Design and synthesis of a novel class of furan-based molecules as potential 20S proteasome inhibitors

Fu, Yiqiu; Xu, Bo; Zou, Xiaomin; Ma, Chao; Yang, Xiaoming; Mou, Ke; Fu, Gang; Lü, Yang; Xu, Ping

doi:10.1016/j.bmcl.2006.11.020

Cited by 26 publications

(18 citation statements)

References 31 publications

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“…After the addition, the pale-yellow solution was warmed to 0 8C and stirred for 30 min. The resulting dark-yellow solution was re-cooled to À78 8C, and a solution of 1 (1.85 g, 6.7 mmol) in THF (10 mL) was added, and the reaction mixture was maintained at À78 8C for another 2.5 h. Then, the dark-orange solution was poured into saturated aqueous NH 4 (S)-2-((tert-Butoxycarbonyl)amino)-3-(4-methoxyphenyl)propanoic acid (7 a): 1n NaOH was added to a solution of 6 a in THF until pH 12-13, and the reaction mixture was stirred at room temperature for 2 h until acidified to pH 2-3 with 1 n HCl. The aqueous phase was extracted with EtOAc (5 10 mL), and the combined organic phases were dried with Na 2 SO 4 .…”

Section: Discussionmentioning

confidence: 99%

“…Much research has indicated that tumor cells are more sensitive to proteasome inhibitors than normal cells, and therefore, the proteasome is regarded as one of the most promising antitumor drug targets. [4] The unique potent compound we identified was peptide derivative 12 (Figure 1 b), with IC 50 values of 7.85 mm against the b5 subunit, and 34.2 and 30.07 mm toward HepG2 and HL-60 cell growth inhibition, respectively. Crystal structure information shows that the active sites of the 20S proteasome are located on the b1, b2, and b5 subunits, which have caspase-like (C-L), trypsin-like (T-L), and chymotrypsin-like (ChT-L) activities, respectively.…”

Section: Introductionmentioning

confidence: 96%

“…[3] We previously reported two series of furan-based b5 subunit inhibitors, among which nine compounds were tripeptide derivatives and six were statine peptidomimetics. [4] The unique potent compound we identified was peptide derivative 12 (Figure 1 b), with IC 50 values of 7.85 mm against the b5 subunit, and 34.2 and 30.07 mm toward HepG2 and HL-60 cell growth inhibition, respectively. The C-terminal furyl ketone group of compound 12 was initially hypothesized to form a covalent bond with Thr1, and the peptide backbone to adopt an antiparallel b-sheet conformation typical for peptide-based inhibitors.…”

Section: Introductionmentioning

confidence: 96%

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Synthesis, Bioactivity, Docking and Molecular Dynamics Studies of Furan‐Based Peptides as 20S Proteasome Inhibitors

Sun¹,

Xu²,

Niu³

et al. 2015

ChemMedChem

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Proteasome inhibitors are promising compounds for a number of therapies, including cardiovascular and eye diseases, diabetes, and cancers. We previously reported a series of furan-based peptidic inhibitors with moderate potencies against the proteasome β5 subunit, hypothesizing that the C-terminal furyl ketone motif could form a covalent bond with the catalytic residue, threonine 1. In this context, we describe further optimizations of the furan-based peptides, and a series of dipeptidic and tripeptidic inhibitors were designed and synthesized, aiming at improved potency and better solubility. Most of the tripeptidic inhibitors demonstrated improved potency and selectivity as β5 subunit inhibitors in both enzymatic and cellular assays, and good antineoplastic activities in various tumor cell lines were also observed. However, no inhibitory effects were observed for the dipeptidic compounds, which led us to presume that a noncovalent binding mode is adopted. Docking studies and molecular dynamics simulations were carried out to verify this presumption, with results showing that the distance between the furyl ketone motif and Thr1 is slightly too long to form covalent bond.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 96%

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Synthesis, Bioactivity, Docking and Molecular Dynamics Studies of Furan‐Based Peptides as 20S Proteasome Inhibitors

Sun¹,

Xu²,

Niu³

et al. 2015

ChemMedChem

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“…Furthermore, other active proteasome inhibitors with diverse structures, such as peptide linked with furan ring [81] and peptidyl vinyl ester derivatives [82] were also obtained using the CADD techniques.…”

Section: Covalent Dockingmentioning

confidence: 99%

Progress of Computer-Aided Drug Design (CADD) of Proteasome Inhibitors

Li¹,

Liu

Zhu³

et al. 2011

CTMC

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The target proteasome has been the focus of drug discovery since the first drug bortezomib was launched in 2003. Many structurally diverse proteasome inhibitors were discovered and even some of them entered the clinical trials. Due to rapid technological progress in chemistry, bioinformatics, structural biology and computer technology, computer-aided drug design (CADD) plays a more and more important role in today's drug discovery. Many CADD technologies were employed in designing various inhibitors of proteasome in the past years. This review gives a global description of the development of computer-aided proteasome inhibitor design by using different commercial or academic software. The binding modes of some structurally novel inhibitors with proteasome were visualized with these new technologies.

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“…Several native and synthetic compounds have been investigated with proteasome activity inhibition [7], and they have some classic structures [8][9][10][11][12][13][14]. C-terminal furanyl substitution is one of the classic structures, which have been identified to contribute to proteasome inhibition with unique mechanism [15], so exploitation of proteasome inhibitory activities of more furan-contained compounds may be a work worth paying attention to.…”

Section: Introductionmentioning

confidence: 99%

Terazosin Suppress Human Prostatic Cancer PC3 Cell Viability via Proteasome Inhibition

Ji¹

2014

Biol Med

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Terazosin is one of classic quinazoline-based selective α1-adrenoreceptor antagonists, which is usually used for the treatment of benign prostate hyperplasia (BPH) patients. Several evidences suggest that terazosin can induce apoptosis of prostatic cancer cells in vitro and suppress prostatic tumor growth in vivo, but molecular mechanism contributing to these processes has not yet been fully elucidated. In this study, we report that the suppression of terazosin on prostatic cancer PC3 cells viability partially mediated by proteasome inhibition. We first examined cytotoxicity of terazosin in human prostatic cancer cell line PC3, including cell viability, cell cycle analysis and cell apoptosis analysis. Then the chymotrypsin-like proteasome activity, levels of ubiquitinated-proteins and selective protein substrate of proteasome were detected, to reflect alteration of proteasome activity. Our results indicate that terazosin treatment results in a significant decrease of cell viability in a dose-and time-dependent manner in PC3 cells, accompanied with cell cycle arrest and apoptotic induction; Exposure to terazosin also causes a significant loss of proteasome activity as well as accumulation of ubiquitinated-proteins and selective protein substrate P27 in PC3 cells, which occurs prior to cell death. In view of these results, we conclude that terazosin suppress human prostatic cancer PC3 cell viability by cell cycle arrest and cell death induction, which is associated with its proteasome inhibitory activity.

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Design and synthesis of a novel class of furan-based molecules as potential 20S proteasome inhibitors

Cited by 26 publications

References 31 publications

Synthesis, Bioactivity, Docking and Molecular Dynamics Studies of Furan‐Based Peptides as 20S Proteasome Inhibitors

Synthesis, Bioactivity, Docking and Molecular Dynamics Studies of Furan‐Based Peptides as 20S Proteasome Inhibitors

Progress of Computer-Aided Drug Design (CADD) of Proteasome Inhibitors

Terazosin Suppress Human Prostatic Cancer PC3 Cell Viability via Proteasome Inhibition

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