156945-58-3Relevant articles and documents
Benzannulated 6,5-Spiroketals from Donor-Acceptor Cyclopropanes
Gai, Sinan,Lucas, Nigel T.,Hawkins, Bill C.
, p. 2872 - 2875 (2019)
A rapid and facile synthesis of benzannulated 6,5-spiroketals from vinyl 1,1-diacylcyclopropanes is reported. The method utilizes mild reaction conditions with good to excellent yields and high diastereoselectivity. This methodology was then used to construct the core of berkelic acid.
Structure-Enabled Discovery of Novel Macrocyclic Inhibitors Targeting Glutaminase 1 Allosteric Binding Site
Xu, Xi,Wang, Jubo,Wang, Min,Yuan, Xinyu,Li, Lei,Zhang, Chao,Huang, Huidan,Jing, Tian,Wang, Chenchen,Tong, Chao,Zhou, Liwen,Meng, Ying,Xu, Pengfei,Kou, Junping,Qiu, Zhixia,Li, Zhiyu,Bian, Jinlei
supporting information, p. 4588 - 4611 (2021/05/04)
The inhibition of glutaminase 1 (GLS1) represents a potential treatment of malignant tumors. Structural analysis led to the design of a novel series of macrocyclic GLS1 allosteric inhibitors. Through extensive structure-activity relationship studies, a promising candidate molecule 13b (LL202) was identified with robust GLS1 inhibitory activity (IC50 = 6 nM) and high GLS1 binding affinity (SPR, Kd = 24 nM; ITC, Kd = 37 nM). The X-ray crystal structure of the 13b-GLS1 complex was resolved, revealing a unique binding mode and providing a novel structural scaffold for GLS1 allosteric inhibitors. Importantly, 13b clearly adjusted the cellular metabolites and induced an increase in the ROS level by blocking glutamine metabolism. Furthermore, 13b exhibited a similar in vivo antitumor activity as CB839. This study adds to the growing body of evidence that macrocyclization provides an alternative and complementary approach for the design of small-molecule inhibitors, with the potential to improve the binding affinity to the targets.
Truncated Itraconazole Analogues Exhibiting Potent Anti-Hedgehog Activity and Improved Drug-like Properties
Wen, Jiachen,Chennamadhavuni, Divya,Morel, Shana R.,Hadden, M. Kyle
supporting information, p. 1290 - 1295 (2019/09/30)
We conducted a structure-activity relationship study to explore simplified analogues of the itraconazole (ITZ) scaffold for their ability to inhibit the hedgehog (Hh) signaling pathway. These analogues were based on exploring the effects of chemical modifications to the linker and triazolone/side chain region of ITZ. Analogue 11 was identified as the most potent compound in our first generation, with an IC50 value of 81 nM in a murine Hh-dependent basal cell carcinoma. Metabolic identification studies led us to identify truncated piperazine (26) as the major metabolite in human liver microsomes (HLMs) and an improved Hh pathway inhibitor (IC50 = 22 nM). This work verifies that continued truncation of the ITZ scaffold is a practical method to maintain potent anti-Hh activity while also reducing the molecular weight for the ITZ scaffold and achieving improved pharmacokinetic properties.
