Structure activity relationship analysis of antiproliferative cyclic C5-curcuminoids without DNA binding: Design, synthesis, lipophilicity and biological activity

Imre Huber, Zsuzsanna Rozmer, Zoltán Gyöngyi, Ferenc Budán, Péter Horváth, Eszter Kiss, Pál Perjési

Research output: Contribution to journalArticle

Abstract

The chemical susceptibility of the β-diketone linker between the two aromatic rings in the structure of curcumin to hydrolysis and metabolism has made it crucial to investigate structurally modified analogs of curcumin without such shortcomings. The synthesis of twenty cyclic C5-curcuminoids is described in this study in order to gain more insight into their anticancer structure-activity relationship (SAR). The design of their synthesis included four different cyclanones and five substituted aromatic aldehydes to form four, five-membered subgroups. These model compounds were evaluated in vitro for antiproliferative activity in an XTT cell viability assay against MCF-7 human non-invasive breast adenocarcinoma cancer cells and Jurkat human T lymphocyte leukemia cells in five different concentrations (10 nM, 100 nM, 1 μM, 10 μM and 20 μM). The majority of the compounds investigated have shown remarkable cytotoxicity with IC50 values in the range of 120 nM and 2 μM with very high relative toxicity values to curcumin. The SAR conclusions are drawn and summarized. A method was developed and applied in a TLC based experimental logP measurement, which is new for such C5-curcuminoids. The logP data and structural modifications have shown a strong correlation. The correlation of these experimental logP and the corresponding IC50 values of the model-compounds were calculated according to the Pearson and Kendall correlation coefficient and showed weak concordance. The physicochemical behaviors of the majority of these compounds are in good accordance with Lipinski's rule. The most promising compound is 7a, which is the most active (IC50 = 0.12–0.32 μM), most potent (80 times of curcumin) with the lowest lipophilicity (experimental logP = 3.22) which is important also from a pharmacokinetic point of view. The analysis of experimental logP and computed ClogP values have revealed good agreement. These cyclic C5-curcuminoids in contrast to curcumin do not bind to natural DNA based on their CD spectra.

Original languageEnglish
Article number127661
JournalJournal of Molecular Structure
Volume1206
DOIs
Publication statusPublished - Apr 15 2020

Fingerprint

Curcumin
Bioactivity
DNA
Cells
Pharmacokinetics
T-cells
Cytotoxicity
Metabolism
Aldehydes
Toxicity
Hydrolysis
Assays

Keywords

  • Antiproliferative
  • Cyclic C-curcuminoids
  • Cytotoxic
  • DNA binding
  • Experimental logP
  • SAR

ASJC Scopus subject areas

  • Analytical Chemistry
  • Spectroscopy
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Structure activity relationship analysis of antiproliferative cyclic C5-curcuminoids without DNA binding : Design, synthesis, lipophilicity and biological activity. / Huber, Imre; Rozmer, Zsuzsanna; Gyöngyi, Zoltán; Budán, Ferenc; Horváth, Péter; Kiss, Eszter; Perjési, Pál.

In: Journal of Molecular Structure, Vol. 1206, 127661, 15.04.2020.

Research output: Contribution to journalArticle

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