104566-44-1Relevant articles and documents
Synthesis of photoswitchable hemithioindigo-based ω-amino acids and application in Boc-based peptide assembly
Herre, Stephan,Steinle, Wencke,Rueck-Braun, Karola
, p. 3297 - 3300 (2005)
Efficient procedures for the preparation of the N-Boc-protected aldehydes 5a and 5b are described which are valuable precursors for the synthesis of hemithioindigo-based ω-amino acids and peptides. Georg Thieme Verlag Stuttgart.
Discovery of Selective Small-Molecule Inhibitors for the ENL YEATS Domain
Ma, Xinyu R.,Xu, Longxia,Xu, Shiqing,Klein, Brianna J.,Wang, Hongkuan,Das, Sukant,Li, Kuai,Yang, Kai S.,Sohail, Sana,Chapman, Andrew,Kutateladze, Tatiana G.,Shi, Xiaobing,Liu, Wenshe Ray,Wen, Hong
, p. 10997 - 11013 (2021/08/03)
Eleven-nineteen leukemia (ENL) protein is a histone acetylation reader essential for disease maintenance in acute leukemias, in particular, the mixed-lineage leukemia (MLL)-rearranged leukemia. In this study, we carried out high-throughput screening of a small-molecule library to identify inhibitors for the ENL YEATS domain. Structure-activity relationship studies of the hits and structure-based inhibitor design led to two compounds, 11 and 24, with IC50 values below 100 nM in inhibiting the ENL-acetyl-H3 interaction. Both compounds, and their precursor compound 7, displayed strong selectivity toward the ENL YEATS domain over all other human YEATS domains. Moreover, 7 exhibited on-target inhibition of ENL in cultured cells and a synergistic effect with the bromodomain and extraterminal domain inhibitor JQ1 in killing leukemia cells. Together, we have developed selective chemical probes for the ENL YEATS domain, providing the basis for further medicinal chemistry-based optimization to advance both basic and translational research of ENL.
Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37- N1)-Methyltransferase (TrmD) by Restructuring the Active Site with a Tyrosine-Flipping Mechanism
Zhong, Wenhe,Pasunooti, Kalyan Kumar,Balamkundu, Seetharamsing,Wong, Yee Hwa,Nah, Qianhui,Gadi, Vinod,Gnanakalai, Shanmugavel,Chionh, Yok Hian,McBee, Megan E.,Gopal, Pooja,Lim, Siau Hoi,Olivier, Nelson,Buurman, Ed T.,Dick, Thomas,Liu, Chuan Fa,Lescar, Julien,Dedon, Peter C.
, p. 7788 - 7805 (2019/10/11)
Among the >120 modified ribonucleosides in the prokaryotic epitranscriptome, many tRNA modifications are critical to bacterial survival, which makes their synthetic enzymes ideal targets for antibiotic development. Here we performed a structure-based design of inhibitors of tRNA-(N1G37) methyltransferase, TrmD, which is an essential enzyme in many bacterial pathogens. On the basis of crystal structures of TrmDs from Pseudomonas aeruginosa and Mycobacterium tuberculosis, we synthesized a series of thienopyrimidinone derivatives with nanomolar potency against TrmD in vitro and discovered a novel active site conformational change triggered by inhibitor binding. This tyrosine-flipping mechanism is uniquely found in P. aeruginosa TrmD and renders the enzyme inaccessible to the cofactor S-adenosyl-l-methionine (SAM) and probably to the substrate tRNA. Biophysical and biochemical structure-activity relationship studies provided insights into the mechanisms underlying the potency of thienopyrimidinones as TrmD inhibitors, with several derivatives found to be active against Gram-positive and mycobacterial pathogens. These results lay a foundation for further development of TrmD inhibitors as antimicrobial agents.
