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Identification of new theobromine-based derivatives as potent VEGFR-2 inhibitors: design, semi-synthesis, biological evaluation, and in silico studies.

ABSTRACT: This study aimed to design anticancer theobromine derivatives inhibiting VEGFR-2. The new compounds were tested in vitro to evaluate their effectiveness against MCF-7 and HepG2 cancer cell lines. Among these compounds, 15a showed the highest cytotoxicity against HepG2, with an IC₅₀ value of 0.76 μM, and significant anti-proliferative effects on MCF-7, with an IC₅₀ value of 1.08 μM. Notably, the selectivity index of 15a against the two cancer cells was 98.97 and 69.64, respectively. Moreover, 15a demonstrated potent VEGFR-2 inhibitory activity (IC₅₀ = 0.239 μM). Further investigations revealed that 15a induced apoptosis in HepG2 cells, significantly increasing early-stage and late-stage apoptosis percentages from 3.06% and 0.71% to 29.49% and 9.63%, respectively. It also upregulated caspase-3 and caspase-9 levels by 3.45-fold and 2.37-fold, respectively compared to control HepG2 cells. Additionally, 15a inhibited the migration and wound healing ability of HepG2 cells. Molecular docking confirmed the binding affinities of the semi-synthesized compounds to VEGFR-2, consistent with in vitro results. Several computational analyses (DFT, MD simulations, MM-GBSA, PLIP, and essential dynamics) supported the stability of the 15a-VEGFR-2 complex. Overall, the biological and computational findings suggest that compound 15a could be a promising lead compound for the development of a novel apoptotic anticancer agent.

SUBMITTER: Eissa IH

PROVIDER: S-EPMC10395314 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Identification of new theobromine-based derivatives as potent VEGFR-2 inhibitors: design, semi-synthesis, biological evaluation, and in silico studies.

Eissa Ibrahim H IH Yousef Reda G RG Elkady Hazem H Elkaeed Eslam B EB Alsfouk Aisha A AA Husein Dalal Z DZ Ibrahim Ibrahim M IM Elhendawy Mostafa A MA Godfrey Murrell M Metwaly Ahmed M AM

RSC advances 20230701 33

This study aimed to design anticancer theobromine derivatives inhibiting VEGFR-2. The new compounds were tested in vitro to evaluate their effectiveness against MCF-7 and HepG2 cancer cell lines. Among these compounds, 15a showed the highest cytotoxicity against HepG2, with an IC50 value of 0.76 μM, and significant anti-proliferative effects on MCF-7, with an IC50 value of 1.08 μM. Notably, the selectivity index of 15a against the two cancer cells was 98.97 and 69.64 ...[more]

PMID: 37538515

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Project description:Methylxanthines and their derivatives are of great interest due to their diverse biological activities. In this work, a new series of twenty-eight semisynthetic theobromine and theophylline derived compounds were designed and synthesized by applying a simple and efficient strategy. First, the corresponding methylxanthine was reacted with a dibromoalkane (n = 3, 5-8) and subsequently, the brominated intermediate was reacted with an amine, including pyrrolidine, piperidine, diethylamine, methylpiperazine, 1-(2-aminoethyl)pyrrolidine, 1-(2-aminoethyl)piperidine, 2-(1-methylpyrrolidin-2-yl)ethanamine, 1-benzylpiperidin-4-amine, 1-benzylpiperidin-4-yl-methanamine, and 2-(1-benzylpiperidin-4-yl)ethan-1-amine. The two synthetic steps were carried out in very short times using a microwave reactor. The biological activity of the new compounds was evaluated on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidases (MAO-A, MAO-B) and beta-secretase (BACE-1). The majority of the new derivatives showed potent and selective in vitro AChE inhibition. Compounds 21, 28 and 30 exhibited the strongest effect on both electric eel and human AChE enzyme, with IC50 values on the low nanomolar scale. The kinetic study of compound 28 in hAChE displayed a mixed inhibition mechanism, suggesting a simultaneous interaction with both the CAS and PAS of the enzyme. This experimental binding mode is consistent with the results of docking and molecular dynamics modelling studies, where it was observed that the piperidinium fragment of 16, 21, 28 and 32 was located at the CAS, whereas the xanthine fragment of each inhibitor interacted with Trp286 in the PAS. These results indicate that these novel xanthine analogues act as selective and potent AChE inhibitors that could also prevent the precipitation of the aberrant Aβ peptide. These properties, in conjunction with their in silico good pharmacokinetic profiles, make these molecules promising lead compounds for the development of new effective drugs against several forms of dementia.

Dataset Information

Identification of new theobromine-based derivatives as potent VEGFR-2 inhibitors: design, semi-synthesis, biological evaluation, and in silico studies.

Publications

Identification of new theobromine-based derivatives as potent VEGFR-2 inhibitors: design, semi-synthesis, biological evaluation, and <i>in silico</i> studies.

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