Design, synthesis and biological evaluation of tripeptide boronic acid proteasome inhibitors

Zhu, Yongqiang; Yao, Shuyang; Xu, Bo; Zhang, Ge; Cui, Jinshi; Cheng, Tanyu; Li, Runtao

doi:10.1016/j.bmc.2009.08.023

Cited by 28 publications

(30 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has an IC 50 value of 0.079 nM and is twofold more active than bortezomib with an IC 50 value of 0.161 nM. Hydrophobic substituents rather than hydrophilic substituents at P 2 or P 3 are found to be beneficial for the cytotoxic activity of the compounds [81]. …”

Section: Therapeutic Applicationsmentioning

confidence: 99%

Boron Chemicals in Diagnosis and Therapeutics

et al. 2013

View full text Add to dashboard Cite

Advances in the field of boron chemistry have expanded the application of boron from material use to medicine. Boron-based drugs represent a new class of molecules that possess several biomedical applications including use as imaging agents for both optical and nuclear imaging as well as therapeutic agents with anticancer, antiviral, antibacterial, antifungal and other disease-specific activities. For example, bortezomib (Velcade®), the only drug in clinical use with boron as an active element, was approved in 2003 as a proteasome inhibitor for the treatment of multiple myeloma and non-Hodgkin’s lymphoma. Several other boron-based compounds are in various phases of clinical trials, which illustrates the promise of this approach for medicinal chemists working in the area of boron chemistry. It is expected that in the near future, several boron-containing drugs should become available in the market with better efficacy and potency than existing drugs. This article discusses the current status of the development of boron-based compounds as diagnostic and therapeutic agents in humans.

show abstract

Section: Therapeutic Applicationsmentioning

confidence: 99%

Boron Chemicals in Diagnosis and Therapeutics

et al. 2013

View full text Add to dashboard Cite

show abstract

“…YSY01A and bortezomib were synthesized as we previously described (Figures 1A,B; Zhu et al, 2009). Both compounds were dissolved in dimethyl sulfoxide (DMSO) to a concentration of 10 mM and preserved at –20°C.…”

Section: Methodsmentioning

confidence: 99%

“…In previous study, we identified a novel proteasome inhibitor, YSY01A, which exhibits antitumor effects in vitro and in vivo (Zhu et al, 2009). Moreover, further studies demonstrate that it modulates a variety of signaling pathways involved in the control of cell proliferation, cell cycle, apoptosis, and autophagy (Wang et al, 2014; Xue et al, 2015; Zhang et al, 2015; Huang et al, 2016b).…”

Section: Introductionmentioning

confidence: 99%

Proteasome Inhibitor YSY01A Abrogates Constitutive STAT3 Signaling via Down-regulation of Gp130 and JAK2 in Human A549 Lung Cancer Cells

et al. 2017

Self Cite

View full text Add to dashboard Cite

Proteasome inhibition interfering with many cell signaling pathways has been extensively explored as a therapeutic strategy for cancers. Proteasome inhibitor YSY01A is a novel agent that has shown remarkable anti-tumor effects; however, its mechanisms of action are not fully understood. Here we report that YSY01A is capable of suppressing cancer cell survival by induction of apoptosis. Paradoxically, we find that YSY01A abrogates constitutive activation of STAT3 via proteasome-independent degradation of gp130 and JAK2, but not transcriptional regulation, in human A549 non-small cell lung cancer cells. The reduction in gp130 and JAK2 can be restored by co-treatment with 3-methyladenine, an early-stage autophagy lysosome and type I/III PI3K inhibitor. YSY01A also effectively inhibits cancer cell migration and lung xenograft tumor growth with little adverse effect on animals. Thus, our findings suggest that YSY01A represents a promising candidate for further development of novel anticancer therapeutics targeting the proteasome.

show abstract

“…NaCl (aq) (30 mL), dried over Na 2 SO 4 , filtered and conventrated. The crude product was purified by column chromatography (SiO 2 , EtOAc/hexanes, 1:1; R f 0.40) to give 1 [11] (100 mg, 0.19 mmol, 73%) as a colorless solid. …”

Section: General Procedures For the Preparation Of Acylated Amino Acidsmentioning

confidence: 99%

“…The reaction mixture was diluted with EtOAc (5 mL), filtered, dried over Na 2 SO 4 , and concentrated to give product 13 (10 mg, 0.028 mmol, 21%). [11]. , 1H), 7.28-7.15 (m, 5H), 6.10 (br, 1H), 4.83 (m, 1H), 3.88 (m, 1H), 3.91-3.31 (m, 2H), 3.24-3.06 (m, 2H), 2.30-2.00 (br, 2H), 1.45-1.38 (m, 1H) N-(1-Oxo-3-phenyl-1-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Methyl-1-((3aR,4R,6R,7aS) -5,5,7a-trimethylhexahydro-4,6-methanobenzo[d] [1,3,2] 3-methyl-1-((3aR,4R,6R,7aS) …”

Section: General Procedures For the Hydrolysis Of Boronic Esters (S)-(mentioning

confidence: 99%

Bortezomib Congeners Induce Apoptosis of Hepatocellular Carcinoma via CIP2A Inhibition

Hou

Huang

Shiau³

et al. 2013

Molecules

View full text Add to dashboard Cite

CIP2A is an oncoprotein that upregulates p-Akt and promotes cancer cell proliferation and survival. The proteasome inhibitor bortezomib has been shown to reduce CIP2A and lead to cell apoptosis. Here; we modified the functional group of bortezomib to generate a series of novel compounds and conducted a structure-activity relationship (SAR) study. The results showed that compound 1 was able to repress CIP2A expression and cell apoptosis in the same manner as bortezomib, but with less potency in inhibition of proteasome activity. This finding provides a new direction for the design of CIP2A inhibitors.

show abstract

Design, synthesis and biological evaluation of tripeptide boronic acid proteasome inhibitors

Cited by 28 publications

References 21 publications

Boron Chemicals in Diagnosis and Therapeutics

Boron Chemicals in Diagnosis and Therapeutics

Proteasome Inhibitor YSY01A Abrogates Constitutive STAT3 Signaling via Down-regulation of Gp130 and JAK2 in Human A549 Lung Cancer Cells

Bortezomib Congeners Induce Apoptosis of Hepatocellular Carcinoma via CIP2A Inhibition

Contact Info

Product

Resources

About