98130-58-6Relevant articles and documents
Fragment-Derived Selective Inhibitors of Dual-Specificity Kinases DYRK1A and DYRK1B
Lee Walmsley, David,Murray, James B.,Dokurno, Pawel,Massey, Andrew J.,Benwell, Karen,Fiumana, Andrea,Foloppe, Nicolas,Ray, Stuart,Smith, Julia,Surgenor, Allan E.,Edmonds, Thomas,Demarles, Didier,Burbridge, Mike,Cruzalegui, Francisco,Kotschy, Andras,Hubbard, Roderick E.
, p. 8971 - 8991 (2021)
The serine/threonine kinase DYRK1A has been implicated in regulation of a variety of cellular processes associated with cancer progression, including cell cycle control, DNA damage repair, protection from apoptosis, cell differentiation, and metastasis. In addition, elevated-level DYRK1A activity has been associated with increased severity of symptoms in Down's syndrome. A selective inhibitor of DYRK1A could therefore be of therapeutic benefit. We have used fragment and structure-based discovery methods to identify a highly selective, well-tolerated, brain-penetrant DYRK1A inhibitor which showed in vivo activity in a tumor model. The inhibitor provides a useful tool compound for further exploration of the effect of DYRK1A inhibition in models of disease.
An expeditious total synthesis of 50-Deoxy-toyocamycin and 50-Deoxysangivamycin
Dong, Xiangyou,Tang, Jie,Hu, Chen,Bai, Jiang,Ding, Haixin,Xiao, Qiang
, (2019/02/26)
In present paper, an expeditious total synthesis of naturally occurring 50-deoxytoyocamycin and 50-deoxysangivamycin was accomplished. Because of the introduction of a benzoyl group at N-6 of 4-amino-5-cyano-6-bromo-pyrrolo[2,3-d]pyrimidine, a Vorbrüggen glycosylation with 1,2,3-tri-O-acetyl-5-deoxy-β-D-ribofuranose afforded a completely regioselective N-9 glycosylation product, which is unambiguously confirmed by X-ray diffraction analysis. All of the involved intermediates were well characterized by various spectra.
Effects of a novel carbocyclic analog of pyrrolo[2,3-d]pyrimidine nucleoside on pleiotropic induction of cell death in prostate cancer cells with different androgen responsiveness
Suh, Hyewon,Choi, Ko-woon,Ryou, Chongsuk,Lee, Chul-Hoon,Lee, Jongbok,Rhee, Hakjune
, p. 1130 - 1135 (2018/05/25)
Prostate cancer is the most frequently diagnosed cancer and is one of the leading causes of male cancer death in the world. Recently, in the course of our screening for a novel anticancer compound, we synthesized carbocyclic analogs of pyrrolo[2,3-d]pyrimidine nucleoside; compounds 5, and 6. In the current study, we report the effects of compound 5 on pleiotropic induction of cell death via up-regulation of AR-associated p21Cip1 protein in prostate cancer cells with different androgen responsiveness, such as LNCaP (androgen-dependent and -sensitive), LNCaPC4-2 (androgen-independent and -sensitive; androgen-refractory), and DU145 (androgen-independent and -insensitive) cells. The treatment of LNCaP cells with 6 μM compound 5 for 24 h stimulated the androgen receptor (AR) activity and dramatically up-regulated transcription (56-fold) of p21Cip1, which, in turn, induces typical apoptosis in the cells. However, induction of apoptosis through up-regulation (23-fold) of AR-associated p21Cip1 achieved in LNCaPC4-2 cells was possible by intensive cell treatment with compound 5 (9 μM, 48 h), because the cells are less sensitive and independent to androgen than LNCaP cells. Furthermore, 6 μM compound 5-treated DU145 cells, which exhibit extremely low AR activation due to no androgen responsiveness and dependency, showed neither up-regulation of p21Cip1 nor apoptotic induction. Instead, a different type of cell death, autophagy-like death through the LC3B-associated autophagosome formation, was obviously induced in DU145 cells. Taken together, our results suggest that pleiotropic induction of prostate cancer cell death by compound 5 is determined by how efficiently and how abundantly androgen-dependent activation of the AR occurs, whereas compound 6 shows no induction of apoptosis in LNCaP cells.
