Furan- and Furopyrimidine-Based Derivatives: Synthesis, VEGFR-2 Inhibition, and <i>In Vitro</i> Cytotoxicity
New derivatives <b>4a</b>-<b>d</b>, <b>6</b>, <b>7a</b>-<b>d</b>, <b>8a</b>-<b>c</b>, <b>9</b>, <b>11a</b>, <b>11b</b>, <b>12a</b>-<b>f</b>, <b>13a</b>-<b>c</b>, and <b>14</b> were synthesized and evaluated for their VEGFR-2 inhibition. Compounds <b>4c</b>, <b>7b</b>, and <b>7c</b> showed remarkable enzyme inhibition <b>(</b>IC<sub>50</sub> = 57.1, 42.5, and 52.5 nM, respectively) relative to sorafenib (IC<sub>50</sub> = 41.1 nM) and were assessed for their cytotoxicity versus HepG2, MCF-7, A549, HT-29, and PC3 cancer cell lines in addition to WI-38. Compound <b>7b</b> displayed nearly equipotent cytotoxicity against A549 and HT-29 (IC<sub>50</sub> = 6.66 and 8.51 μM) compared to sorafenib (IC<sub>50</sub> = 6.60 and 8.78 μM). Cell cycle analysis and apoptotic assay of <b>7b</b> in the HT-29 cell line showed cellular growth arrest at the G2/M phase in addition to the induction of apoptosis. Western blot analysis of compound <b>7b</b> revealed the deactivation of VEGFR-2. Moreover, a wound healing assay of <b>7b</b> showed inhibition of wound closure. Additionally, molecular modeling studies of compounds <b>4c</b>, <b>7b</b>, and <b>7c</b> were carried out.
Authors
- Mohamed R. Elnagar (ORCID: https://orcid.org/0000-0003-0434-2369)
- Moustapha Kassem (ORCID: https://orcid.org/0000-0003-1557-0869)
- Ahmed M. El Kerdawy (ORCID: https://orcid.org/0000-0003-4127-9055)
- Ahmed K.B.A.W. Farouk
- Akram Hifny Abd El-Haleem
- Safinaz E‐S. Abbas
Institutions
- Cairo University (EG)
- Misr University for Science and Technology (EG)
- Al-Azhar University (EG)
- Iraqi University (IQ)
- University of Lincoln (GB)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2024-11-25
- DOI
- https://doi.org/10.1021/acsmedchemlett.4c00438
- Citations
- 5
- Primary Topic
- PI3K/AKT/mTOR signaling in cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.17