87694-53-9Relevant articles and documents
Convenient Synthesis of Alternatively Bridged Tryptophan Ketopiperazines and Their Activities against Trypanosomatid Parasites
Cockram, Peter E.,Turner, Callum A.,Slawin, Alexandra M. Z.,Smith, Terry K.
, (2022/01/11)
There is an urgent need for the development of new treatments against trypanosomatid parasites; the causative agents of some of the most debilitating diseases in the developing world. This work targets an interesting 6-5-6-6 fused carboline scaffold, accessing a range of substituted derivatives through stereospecific intramolecular Pictet–Spengler condensation. Modification of the cyclisation conditions allowed retention of the carbamate protecting group and gave insight into the reaction mechanism. Compounds’ bioactivities were measured against T. brucei, T. cruzi, L. major and HeLa cells. We have identified promising pan-trypanocidal lead compounds based on the core scaffold, and highlight key SAR trends which will be useful for the future development of these compounds as potent trypanocidal agents.
Macrocyclic Immunoproteasome Inhibitors as a Potential Therapy for Alzheimer's Disease
Lee, Min Jae,Bhattarai, Deepak,Jang, Hyeryung,Baek, Ahreum,Yeo, In Jun,Lee, Seongsoo,Miller, Zachary,Lee, Sukyeong,Hong, Jin Tae,Kim, Dong-Eun,Lee, Wooin,Kim, Kyung Bo
, p. 10934 - 10950 (2021/08/20)
Previously, we reported that immunoproteasome (iP)-targeting linear peptide epoxyketones improve cognitive function in mouse models of Alzheimer's disease (AD) in a manner independent of amyloid β. However, these compounds' clinical prospect for AD is limited due to potential issues, such as poor brain penetration and metabolic instability. Here, we report the development of iP-selective macrocyclic peptide epoxyketones prepared by a ring-closing metathesis reaction between two terminal alkenes attached at the P2 and P3/P4 positions of linear counterparts. We show that a lead macrocyclic compound DB-60 (20) effectively inhibits the catalytic activity of iP in ABCB1-overexpressing cells (IC50: 105 nM) and has metabolic stability superior to its linear counterpart. DB-60 (20) also lowered the serum levels of IL-1α and ameliorated cognitive deficits in Tg2576 mice. The results collectively suggest that macrocyclic peptide epoxyketones have improved CNS drug properties than their linear counterparts and offer promising potential as an AD drug candidate.
Discovery of novel tripeptide propylene oxide proteasome inhibitors for the treatment of multiple myeloma
Zhang, Wen,Wang, Xueyuan,Zhang, Haoyang,Wen, Tiantian,Yang, Lin,Miao, Hang,Wang, Jia,Liu, Hailong,Yang, Xu,Lei, Meng,Zhu, Yongqiang
supporting information, (2021/05/13)
The ubiquitin proteasome pathway (UPP) plays a critical role in the maintenance of cell homeostasis and the development of diseases, such as cancer and neurodegenerative disease. A series of novel tripeptide propylene oxide compounds as proteasome inhibitors were designed, synthesized and biologically investigated in this manuscript. The enzymatic activities of final compounds against 20S human proteasome were investigated and structure-activity relationship (SAR) was summarized. Some potent compounds were further evaluated to inhibit the proliferation of multiple myeloma (MM) cancer cell lines RPMI8226 and U266B. The results showed that some compounds were active against MM cancer cell lines with IC50 values of less than 50 nM. The microsomal metabolic stabilities in human, rat and mice species were carried out and the results showed that compounds 30 and 31 were stable enough to be in vivo investigated. The in vivo pharmacokinetic results showed that compounds 30 and 31 had acceptable biological parameters for both ig and iv administrations. In vivo antitumor activities of compounds 30 and 31 with the doses of 100 mg/kg and 50 mg/kg BIW were performed by using RPMI8226 xenograft nude mouse model. Toxicities of compounds 30 and 31 were not observed during the experiment and dose dependent effect was obvious and the tumor volume was greatly inhibited.
