2. Academic Validation
  3. Discovery of new 1,3-diphenylurea appended aryl pyridine derivatives as apoptosis inducers through c-MET and VEGFR-2 inhibition: design, synthesis, in vivo and in silico studies

Discovery of new 1,3-diphenylurea appended aryl pyridine derivatives as apoptosis inducers through c-MET and VEGFR-2 inhibition: design, synthesis, in vivo and in silico studies

  • RSC Med Chem. 2024 Jun 12;15(7):2553-2569. doi: 10.1039/d4md00280f.
Heba A Elsebaie 1,  Mohamed S Nafie 2 3,  Haytham O Tawfik 1 4,  Amany Belal 5,  Mohammed M Ghoneim 6,  Ahmad J Obaidullah 7,  Salwa Shaaban 8 9,  Abdelmoneim A Ayed 10,  Mohamed El-Naggar 11,  Ahmed B M Mehany 12,  Moataz A Shaldam 4 13
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University Tanta 31527 Egypt [email protected].
  • 2 Department of Chemistry, College of Sciences, University of Sharjah Sharjah 27272 United Arab Emirates.
  • 3 Chemistry Department, Faculty of Science, Suez Canal University Ismailia 41522 Egypt.
  • 4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, AlSalam University in Egypt Kafr Al Zaiyat 6615062 Egypt.
  • 5 Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University P.O. Box 11099 Taif 21944 Saudi Arabia.
  • 6 Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University Ad Diriyah Riyadh 13713 Saudi Arabia.
  • 7 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University P.O. Box 2457 Riyadh 11451 Saudi Arabia.
  • 8 Department of Microbiology & Immunology, Faculty of pharmacySuef University Beni-Suef Egypt.
  • 9 Department of Clinical Laboratory Sciences, Faculty of Applied medical Sciences, King Khalid University Abha Saudi Arabia.
  • 10 Department of Chemistry, Faculty of Science, Cairo University Giza Cairo 12613 Egypt.
  • 11 Chemistry department, Faculty of Sciences, Pure and Applied Chemistry Group, University of Sharjah P. O. Box 27272 Sharjah United Arab Emirates.
  • 12 Zoology Department, Faculty of Science (Boys), Al-Azhar University Cairo 11884 Egypt.
  • 13 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University P.O. Box 33516 Kafrelsheikh Egypt [email protected].
PMID: 39026631 DOI: 10.1039/d4md00280f
Abstract

Interest has been generated in VEGFR-2 and c-MET as potential receptors for the treatment of different malignancies. Using aryl pyridine derivatives with 1,3-diphenylurea attached, a number of promising dual VEGFR-2 and c-MET inhibitors were developed and synthesized. Regarding the molecular target, compounds 2d, 2f, 2j, 2k, and 2n had potent IC50 values of 65, 24, 150, 170, and 18 nM against c-MET, respectively. Additionally, they had potent IC50 values of 310, 35, 290, 320, and 24 nM against VEGFR-2, respectively. Regarding cytotoxicity, compounds 2d, 2f, 2j, 2k and 2n exhibited potent cytotoxicity against MCF-7 with IC50 values in the range 0.76-21.5 μM, and they showed promising cytotoxic activity against PC-3 with IC50 values in the range 1.85-3.42 μM compared to cabozantinib (IC50 = 1.06 μM against MCF-7 and 2.01 μM against PC-3). Regarding cell death, compound 2n caused cell death in MCF-7 cells by 87.34-fold; it induced total Apoptosis by 33.19% (8.04% for late Apoptosis, 25.15% for early Apoptosis), stopping their growth in the G2/M phase, affecting the expression of apoptosis-related genes P53, Bax, caspases 3 and 9 and the anti-apoptotic gene, Bcl-2. In vivo study illustrated the Anticancer activity of compound 2n by reduction of tumor mass and volume, and the tumor inhibition ratio reached 56.1% with an improvement of hematological parameters. Accordingly, compound 2n can be further developed as a selective target-oriented chemotherapeutic against breast Cancer.

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