2. Academic Validation
  3. Design and synthesis of novel (S)-Naproxen hydrazide-hydrazones as potent VEGFR-2 inhibitors and their evaluation in vitro/in vivo breast cancer models

Design and synthesis of novel (S)-Naproxen hydrazide-hydrazones as potent VEGFR-2 inhibitors and their evaluation in vitro/in vivo breast cancer models

  • Bioorg Med Chem. 2021 May 1:37:116097. doi: 10.1016/j.bmc.2021.116097.
M İhsan Han 1,  Pınar Atalay 2,  Cansu Ümran Tunç 3,  Gökhan Ünal 4,  Serkan Dayan 5,  Ömer Aydın 6,  Ş Güniz Küçükgüzel 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, 38039 Kayseri, Turkey. Electronic address: hanihsan@erciyes.edu.tr.
  • 2 Department of Basic Sciences, Faculty of Pharmacy, Erciyes University, 38039 Kayseri, Turkey; Drug Application and Research Center, Erciyes University, 38039 Kayseri, Turkey.
  • 3 Drug Application and Research Center, Erciyes University, 38039 Kayseri, Turkey; Department of Biomedical Engineering, Faculty of Engineering, Erciyes University, 38039 Kayseri, Turkey; Genom and Stem Cell Center, Erciyes University, 38039 Kayseri, Turkey.
  • 4 Drug Application and Research Center, Erciyes University, 38039 Kayseri, Turkey; Department of Pharmacology, Faculty of Pharmacy, Erciyes University, 38039 Kayseri, Turkey; DEKAM - Experimental Research and Application Center, Erciyes University, 38040 Kayseri, Turkey.
  • 5 Drug Application and Research Center, Erciyes University, 38039 Kayseri, Turkey.
  • 6 Department of Biomedical Engineering, Faculty of Engineering, Erciyes University, 38039 Kayseri, Turkey; Genom and Stem Cell Center, Erciyes University, 38039 Kayseri, Turkey; ERKAM - Clinical Engineering Research and Application Center, Erciyes University, 38040 Kayseri, Turkey; ERNAM - Nanotechnology Research and Application Center, Erciyes University, 38040 Kayseri, Turkey.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, 34854 İstanbul, Turkey.
PMID: 33743356 DOI: 10.1016/j.bmc.2021.116097
Abstract

Naproxen is a common non-steroidal anti-inflammatory drug, which is the most usually used propionic acid derivative for the treatment of many types of diseases. In this study, a series of novel (S)-Naproxen derivatives bearing hydrazide-hydrazone moiety were designed, synthesized, and evaluated for Anticancer activity. The structures of these compounds were characterized by spectral (1H-13C NMR, FT-IR, and HR-MS analyses) methods. All synthesized compounds were screened for Anticancer activity against two different human breast Cancer cell lines (MDA-MB-231 and MCF-7). Among them, (S)-2-(6-methoxynaphthalen-2-yl)-N'-{(E)-[2-(trifluoromethoxy)phenyl]methylidene} propanehydrazide (3a) showed the most potent Anticancer activity against both Cancer cell lines with a good selectivity (IC50 = 22.42 and 59.81 µM, respectively). Furthermore, the molecular modeling of these compounds was studied on Vascular Endothelial Growth Factor Receptor 2. Inhibition of VEGFR-2 and apoptotic protein Bcl-2 was investigated in MDA-MB-231 cells treated with compound 3a by using Western Blotting. Apoptosis was also detected by staining with DAPI in fluorescence microscopy. Flow Cytometry analyses related to cell cycle phases showed that a dramatic increase in S and M phases was established compared to untreated control cells indicating the Cancer cell cycle arrest. The Anticancer activity of compound 3a was investigated in the Ehrlich acid tumor model, a well-validated in vivo ectopic breast Cancer model, in mice. Our results showed that compound 3a had Anticancer activity and decreased the tumor volume in both low (60 mg/kg) and high (120 mg/kg) doses in mice.

Keywords

Anticancer; Breast cancer; Hydrazide-hydrazone; In vivo; Naproxen; VEGFR-2.

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