Design, Synthesis, and Biological Evaluation of Tetrahydro-β-carboline Derivatives as Selective Sub-Nanomolar Gelatinase Inhibitors

ChemMedChem. 2018 Jul 6;13(13):1343-1352. doi: 10.1002/cmdc.201800237. Epub 2018 Jun 12.

Abstract

Targeting matrix metalloproteinases (MMPs) is a pursued strategy for treating several pathological conditions, such as multiple sclerosis and cancer. Herein, a series of novel tetrahydro-β-carboline derivatives with outstanding inhibitory activity toward MMPs are present. In particular, compounds 9 f, 9 g, 9 h and 9 i show sub-nanomolar IC50 values. Interestingly, compounds 9 g and 9 i also provide remarkable selectivity toward gelatinases; IC50 =0.15 nm for both toward MMP-2 and IC50 =0.63 and 0.58 nm, respectively, toward MMP-9. Molecular docking simulations, performed by employing quantum mechanics based partial charges, shed light on the rationale behind binding involving specific interactions with key residues of S1' and S3' domains. Taken together, these studies indicate that tetrahydro-β-carboline represents a promising scaffold for the design of novel inhibitors able to target MMPs and selectively bias gelatinases, over the desirable range of the pharmacokinetics spectrum.

Keywords: gelatinases; metalloproteinases; molecular docking; selectivity; β-carbolines.

MeSH terms

  • Carbolines / chemical synthesis
  • Carbolines / chemistry*
  • Carbolines / pharmacokinetics
  • Drug Design
  • Enzyme Assays
  • Gelatinases / antagonists & inhibitors*
  • Gelatinases / chemistry
  • Humans
  • Matrix Metalloproteinase 2 / chemistry
  • Matrix Metalloproteinase 9 / chemistry
  • Matrix Metalloproteinase Inhibitors / chemical synthesis
  • Matrix Metalloproteinase Inhibitors / chemistry*
  • Matrix Metalloproteinase Inhibitors / pharmacokinetics
  • Molecular Docking Simulation
  • Stereoisomerism

Substances

  • Carbolines
  • Matrix Metalloproteinase Inhibitors
  • Gelatinases
  • Matrix Metalloproteinase 2
  • MMP9 protein, human
  • Matrix Metalloproteinase 9