Novel curcumin inspired antineoplastic 1-sulfonyl-4-piperidones: Design, synthesis and molecular modeling studies

Nehmedo G. Fawzy, Siva S. Panda, Walid Fayad, May A. El-Manawaty, Aladdin M. Srour, Adel S. Girgis

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Background: Curcumin is a well-known example of plant origin exhibiting promising diverse biological properties such as, anti-inflammatory and antitumor as well as poor pharmacokinetic/pharmacodynamic properties. This is why effective agents based on its chemical scaffold were explored. Methods: A set of 3,5-bis(ylidene)-1-(alkylsulfonyl)piperidin-4-ones were synthesized in excellent yield (80- 96%) through dehydrohalogenation reaction of 3,5-bis(ylidene)-4-piperidinones with the corresponding alkane sulfonyl chloride in the presence of triethylamine. Antiproliferative properties of the synthesized compounds (dienone/curcumin inspired analogues) were studied by the standard MTT technique. Results: Most of the synthesized compounds revealed antiproliferative properties against HCT116 (colon) and A431 (skin/squamous) cancer cell lines with IC50 values at sub-micromolar level. Compound 36 also exhibited potency against MCF7 (breast) and A549 (lung) cancer cell lines (IC50 = 2.23, 4.27µM, respectively) higher than that of the reference standards (IC50 = 3.15, 5.93µM for 5-fluorouracil and doxorubicin against MCF7 and A549 cell lines, respectively). Cytotoxic properties of the synthesized compounds against non-cancer RPE1 cell line supported the safety profile of the effective agents against normal cells. Molecular modeling (3Dpharmacophore and 2D-QSAR) studies validated the observed bio-properties and explained the parameters governing activity. Inhibitory properties of compounds 27 and 29 (representative examples of the promising antiproliferative agents synthesized) supported their mode of action against topoisomerase IIa. Conclusion: The synthesized scaffold is a promising antitumor agent (with special selectivity against colon and skin/squamous cancer cell lines) so, it can be considered for further investigation and development of highly effective hits/leads based on the computational models obtained.

Original languageEnglish (US)
Pages (from-to)1069-1078
Number of pages10
JournalAnti-Cancer Agents in Medicinal Chemistry
Volume19
Issue number8
DOIs
StatePublished - Jan 1 2019

Keywords

  • 2D-QSAR
  • 3D-pharmacophore
  • Antitumor
  • Computational models
  • Molecular modeling
  • Piperidone
  • Sulfonyl

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Cancer Research

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