An Insight into the Structural Modification and Mechanism of Ursolic Acid at C-3 and C-28: Strategy for Searching...

Ursolic acid (UA), a pentacyclic triterpenoid abundantly found in botanical sources, has emerged as a promising anticancer agent. However, its clinical translation is hindered by poor water solubility and limited bioavailability, necessitating the development of structural optimisation strategies.

A comprehensive literature review was conducted using PubMed, Scopus, ScienceDirect, Google Scholar, and Crossref databases. Search terms included "ursolic acid," "anticancer," "C-3 modification," "C-28 modification," "antitumor," "cell cycle," and "mechanism." Peer-reviewed publications discussing structural modifications and therapeutic applications with experimental validation were included, while articles lacking empirical evidence were excluded.

Structural modifications at C-3 (oxidation, esterification, and hydroxylation) and C-28 (amide/ester formation) significantly enhanced the anticancer activity of UA. C-3-modified derivatives demonstrated 2- to 3-fold increased cytotoxicity against KB, HepG2, MCF7, and LU cell lines. C-28 modifications, particularly piperidine-containing derivatives, exhibited IC₅₀ values of 2.50-11.4 μM against various cancer cell lines. These derivatives induced apoptosis through caspase activation, caused cell cycle arrest (G1, G2/M, and Sub-G1 phases), and modulated key survival pathways, including PI3K/Akt/mTOR, NF-κB, and MAPK/ERK.

Strategic modifications at C-3 and C-28 positions address pharmacokinetic limitations of UA while preserving and enhancing its multi-targeted anticancer properties. These derivatives demonstrate superior cellular membrane permeability, target affinity, and cytotoxic potential across haematological and solid malignancies.

C-3 and C-28 modifications represent viable strategies for developing next-generation UA-based anticancer therapeutics. Future research should focus on comprehensive pharmacokinetic studies, toxicological evaluations, and clinical translation through advanced delivery systems and combination therapy approaches.