, >4) against CA IX/XII over off-target isoforms. A thorough X-ray crystallographic study depicted their binding mode to both CA II and IX-mimic. The most representative BTDs were characterized in vitro for their antitumor activity against A549, PC-3, and HCT-116 cancer cell lines both in normoxia and hypoxia. The two most effective compounds were assayed for their effect on several apoptosis markers, identifying promising leads for the development of new anticancer drugs.
中文翻译：
“甜蜜的组合”：开发糖精和乙酰磺胺酸钾结构用于选择性靶向肿瘤相关的碳酸酐酶IX和XII。
甜味剂糖精（SAC）和乙酰磺胺酸钾（ACE）最近成为抗癌人类碳酸酐酶（CA，EC 4.2.1.1）抑制剂的主题，因为它们显示出比普遍存在的CA选择性抑制肿瘤相关的CA IX / XII。此处报道了一种药物设计策略，该策略以SAC和ACE为先导，并产生了一系列2H-苯并[e] [1,2,4]噻二嗪-3（4H）-one-1,1-dioxides（BTD） 。与导联（KIs-CA IX 103，2400 nM; II / IX-SI 56，> 4）相比，许多衍生物显示出更高的效价（KIs-CA IX 19.1-408.5 nM）和选择性（II / IX SI 2-76） CA IX / XII脱离目标异构体。彻底的X射线晶体学研究描述了它们与CA II和IX-mimic的结合模式。最典型的BTD在正常氧和低氧条件下均具有体外针对A549，PC-3和HCT-116癌细胞系的抗肿瘤活性。
更新日期：2019-12-19
中文翻译：
“甜蜜的组合”：开发糖精和乙酰磺胺酸钾结构用于选择性靶向肿瘤相关的碳酸酐酶IX和XII。
甜味剂糖精（SAC）和乙酰磺胺酸钾（ACE）最近成为抗癌人类碳酸酐酶（CA，EC 4.2.1.1）抑制剂的主题，因为它们显示出比普遍存在的CA选择性抑制肿瘤相关的CA IX / XII。此处报道了一种药物设计策略，该策略以SAC和ACE为先导，并产生了一系列2H-苯并[e] [1,2,4]噻二嗪-3（4H）-one-1,1-dioxides（BTD） 。与导联（KIs-CA IX 103，2400 nM; II / IX-SI 56，> 4）相比，许多衍生物显示出更高的效价（KIs-CA IX 19.1-408.5 nM）和选择性（II / IX SI 2-76） CA IX / XII脱离目标异构体。彻底的X射线晶体学研究描述了它们与CA II和IX-mimic的结合模式。最典型的BTD在正常氧和低氧条件下均具有体外针对A549，PC-3和HCT-116癌细胞系的抗肿瘤活性。
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