Dihydropyrazothiazole derivatives as potential MMP-2/MMP-8 inhibitors for cancer therapy

Wang, Zhongchang; Shen, Fa-Qian; Yang, Meng-Ru; You, Ling-Xia; Chen, Lizhi; Zhu, Hai‐Liang; Lu, Yinan; Kong, Fanlei; Wang, Minghua

doi:10.1016/j.bmcl.2018.05.004

Cited by 11 publications

(7 citation statements)

References 34 publications

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“…Among the sulfated benzofurans, the closely related monomers (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) and dimers (27)(28)(29)(30)(31)(32)(33)(34)(35) did not inhibit MMP-8 in contrast to 26, which was one of the three most active NSGMs. In each case, the structural changes were primarily in the terminal substituents (R 1 and R 4 , Figure 1), suggesting a stringent size dependence.…”

Section: Structure−activity Relationships For the Library Of Nsgmsmentioning

confidence: 92%

“…Although small molecule inhibitors are likely to prevent and treat multiple diseases ( Table 1 ), few reports are available on the development of MMP-8 inhibitors. In fact, only two publications have reported MMP-8 inhibitors in the last decade [ 19 , 20 ]. Thus, the vast chemical space offered by small molecules appears to be almost untouched for MMP-8 inhibitor development.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of Sulfated Small Molecule Inhibitors of Matrix Metalloproteinase-8

Morla

Desai

2020

Biomolecules

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Elevated matrix metalloproteinase-8 (MMP-8) activity contributes to the etiology of many diseases, including atherosclerosis, pulmonary fibrosis, and sepsis. Yet, very few small molecule inhibitors of MMP-8 have been identified. We reasoned that the synthetic non-sugar mimetics of glycosaminoglycans may inhibit MMP-8 because natural glycosaminoglycans are known to modulate the functions of various MMPs. The screening a library of 58 synthetic, sulfated mimetics consisting of a dozen scaffolds led to the identification of only two scaffolds, including sulfated benzofurans and sulfated quinazolinones, as promising inhibitors of MMP-8. Interestingly, the sulfated quinazolinones displayed full antagonism of MMP-8 and sulfated benzofuran appeared to show partial antagonism. Of the two, sulfated quinazolinones exhibited a >10-fold selectivity for MMP-8 over MMP-9, a closely related metalloproteinase. Molecular modeling suggested the plausible occupancy of the S1′ pocket on MMP-8 as the distinguishing feature of the interaction. Overall, this work provides the first proof that the sulfated mimetics of glycosaminoglycans could lead to potent, selective, and catalytic activity-tunable, small molecular inhibitors of MMP-8.

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Section: Structure−activity Relationships For the Library Of Nsgmsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Discovery of Sulfated Small Molecule Inhibitors of Matrix Metalloproteinase-8

Morla

Desai

2020

Biomolecules

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“…Iproteos company researchers in Spain developed new gelatinase inhibitors, compounds 22 and 23, that were capable of inhibiting MMP-2 and MMP-9 with high potency and selectivity among different MMPs [11,104]. thesis was achieved by cross-condensation reactions, and the biological evaluation was performed against MCF-7, Hela, and HepG2 cell lines [100].…”

Section: Mmp-2 Inhibitorsmentioning

confidence: 99%

Matrix Metalloproteinases Inhibitors in Cancer Treatment: An Updated Review (2013–2023)

Almutairi,

Kalloush,

Manoon

et al. 2023

Molecules

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Matrix metalloproteinases (MMPs) are identifiable members of proteolytic enzymes that can degrade a wide range of proteins in the extracellular matrix (ECM). MMPs can be categorized into six groups based on their substrate specificity and structural differences: collagenases, gelatinases, stromelysins, matrilysins, metalloelastase, and membrane-type MMPs. MMPs have been linked to a wide variety of biological processes, such as cell transformation and carcinogenesis. Over time, MMPs have been evaluated for their role in cancer progression, migration, and metastasis. Accordingly, various MMPs have become attractive therapeutic targets for anticancer drug development. The first generations of broad-spectrum MMP inhibitors displayed effective inhibitory activities but failed in clinical trials due to poor selectivity. Thanks to the evolution of X-ray crystallography, NMR analysis, and homology modeling studies, it has been possible to characterize the active sites of various MMPs and, consequently, to develop more selective, second-generation MMP inhibitors. In this review, we summarize the computational and synthesis approaches used in the development of MMP inhibitors and their evaluation as potential anticancer agents.

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“…The second data set is used for external validation of the models that have been created. All the references [6][7][8][9][10][11][12][13][14] can be found for the external test dataset in table 1 and the supplementary file. Therefore, in these sections 3.1 and 3.2, we can discuss how to build the QSARMLR and QSARANN models.…”

Section: Qsarmlr Modelmentioning

confidence: 99%

Discovery of novel thiazole derivatives as anti‐breast cancer agents (MCF‐7) and validation of homologous effects on SARS‐CoV‐2 virus using in silico approaches

Quang,

Linh,

Uyen

et al. 2023

Vietnam Journal of Chemistry

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The development of new drugs with activity against breast cancer (MCF‐7) and SARS‐CoV‐2 based on new thiazole derivatives is still of great interest to many scientists. In silico models have been successfully used to orient the design of novel substances, predict IC50 activity, and screen 12 newly designed derivatives of TAZD. The predictive quality of the QSAR models are shown in the statistical values R2train = 0.945, Q2LOO = 0.919, and SE = 8.40 for QSARMLR, and the statistical values R2 = 0.984, Q2test = 0.985, and Q2CV = 0.996 for the QSARANN I(8)‐HL(10)‐O(1) models. The PPI interaction network pharmacological model was used to screen and evaluate the specific effects of TAZDs on target proteins for breast cancer and SARS‐CoV‐2. The obtained TAZD derivatives were consistent in drug‐likeness according to the Lipinski principle. The compound TAZD8 has good inhibitory potential for the 1R42‐PDB protein of breast cancer cells MCF‐7 and the SARS‐CoV‐2 virus. The compound TAZD8 has the ability to strongly bind to the middle region of two proteins, ACE2‐PDB and 6LU7‐PDB. Therefore, thiazole‐based TAZD8 was found to be a derivative with good potential inhibitory activity against Mpro SARS‐CoV‐2 and the 1R42‐PDB protein for breast cancer MCF‐7.

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Dihydropyrazothiazole derivatives as potential MMP-2/MMP-8 inhibitors for cancer therapy

Cited by 11 publications

References 34 publications

Discovery of Sulfated Small Molecule Inhibitors of Matrix Metalloproteinase-8

Discovery of Sulfated Small Molecule Inhibitors of Matrix Metalloproteinase-8

Matrix Metalloproteinases Inhibitors in Cancer Treatment: An Updated Review (2013–2023)

Discovery of novel thiazole derivatives as anti‐breast cancer agents (MCF‐7) and validation of homologous effects on SARS‐CoV‐2 virus using in silico approaches

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