Enhancing the Anticancer Potential of Targeting Tumor-Associated Metalloenzymes via VEGFR Inhibition by New Triazolo[4,3-a]pyrimidinone Acyclo C-Nucleosides Multitarget Agents

Abstract

The role of metalloenzymes in tumor progression had broadened their application in cancer therapy. Of these, MMPs and CAs are validated druggable targets that share some pivotal signaling pathways. The majority of MMPs or CAs inhibitors are designed as single-target agents. Despite their transient efficacy, these agents are often susceptible to resistance. This set the stage to introduce dual inhibitors of correlated MMPs and CAs. The next step is expected to target the common vital signaling nodes as well. In this regard, VEGFR-2 is central to various tumorigenesis events involving both families, especially MMP-2 and CA II. Herein, we report simultaneous inhibition of MMP-2, CA II, and VEGFR-2 via rationally designed hybrid 1,2,4-triazolo[4,3-a]pyrimidinone acyclo C-nucleosides. The promising derivatives were nanomolar inhibitors of VEGFR-2 (8; IC50 = 5.89 nM, 9; IC50 = 10.52 nM) and MMP-2 (8; IC50 = 17.44 nM, 9; IC50 = 30.93 nM) and submicromolar inhibitors of CA II (8; IC50 = 0.21 µM, 9; IC50 = 0.36 µM). Docking studies predicted their binding modes into the enzyme active sites and the structural determinants of activity regarding substitution and regioselectivity. MTT assay demonstrated that both compounds were 12 folds safer than doxorubicin with superior anticancer activities against three human cancers recording single-digit nanomolar IC50, thus echoing their enzymatic activities. Up to our knowledge, this study introduces the first in class triazolopyrimidinone acyclo C-nucleosides VEGFR-2/MMP-2/CA II inhibitors that deserve further investigation.

Revealing the contributions of DFT to the spectral interpretation for an amino benzoyl thiourea derivative: Insights into experimental studies from theoretical perspectives, and biological evaluation

“…The docking protocol was conducted as reported. 87–89 Sorafenib was docked into the active sites of VEGFR-2, where the ligand interactions were recreated with an acceptable binding energy (Δ G = −10.35 kcal mol −1 ) and RMSD values (1.39). As illustrated in Fig.…”

Discovery of novel benzimidazole acyclic C‐nucleoside DNA intercalators halting breast cancer growth

“…[ 7 ] Continuous progress has resulted in a variety of small compounds targeting DNA, [ 8–11 ] mirrored by molecular investigations explaining the cellular response to induced DNA damage. Along these lines, the “sugar approach” design of various anticancer agents [ 12–16 ] sparked our interest, where carbohydrate appendages were tethered to pharmacophoric motifs as exemplified by the widespread active carbohydrate‐based scaffolds acting as potent carbonic anhydrases inhibitors [ 13 ] as well as carbohydrate‐based matrix as metalloproteinases inhibitors. [ 14 ] Nevertheless, many carbohydrate‐containing compounds showing broad‐spectrum anticancer activities have been reported.…”

A Novel Triazolopyrimidinone Derivative: A Portable Electrochemical Approach to Investigate DNA Interactions

“…They may interfere with cellular processes and pathways that are crucial for cancer cell survival and proliferation. Triazolopyrimidinones have also exhibited antiviral activity against certain viruses [5]. They may inhibit viral replication and entry into host cells, making them potential candidates for antiviral drug development.…”