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.

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.

Lead Optimization of BIBR1591 To Improve Its Telomerase Inhibitory Activity: Design and Synthesis of Novel Four Chemical Series with In Silico, In Vitro, and In Vivo Preclinical Assessments.

Herein, modifications to the previously reported BIBR1591 were conducted to obtain bioisosteric candidates with improved activities. The % inhibition of the newly afforded candidates against the telomerase target was investigated. Notably, 6f achieved superior telomerase inhibition (63.14%) compared to BIBR1532 and BIBR1591 (69.64 and 51.58%, respectively). In addition, 8a and 8b showed comparable promising telomerase inhibition with 58.65 and 55.57%, respectively, which were recorded to be frontier to that of BIBR1591. 6f, 8a, and 8b were tested against five cancer cell lines related to the lung and liver subtypes. Moreover, 6f was examined on both cell cycle progression and apoptosis induction in HuH7 cancer cells. Furthermore, the in vivo antitumor activity of 6f was further assessed in female mice with solid Ehrlich carcinoma. In addition, molecular docking and molecular dynamics simulations were carried out. Collectively, 6f, 8a, and 8b could be considered potential new telomerase inhibitors to be subjected to further investigation and/or optimization.