Discovery of potential anticancer multi-targeted ligustrazine based cyclohexanone and oxime analogs overcoming the cancer multidrug resistance

Gao Feng Zha, Hua Li Qin, Bahaa G.M. Youssif, Muhammad Wahab Amjad, Maria Abdul Ghafoor Raja, Ahmed H. Abdelazeem, Bukhari Syed Nasir Abbas

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The drug research and development nowadays is focusing on multi-target drugs. In the treatment of cancer, therapies using drugs inhibiting one numerous targets signify a novel viewpoint. In comparison with traditional therapy, multi-targeted drugs directly aim cell subpopulations which are involved in progression of tumor. The current study comprises the synthesis of 34 novel ligustrazine-containing α, β-unsaturated carbonyl-based compounds and oximes. The growth of 5 various cancer cell types was strongly inhibited by ligustrazine-containing oximes as revealed by biological evaluation. A strong SAR was provided by the antiproliferative activity. The mechanistic effects of most active antiproliferative compounds on tubulin polymerization, EGFR TK kinases, KAF and BRAFV600E were investigated, followed by in vitro investigation of reversal of efflux-based resistance developed by cancer cells. EGFR was strongly inhibited by two oximes 7e and 8o. Out of all linkers including positive control, 1-isopropyl-piperidin-4-one linker-bearing compounds showed best inhibition of FAK. The strongest inhibitory activity of BRAFV600E was showed by compound 5e with an IC50 of 0.7 μM. Analogs such as 5 and 7 (b,e,f) exhibited a dual role as anticancer as well as MDR reversal agents. For understanding the target protein integrations with new compounds, molecular docking studies were also carried out.

Original languageEnglish
Pages (from-to)34-48
Number of pages15
JournalEuropean Journal of Medicinal Chemistry
Volume135
DOIs
Publication statusPublished - 28 Jul 2017
Externally publishedYes

Fingerprint

Oximes
Multiple Drug Resistance
Bearings (structural)
Cells
Pharmaceutical Preparations
Drug therapy
Neoplasms
Tubulin
Tumors
Phosphotransferases
Polymerization
Inhibitory Concentration 50
Drug Therapy
tetramethylpyrazine
cyclohexanone oxime
Proteins
Therapeutics
Growth
Research

Keywords

  • BRAF
  • Cancer cell lines
  • Epidermal growth factor receptor (EGFR)
  • Focal adhesion kinase (FAK)
  • Tubulin polymerization

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Discovery of potential anticancer multi-targeted ligustrazine based cyclohexanone and oxime analogs overcoming the cancer multidrug resistance. / Zha, Gao Feng; Qin, Hua Li; Youssif, Bahaa G.M.; Amjad, Muhammad Wahab; Raja, Maria Abdul Ghafoor; Abdelazeem, Ahmed H.; Syed Nasir Abbas, Bukhari.

In: European Journal of Medicinal Chemistry, Vol. 135, 28.07.2017, p. 34-48.

Research output: Contribution to journalArticle

Zha, Gao Feng ; Qin, Hua Li ; Youssif, Bahaa G.M. ; Amjad, Muhammad Wahab ; Raja, Maria Abdul Ghafoor ; Abdelazeem, Ahmed H. ; Syed Nasir Abbas, Bukhari. / Discovery of potential anticancer multi-targeted ligustrazine based cyclohexanone and oxime analogs overcoming the cancer multidrug resistance. In: European Journal of Medicinal Chemistry. 2017 ; Vol. 135. pp. 34-48.
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