Synthesis of α,β-Unsaturated Carbonyl-Based Compounds, Oxime and Oxime Ether Analogs as Potential Anticancer Agents for Overcoming Cancer Multidrug Resistance by Modulation of Efflux Pumps in Tumor Cells

Hua-Li Qin; Jing Leng; Cheng-Pan Zhang; Ibrahim Jantan; Muhammad Wahab Amjad; Muhammad Sher; Muhammad Naeem-Ul-Hassan; Muhammad Ajaz Hussain; Syed Nasir Abbas Bukhari

doi:10.1021/acs.jmedchem.6b00276

Synthesis of α,β-Unsaturated Carbonyl-Based Compounds, Oxime and Oxime Ether Analogs as Potential Anticancer Agents for Overcoming Cancer Multidrug Resistance by Modulation of Efflux Pumps in Tumor Cells

J Med Chem. 2016 Apr 14;59(7):3549-61. doi: 10.1021/acs.jmedchem.6b00276. Epub 2016 Apr 4.

Authors

Hua-Li Qin¹, Jing Leng¹, Cheng-Pan Zhang¹, Ibrahim Jantan², Muhammad Wahab Amjad², Muhammad Sher³, Muhammad Naeem-Ul-Hassan³, Muhammad Ajaz Hussain³, Syed Nasir Abbas Bukhari²

Affiliations

¹ Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology , 205 Luoshi Road, Wuhan 430070, P.R. China.
² Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia , Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
³ Department of Chemistry, University of Sargodha , Sargodha 40100, Pakistan.

PMID: 27010345
DOI: 10.1021/acs.jmedchem.6b00276

Abstract

Sixty-nine novel α,β-unsaturated carbonyl based compounds, including cyclohexanone, tetralone, oxime, and oxime ether analogs, were synthesized. The antiproliferative activity determined by using seven different human cancer cell lines provided a structure-activity relationship. Compound 8ag exhibited high antiproliferative activity against Panc-1, PaCa-2, A-549, and PC-3 cell lines, with IC50 value of 0.02 μM, comparable to the positive control Erlotinib. The ten most active antiproliferative compounds were assessed for mechanistic effects on BRAF(V600E), EGFR TK kinases, and tubulin polymerization, and were investigated in vitro to reverse efflux-mediated resistance developed by cancer cells. Compound 8af exhibited the most potent BRAF(V600E) inhibitory activity with an IC50 value of 0.9 μM. Oxime analog 7o displayed the most potent EGFR TK inhibitory activity with an IC50 of 0.07 μM, which was analogous to the positive control. Some analogs including 7f, 8af, and 8ag showed a dual role as anticancer and MDR reversal agents.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Cyclohexanones / chemistry*
Drug Resistance, Multiple / drug effects*
ErbB Receptors / antagonists & inhibitors
Ethers / chemistry*
Humans
Models, Molecular
Mutation / genetics
Neoplasms / drug therapy*
Neoplasms / pathology
Oximes / chemical synthesis
Oximes / chemistry*
Oximes / pharmacology
Piperidones / chemical synthesis*
Piperidones / pharmacology*
Proto-Oncogene Proteins B-raf / antagonists & inhibitors
Proto-Oncogene Proteins B-raf / genetics
Structure-Activity Relationship
Tetralones / chemical synthesis*
Tetralones / pharmacology*
Tubulin / chemistry
Tubulin Modulators / chemical synthesis
Tubulin Modulators / pharmacology
Tumor Cells, Cultured

Substances

2-(2-chloro-3,4-dimethoxybenzylidene)-8-nitrotetralone oxime
3,5-bis(2-bromo-3,4,5-trimethoxybenzylidene)-1-methylpiperidin-4-one oxime
Antineoplastic Agents
Cyclohexanones
Ethers
Oximes
Piperidones
Tetralones
Tubulin
Tubulin Modulators
cyclohexanone
EGFR protein, human
ErbB Receptors
BRAF protein, human
Proto-Oncogene Proteins B-raf