864528-33-6Relevant articles and documents
Hit-to-lead optimization of a latency-associated nuclear antigen inhibitor against Kaposi's sarcoma-associated herpesvirus infections
Berwanger, Aylin,Empting, Martin,Jakob, Valentin,Kirsch, Philine,Rinkes, Julia,Schulz, Thomas F.,Stein, Saskia C.
supporting information, (2020/07/07)
The Latency-associated nuclear antigen (LANA) plays a central role for the latent persistence of the Kaposi's Sarcoma Herpesvirus (KSHV) in the human host and helps to establish lifelong infections. Herein, we report our efforts towards hit-to-lead generation starting from a previously discovered LANA-DNA inhibitor. By tethering the viral genome to the host nucleosomes, LANA ensures the segregation and persistence of the viral DNA during mitosis. LANA is also required for the replication of the latent viral episome during the S phase of the cell cycle. We aim to inhibit the interaction between LANA and the viral genome to prevent the latent persistence of KSHV in the host organism. Medicinal chemistry-driven optimization studies and structure-activity-relationship investigation led to the discovery of an improved LANA inhibitor. The functional activity of our compounds was evaluated using a fluorescence polarization (FP)-based interaction inhibition assay and electrophoretic mobility shift assay (EMSA). Even though a crystal structure of the ligand protein complex was not available, we successfully conducted hit optimization toward a low micromolar protein-nucleic acid-interaction inhibitor. Additionally, we applied STD-NMR studies to corroborate target binding and to gain insights into the binding orientation of our most potent inhibitor, providing opportunities for further rational design of more efficient LANA-targeting anti KSHV agents in future studies.
Novel leucine ureido derivatives as aminopeptidase N inhibitors using click chemistry
Cao, Jiangying,Ma, Chunhua,Zang, Jie,Gao, Shuai,Gao, Qianwen,Kong, Xiujie,Yan, Yugang,Liang, Xuewu,Ding, Qin'ge,Zhao, Chunlong,Wang, Binghe,Xu, Wenfang,Zhang, Yingjie
, p. 3145 - 3157 (2018/06/01)
The over-expression of aminopeptidase N on diverse malignant cells is associated with the tumor angiogenesis and metastasis. In this report, one new series of leucine ureido derivatives containing the triazole moiety was designed, synthesized and evaluated as APN inhibitors. Among them, compound 13v showed the best APN inhibition with an IC50 value of 0.089 ± 0.007 μM, which was two orders of magnitude lower than that of bestatin (IC50 = 9.4 ± 0.5 μM). Compound 13v also showed dose-dependent anti-angiogenesis activities. Even at the lower concentration (10 μM), compound 13v presented similar anti-angiogenesis activity compared with bestatin at 100 μM in both the human umbilical vein endothelial cells (HUVECs) capillary tube formation assay and the rat thoracic aorta rings test. Moreover, compared with bestatin, 13v exhibited comparable, if not better in vivo anti-metastasis activity in a mouse H22 pulmonary metastasis model.
METHOD FOR PRODUCING A RADIOACTIVE TRACER
-
Paragraph 0166-0170, (2013/03/26)
A method for preparing a radioactive tracer provided with a radioactive fluorine isotope, including providing a precursor of the radioactive tracer, comprising at least one leaving group completely or partially formed by a labelling entity, wherein said leaving group can be moved by a fluoride ion, providing a molecularly imprinted polymer dedicated to the molecular recognition of at least the aforementioned labelling entity, exposing the precursor to a radioactive fluoride ion source under conditions suitable for movement of the leaving group by a radioactive fluoride ion, placing the mixture resulting from step (iii) in contact with the molecularly imprinted polymer under conditions suitable for the recognition of the labelling entity, and obtaining a solution containing the radioactive tracer provided with a radioactive isotope of fluorine obtained at the end of step (iii).
