Exploring the Anticancer Potential of Plant, Marine, and Synthetic Glycosides: A Comprehensive Review

Despite advances in pharmaceutical and technological development, cancer continues to be a life-threatening illness globally. In addition to other specialized procedures, radiotherapy, chemotherapy, and surgery are methods used to treat cancer. However, in recent years, natural products have either been used as food supplements or complementary medicine in the management and treatment of cancer. Natural products are the secondary metabolites present in the cells of medicinal plants, microbes, and marine organisms. Glycosides are a naturally occurring class of metabolites with exceptional therapeutic value and clinical efficacy. The structure of all glycosides is similar; it consists of two parts: a hydrophilic glycone unit made up of one or more sugar components, and a lipophilic aglycone unit. Over the past few years, the potential anti-cancer properties of several natural and synthetic glycosides have been investigated. In this review, we compile and analyze 224 naturally occurring glycosides from plant and marine sources, along with more than 40 synthetic glycosides, that exhibit anticancer properties. Reported anticancer activities span a wide potency range and involve multiple mechanisms, including apoptosis, cell-cycle arrest, oxidative stress, mitochondrial dysfunction, inhibition of PI3K/AKT, MAPK, STAT3, Wnt/β-catenin, and Na+/K+-ATPase signaling, as well as suppression of migration and invasion. Several compounds show potency comparable to or exceeding standard chemotherapeutics under matched assay conditions: for example, an epigallocatechin-3-O-gallate derivative inhibited MDA-MB-231 cells at an IC50 of 3.27 ± 0.18 µM versus 5.20 ± 0.89 µM for capecitabine, and a synthetic N-glycosyl heterocycle (compound 479a) outperformed erlotinib against HepG-2 and HCT-116 cells (IC50 = 1.64 ± 0.11 and 5.00 ± 0.51 µM vs. 2.07 ± 0.07 and 5.14 ± 0.33 µM). Other studies reported glycosides with activities comparable to or greater than reference agents such as capecitabine, tamoxifen, and erlotinib. Despite these promising findings, the evidence remains predominantly preclinical, with substantial limitations in normal-cell selectivity, standardized cytotoxicity assessment, pharmacokinetic characterization, and in vivo and clinical validation. Overall, glycosides represent promising anticancer scaffolds, but systematic optimization of potency, selectivity, stability, bioavailability, and safety is required to facilitate their translation into clinically useful therapeutics.