Design, synthesis, crystal structures and anticancer activity of 4-substituted quinolines to target PDK1

K N Vennila; D Sunny; S Madhuri; Samuele Ciattini; Laura Chelazzi; Kuppanagounder P Elango

doi:10.1016/j.bioorg.2018.08.007

Design, synthesis, crystal structures and anticancer activity of 4-substituted quinolines to target PDK1

Bioorg Chem. 2018 Dec:81:184-190. doi: 10.1016/j.bioorg.2018.08.007. Epub 2018 Aug 7.

Authors

K N Vennila¹, D Sunny², S Madhuri², Samuele Ciattini³, Laura Chelazzi³, Kuppanagounder P Elango⁴

Affiliations

¹ Department of Chemistry, Gandhigram Rural Institute (Deemed to be University), Gandhigram 624 302, India.
² National Institute of Animal Biotechnology, Hyderabad 500 049, India.
³ Structural Crystallography Center, University of Florence, Sesto Fiorentino (Florence), Italy.
⁴ Department of Chemistry, Gandhigram Rural Institute (Deemed to be University), Gandhigram 624 302, India. Electronic address: drkpelango@rediffmail.com.

PMID: 30138906
DOI: 10.1016/j.bioorg.2018.08.007

Abstract

The induced fit docking of anilino quinoline scaffold results in the required hydrogen bonding interactions with amino acid residues in the orthosteric site of 3 Phosphoinositide dependent kinase (PDK1). The rational design of 4-substituted amino quinolines is carried out and eight compounds are synthesized. Four crystal structures are determined and their binding mode with adenosine triphosphate (ATP) site of PDK1 is analyzed. The anticancer activity in A549 cell lines of the test compounds by MTT assay resulted in an inhibitor with IC₅₀ value of 0.96 µM which is less than the pemetrexed, a marketed lung cancer drug.

Keywords: Induced fit docking, A549 inhibitor; PDK1; Quinoline.

Publication types

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

MeSH terms

A549 Cells
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
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
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Quinolines / chemical synthesis
Quinolines / chemistry
Quinolines / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
PDK1 protein, human
Protein Kinase Inhibitors
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Quinolines
Protein Serine-Threonine Kinases