First-in-Class Star-Shaped Triazine Dendrimers Endowed with MMP-9 Inhibition and VEGF Suppression Capacity: Design, Synthesis, and Anticancer Evaluation.

Off-target side effects are major challenges hindering the clinical success of matrix metalloproteinase (MMP) inhibitors. Various targeting strategies revitalized MMP research to eliminate this drawback. Herein, we developed s-triazine-based dendrimeric architecture not only amenable to tumor targeting but also decorated with pharmacophoric entities to endow MMP-9 inhibition for halting cancer progression. The design rationale utilized hydrazide branching chains as well as carboxylic and hydroxamic acid termini as Zn-binding groups to confer substantial MMP inhibitory potential. The carboxylic acids are tetherable to tumor targeting ligands and other cargo payloads as synergistic drugs via biodegradable linkages. The synthesized series were screened for cytotoxicity against normal fibroblasts (Wi-38) and two selected cancers (MDA-MB 231 and Caco-2) via MTT assay. The most active hexacarboxylic acid dendrimer 8a was more potent and safer than Dox against MDA-MB 231 and Caco-2 cells. It intrinsically inhibited MMP-9 with selectivity over MMP-2. Docking simulations demonstrated that the extended carboxylic acid termini of 8a could possibly chelate the active site Zn of MMP-9 and form hydrogen-bonding interactions with the ligand essential backbone Tyr423. In addition, it suppressed the correlated oncogenic mediators VEGF and cyclin D, upregulated p21 expression, induced apoptosis (>75%), and inhibited the tumor cell migration (∼84%) in the treated cancer cells. Thus, up to our knowledge, it is the first triazine-based MMP-9 inhibitor dendrimer endowed with VEGF suppression potential that can be employed as a bioactive carrier.