Boswellic acids, a class of pentacyclic triterpenes derived from the resin of Boswellia species, have garnered considerable attention due to their well-established anti-inflammatory, anti-arthritic, anti-asthmatic, and gastroprotective properties [1,2]. Recent pharmacological investigations have focused on exploring the anti-cancer potential of boswellic acids, particularly β-boswellic acid, due to their ability to modulate multiple intracellular targets and signaling pathways involved in carcinogenesis [3]. Despite these promising pharmacodynamic attributes, the clinical translation of boswellic acids has been significantly hampered by their poor water solubility and limited cell permeability, characteristics common to many hydrophobic natural products. These physicochemical limitations hinder effective intracellular delivery, reduce bioavailability, and potentially contribute to off-target effects and dose-limiting toxicities. Addressing these drawbacks is essential for the development of boswellic acid-based therapeutics. One approach to overcome this challenge is the conjugation of boswellic acids with amino acids [4]. Amino acids possess diverse side chains with varying polarity and charge, which can facilitate passive or active transport across cellular membranes, improve aqueous solubility, and enable targeted interactions with intracellular biomolecules. Over the past decade, there has been a growing interest in amino acid conjugation strategies to enhance the pharmacokinetic and pharmacodynamic profiles of natural and synthetic molecules, particularly in the design of prodrugs and advanced drug delivery systems [5,6]. Several studies have highlighted that amino acid or peptide conjugation can enhance selectivity, stability, bioavailability, and cellular uptake of therapeutic compounds, thereby amplifying their therapeutic efficacy [7,8].

In light of these considerations, and as part of our ongoing efforts to derive bioactive leads from natural products, we synthesized a focused library of β-boswellic acid–amino acid conjugates, with the primary aim of enhancing their anti-cancer potential. The initial synthesis involved ester-amide linkages (4), which demonstrated moderate antiproliferative activity but were limited by suboptimal solubility and cellular uptake. To address these limitations, we incorporated a hydrophilic urea linker, resulting in compound 8b (Fig. 1), which improved its aqueous solubility and cytotoxicity as evidenced by IC50 values in colon cancer cell lines HCT-116 and HCT-15, which harbor the KRASG13D mutation—a clinically relevant oncogenic driver known to confer resistance to conventional KRAS-targeted therapies. Mechanistic investigations revealed that compound 8b induced cellular senescence, characterized by a flattened and enlarged cellular morphology, as well as a prominent G1 phase cell cycle arrest. Notably, 8b treatment led to inhibition of CDK6 and its downstream effector TWIST1, both of which are implicated in tumor progression and therapy resistance. The simultaneous suppression of CDK6/TWIST1 by 8b in mutant KRAS cells mirrored the effects of genetic co-depletion, underscoring the synthetic lethal interactions between boswellic acid conjugates and aberrant cell cycle regulatory pathways in KRAS-driven cancers. Importantly, the ability of 8b to selectively target oncogenic signaling and promote senescence highlights its potential utility as a targeted therapeutic agent with reduced toxicity. Furthermore, its favorable pharmacological profile, stemming from amino acid conjugation, underscores the broader applicability of such molecular modifications in optimizing natural product-based drug candidates.

In this study, we report the rational design, synthesis, and biological evaluation of β-boswellic acid-amino acid conjugates, with a focus on their anticancer activity, particularly against KRASG13D mutant colon cancer. Our findings not only demonstrate the therapeutic potential of compound 8b but also support amino acid conjugation as a viable strategy to improve the bioactivity and cell permeability of hydrophobic natural products for oncology applications [[9], [10], [11]].