Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA.
Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
Bioorg Med Chem. 2020 Oct 15;28(20):115698. doi: 10.1016/j.bmc.2020.115698. Epub 2020 Aug 6.
A series of allosteric kidney-type glutaminase (GLS) inhibitors possessing a mercaptoethyl (SCHCH) linker were synthesized in an effort to further expand the structural diversity of chemotypes derived from bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a prototype allosteric inhibitor of GLS. BPTES analog 3a with a mercaptoethyl linker between the two thiadiazole rings was found to potently inhibit GLS with an IC value of 50 nM. Interestingly, the corresponding derivative with an n-propyl (CHCHCH) linker showed substantially lower inhibitory potency (IC = 2.3 μM) while the derivative with a dimethylsulfide (CHSCH) linker showed no inhibitory activity at concentrations up to 100 μM, underscoring the critical role played by the mercaptoethyl linker in the high affinity binding to the allosteric site of GLS. Additional mercaptoethyl-linked compounds were synthesized and tested as GLS inhibitors to further explore SAR within this scaffold including derivatives possessing a pyridazine as a replacement for one of the two thiadiazole moiety.
我们合成了一系列具有巯基乙基（SCHCH）连接基的别构肾型谷氨酰胺酶（GLS）抑制剂，旨在进一步扩展源于双-2-（5-苯乙酰氨基-1,3,4-噻二唑-2-基）乙基亚砜（BPTES）的化学型别构抑制剂的结构多样性。BPTES 类似物 3a 中两个噻二唑环之间具有巯基乙基连接基，对 GLS 表现出很强的抑制作用，IC 值为 50 nM。有趣的是，具有正丙基（CHCHCH）连接基的相应衍生物表现出明显较低的抑制效力（IC=2.3 μM），而具有二甲亚砜（CHSCH）连接基的衍生物在高达 100 μM 的浓度下没有表现出抑制活性，这突出了巯基乙基连接基在与 GLS 的别构位点高亲和力结合中发挥的关键作用。我们还合成了其他具有巯基乙基连接基的化合物并将其作为 GLS 抑制剂进行了测试，以进一步探索该支架内的 SAR，包括用嘧啶嗪替代两个噻二唑部分之一的衍生物。
