Abstract
Curcumin, a widely utilized flavor and coloring agent in food, has been shown to demonstrate powerful antioxidant, antitumor promoting and anti-inflammatory properties in vitro and in vivo. In the present work, synthesis of new heterocyclic derivatives based on Curcumin was studied. Compound 3 was synthesized via the reaction of furochromone carbaldehyde (1) with Curcumin (2) using pipredine as catalyst. Also, novel, 4,9-dimethoxy-5H-furo [3, 2-g] chromen-5-one derivatives 4a–d, 6a–d, 7, 8a–d, 9 and 10 were synthesized by the reactions of furochromone carbaldehyde (1) with different reagents (namely: appropriate amine 3a–d, appropriate hydrazine 5a–d, hydroxylamine hydrochloride, urea/thiourea, malononitrile, malononitrile with hydrazine hydrate). The structure of the synthesized products had been confirmed from their spectroscopic data (IR, 1H-NMR, 13C-NMR and mass spectra). In the present investigation, the newly synthesized products were screened using the MTT colorimetric assay for their in vitro inhibition capacity in two human cancer cell lines (hepatocellular carcinoma (HEPG2) and breast cancer (MCF-7) as well as the normal cell line (human normal melanocyte, HFB4) in comparison to the known anticancer drugs: 5-flurouracil and doxorubicin. The anticancer activity results indicated that the synthesized products 4c and 8b showed growth inhibition activity against HEPG2 cell line and synthesized products 4b and 8a showed growth inhibition activity against MCF-7, but with varying intensities in comparison to the known anticancer drugs, 5-flurouracil and doxorubicin. Cyclin dependent kinase 2 (CDK2), a major cell cycle protein, was identified as a potential molecular target of Curcumin. Furthermore, Curcumin induced G1 cell cycle arrest, which is regulated by CDK2 in cancer cells. Therefore, we used molecular modelling to study in silico the possible inhibitory effect of CDK2 by Curcumin derivatives as a possible mechanism of these compounds as anticancer agents. The molecular docking study revealed that compounds 4b, 8a and 8b were the most effective compounds in inhibiting CDk2, and, this result was in agreement with cytotoxicity assay.
Highlights
Heterocyclic compounds are considered an exceptionally important class of compounds which play a key role in health care and prescription drug design [1]
Our results showed that some of the newly synthesized products exhibited a moderate to strong growth inhibition activity on the tested cell lines between 0 and 50 μg/mL concentrations in comparison to the reference anticancer drugs
Curcumin (2), with different amines, hydrazines, urea/thiourea, malononitrile and malononitrile with hydrazine hydrate in a simple one-pot for the synthesis of a series of new 5H-furo[3,2-g]chromene derivatives 4a–d, 6a–d, 8–10
Summary
Heterocyclic compounds are considered an exceptionally important class of compounds which play a key role in health care and prescription drug design [1]. Several heterocyclic chemical substances are available commercially as anti-cancer drugs. Molecules 2018, 23, 1398; doi:10.3390/molecules23061398 www.mdpi.com/journal/molecules Molecules. 23, 1398 x FOR PEER REVIEW 22 of of 18. Curcumin is one of the key components of the curcuminoids group It is the bioactive ingredient of turmeric. Curcumin is considered an outstanding source of new medication development [2]
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