Synthesis and evaluation of 7-azaindole derivatives bearing benzocycloalkanone motifs as protein kinase inhibitors

Malikotsi A Qhobosheane; Lesetja J Legoabe; Béatrice Josselin; Stéphane Bach; Sandrine Ruchaud; Jacobus P Petzer; Richard M Beteck

doi:10.1016/j.bmc.2020.115468

Synthesis and evaluation of 7-azaindole derivatives bearing benzocycloalkanone motifs as protein kinase inhibitors

Bioorg Med Chem. 2020 Jun 1;28(11):115468. doi: 10.1016/j.bmc.2020.115468. Epub 2020 Mar 31.

Authors

Malikotsi A Qhobosheane¹, Lesetja J Legoabe², Béatrice Josselin³, Stéphane Bach³, Sandrine Ruchaud⁴, Jacobus P Petzer⁵, Richard M Beteck¹

Affiliations

¹ Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
² Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa. Electronic address: lesetja.legoabe@nwu.ac.za.
³ Sorbonne Université, CNRS, UMR 8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680 Roscoff, France; Sorbonne Université, CNRS, FR 2424, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening facility), Station Biologique de Roscoff, 29680 Roscoff, France.
⁴ Sorbonne Université, CNRS, UMR 8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680 Roscoff, France.
⁵ Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa; Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.

PMID: 32284225
DOI: 10.1016/j.bmc.2020.115468

Abstract

Protein kinases are important drug targets, especially in the area of oncology. This paper reports the synthesis and biological evaluation of new 7-azaindole derivatives bearing benzocycloalkanone motifs as potential protein kinase inhibitors. Four compounds 8g, 8h, 8i, and 8l were discovered to inhibit cyclin-dependent kinase 9 (CDK9/CyclinT) and/or Haspin kinase in the micromolar to nanomolar range. 8l was identified as the most potent Haspin inhibitor (IC₅₀ = 14 nM), while 8g and 8h acted as dual inhibitors of CDK9/CyclinT and Haspin. These novel compounds constitute a promising starting point for the discovery of dual protein kinase inhibitors that have potential to be developed as anticancer agents, since both CDK9/CyclinT and Haspin are considered to be drug targets in oncology.

Keywords: 7-azaindole; Benzocycloalkanone; CDK9/CyclinT; Dual inhibitor; Haspin; Oncology; Protein kinase; Structure-activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cyclin-Dependent Kinase 9 / antagonists & inhibitors*
Cyclin-Dependent Kinase 9 / metabolism
Dose-Response Relationship, Drug
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Intracellular Signaling Peptides and Proteins / metabolism
Ketones / chemistry
Ketones / pharmacology*
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Structure-Activity Relationship

Substances

7-azaindole dimer
Indoles
Intracellular Signaling Peptides and Proteins
Ketones
Protein Kinase Inhibitors
HASPIN protein, human
Protein Serine-Threonine Kinases
CDK9 protein, human
Cyclin-Dependent Kinase 9