A Theobromine Derivative with Anticancer Properties Targeting VEGFR‐2: Semisynthesis, in silico and in vitro Studies

Abstract

A computer‐assisted drug design (CADD) approach was utilized to design a new acetamido‐N‐(para‐fluorophenyl)benzamide) derivative of the naturally occurring alkaloid, theobromine, (T‐1‐APFPB), following the pharmacophoric features of VEGFR‐2 inhibitors. The stability and reactivity of T‐1‐AFPB were assessed through density functional theory (DFT) calculations. Molecular docking assessments showed T‐1‐AFPB’s potential to bind with and inhibit VEGFR‐2. The precise binding of T‐1‐AFPB against VEGFR‐2 with optimal energy was further confirmed through several molecular dynamics (MD) simulations, PLIP, MM‐GBSA, and PCA studies. Then, T‐1‐AFPB (4‐(2‐(3,7‐Dimethyl‐2,6‐dioxo‐2,3,6,7‐tetrahydro‐1H‐purin‐1‐yl)acetamido)‐N‐(4‐fluorophenyl)benzamide) was semi‐synthesized and the in vitro assays showed its potential to inhibit VEGFR‐2 with an IC50 value of 69 nM (sorafenib's IC50 was 56 nM) and to inhibit the growth of HepG2 and MCF‐7 cancer cell lines with IC50 values of 2.24±0.02 and 3.26±0.02 μM, respectively. Moreover, T‐1‐AFPB displayed very high selectivity indices against normal Vero cell lines. Furthermore, T‐1‐AFPB induced early (from 0.72 to 19.12) and late (from 0.13 to 6.37) apoptosis in HepG2 cell lines. In conclusion, the combined computational and experimental approaches demonstrated the efficacy and safety of T‐1‐APFPB providing it as a promising lead VEGFR‐2 inhibitor for further development aiming at cancer therapy.

Design and In Silico and In Vitro Evaluations of a Novel Nicotinamide Derivative as a VEGFR-2 Inhibitor

“…Tis protein was specifcally selected for its clear binding mode with sorafenib, as well as its accurate manifestation of the pharmacophoric features. Te binding mode of sorafenib to the VEGFR-2 active site cavity was consistent with previously observed interactions [25,26]. Sorafenib occupied key structural components of the receptor, including the hinge region (forming a hydrogen bond with Cys917) and the DFG-motif region (establishing hydrogen bonds with Glu883 and Asp1044).…”

Novel Thiazolidine‐2,4‐Dione Derivatives as Potential VEGFR‐2 Inhibitors: Synthesis, Biological Testing, and in Silico Studies

“…In recent years, our laboratory has successfully utilized computational chemistry to identify a plethora of potential anti‐cancer agents with demonstrated VEGFR‐2 inhibitory activity. These agents originate from diverse chemical classes and their derivatives, including but not limited to nicotinamides, [20] theobromines, [21–24] thiazolidines, [25–27] naphthalenes, [28] pyridines, [29] quinolines, [30] indoles, [31] quinoxaline, [32,33] phthalazine, [34] and isatins [35] …”

Rationale design and synthesis of new apoptotic thiadiazole derivatives targeting VEGFR-2: computational andin vitrostudies

“…27 These tools have been utilized to identify compounds that show potential for effective anticancer activity in numerous research studies. [28][29][30][31] Our laboratory has employed computational chemistry to present new VEGFR-2 inhibitors, including quinolones, 32 isatins, 33 theobromines, [34][35][36][37][38] benzoxazoles, 39,40 nicotinamides, 41,42 thiazolidines, 43 pyridines, 44 naphthalenes, 45 and indoles. 46 This manuscript introduces novel apoptotic thiadiazole analogues, which were synthesized for the rst time and exhibited promising anticancer properties in silico and in vitro.…”