Design and synthesis of tricyclic terpenoid derivatives as novel PTP1B inhibitors with improved pharmacological property and in vivo antihyperglycaemic efficacy

AbstractImpaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL–HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.

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Design and synthesis of a potent and specific renin inhibitor with a prolonged duration of action in vivo

Journal of Medicinal Chemistry ◽

10.1021/jm00160a049 ◽

1986 ◽

Vol 29 (10) ◽

pp. 2088-2093 ◽

Cited By ~ 41

Author(s):

Suvit Thaisrivongs ◽

Donald T. Pals ◽

Douglas W. Harris ◽

Warren M. Kati ◽

Steve R. Turner

Keyword(s):

Renin Inhibitor ◽

Duration Of Action ◽

Design And Synthesis ◽

Prolonged Duration

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Design and Synthesis of Pyrazole-3-one Derivatives as Hypoglycaemic Agents

International Journal of Medicinal Chemistry ◽

10.1155/2015/670181 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Prasanna A. Datar ◽

Sonali R. Jadhav

Keyword(s):

Amino Acid ◽

Docking Studies ◽

Diabetic Rats ◽

Hypoglycemic Activity ◽

Amino Acid Residues ◽

Docking Score ◽

Design And Synthesis ◽

Hypoglycaemic Agents ◽

Standard Compound

Pyrazole-3-one compounds were designed on the basis of docking studies of previously reported antidiabetic pyrazole compounds. The amino acid residues found during docking studies were used as guidelines for the modification of aromatic substitutions on pyrazole-3-one structure. Depending on the docking score, the designed compounds were selectively prioritized for synthesis. The synthesized compounds were subjected to in vivo hypoglycemic activity using alloxan induced diabetic rats and metformin as a standard. Compound 4 having sulphonamide derivative was found to be the most potent compound among the series.

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Structure Based Design and Synthesis of Peptide Inhibitor of Human LOX-12: In Vitro and In Vivo Analysis of a Novel Therapeutic Agent for Breast Cancer

PLoS ONE ◽

10.1371/journal.pone.0032521 ◽

2012 ◽

Vol 7 (2) ◽

pp. e32521 ◽

Cited By ~ 15

Author(s):

Abhay kumar Singh ◽

Ratnakar Singh ◽

Farhat Naz ◽

Shyam Singh Chauhan ◽

Amit Dinda ◽

...

Keyword(s):

Breast Cancer ◽

Therapeutic Agent ◽

Peptide Inhibitor ◽

Design And Synthesis ◽

In Vivo Analysis ◽

Novel Therapeutic

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The Antiviral Effect of Novel Steroidal Derivatives on Flaviviruses

Frontiers in Microbiology ◽

10.3389/fmicb.2021.727236 ◽

2021 ◽

Vol 12 ◽

Author(s):

Luping Zhang ◽

Dengyuan Zhou ◽

Qiuyan Li ◽

Shuo Zhu ◽

Muhammad Imran ◽

...

Keyword(s):

Antiviral Effect ◽

Therapeutic Drug ◽

Dependent Manner ◽

Design And Synthesis ◽

Invasion Stage ◽

Synthetic Derivatives ◽

Dose Dependent ◽

The Brain

Flaviviruses are the major emerging arthropod-borne pathogens globally. However, there is still no practical anti-flavivirus approach. Therefore, existing and emerging flaviviruses desperately need active broad-spectrum drugs. In the present study, the antiviral effect of steroidal dehydroepiandrosterone (DHEA) and 23 synthetic derivatives against flaviviruses such as Japanese encephalitis virus (JEV), Zika virus (ZIKV), and Dengue virus (DENV) were appraised by examining the characteristics of virus infection both in vitro and in vivo. Our results revealed that AV1003, AV1004 and AV1017 were the most potent inhibitors of flavivirus propagation in cells. They mainly suppress the viral infection in the post-invasion stage in a dose-dependent manner. Furthermore, orally administered compound AV1004 protected mice from lethal JEV infection by increasing the survival rate and reducing the viral load in the brain of infected mice. These results indicate that the compound AV1004 might be a potential therapeutic drug against JEV infection. These DHEA derivatives may provide lead scaffolds for further design and synthesis of potential anti-flavivirus potential drugs.

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