Effects of 1 H-1,2,3-Triazole Derivatives of 3- O-Acetyl-11-Keto-Beta-Boswellic Acid from Boswellia sacra Resin on T-Cell Proliferation and Activation
Abstract
Background
The natural triterpene 3-O-acetyl-11-keto-β-boswellic acid, widely recognized as β-AKBA, stands out as a principal active constituent derived from the resin of *Boswellia sacra* (BSR). This compound has garnered considerable scientific interest due to its documented array of biological properties, particularly its significant immunomodulatory effects, which have been explored in various preclinical studies. Building upon the established pharmacological profile of β-AKBA, a series of novel chemical entities, specifically 1H-1,2,3-triazole derivatives designated as 6a through 6d, were successfully synthesized through strategic modifications of the parent β-AKBA molecule. The incorporation of the 1H-1,2,3-triazole moiety is a deliberate choice in medicinal chemistry, given that compounds featuring this structural element are extensively recognized for their broad spectrum of biological and pharmacological activities, as consistently demonstrated across numerous *in vitro* and *in vivo* investigations. Given this premise, the central objective of the current investigation was to thoroughly examine and characterize the precise effects of these newly synthesized 1H-1,2,3-triazole derivatives of β-AKBA on fundamental processes of human T-cell biology, namely their proliferation and activation state. This inquiry is crucial for identifying novel compounds with potential therapeutic utility in immune-related disorders.
Methods
To achieve the stated objectives, human peripheral blood mononuclear cells (PBMCs) were carefully isolated from healthy donors, providing a relevant and reliable primary cell model for immunological studies. These isolated PBMCs were then subjected to a robust activation stimulus designed to mimic physiological T-cell receptor engagement and co-stimulation, employing anti-CD3/CD28 monoclonal antibodies. This standardized activation protocol ensures a consistent and measurable T-cell response. Throughout the activation period, the cells were concurrently exposed to either the parent compound β-AKBA (designated as 1), one of the newly synthesized 1H-1,2,3-triazole derivatives of β-AKBA (6a-6d), or a vehicle control of dimethyl sulfoxide (DMSO). The DMSO control served as a crucial baseline for comparison, allowing for the accurate attribution of observed effects to the test compounds. Following treatment, comprehensive analyses were conducted to evaluate T-cell proliferation and to quantify the expression levels of the CD25 activation marker on both CD4+ and CD8+ T lymphocyte subsets, alongside assessments of overall T-cell viability.
Results
Our experimental findings revealed a consistent and noteworthy immunoinhibitory profile among most of the tested compounds. Specifically, we observed that similar to the parent compound β-AKBA (1), the derivatives 6a, 6b, and 6d each exerted a significant suppressive effect on T-cell expansion and proliferation. Complementing this observation, these same derivatives also led to a marked reduction in the surface expression of CD25, a critical early activation marker, on both the CD4+ and CD8+ T-cell populations, indicating their capacity to modulate T-cell activation pathways. Importantly, these beneficial immunoinhibitory effects were achieved without compromising T-cell viability, as no significant cytotoxic effects were detected at the tested concentration of 25 µM, suggesting a favorable therapeutic window for these specific analogues. In contrast, while compound 6c also demonstrated a profound inhibitory effect on both T-cell expansion/proliferation and CD25 expression, its profile was notably distinct. At the equivalent concentration of 25 µM, compound 6c regrettably exhibited a significant cytotoxic effect on cell viability, indicating a different mode of action or a narrower margin of safety compared to its structural analogues.
Conclusions
The collective findings from this study unequivocally demonstrate the potent immunoinhibitory effects intrinsic to both β-AKBA (1) and its corresponding novel 1H-1,2,3-triazole derivatives. These compounds exert a clear and measurable suppressive influence on key aspects of T-cell biology, specifically inhibiting their proliferation and dampening their activation. The differential cytotoxicity observed among the derivatives, particularly highlighting the non-cytotoxic nature of 6a, 6b, and 6d at effective concentrations, underscores their promising therapeutic potential. These insights suggest that these compounds, especially those exhibiting a favorable safety profile, could represent valuable candidates for the development of innovative pharmacological agents aimed at managing T-cell-mediated diseases. This includes a range of conditions where aberrant or overactive T-cell responses contribute to pathology, such as autoimmune disorders or inflammatory conditions, thereby opening new avenues for therapeutic intervention.
Keywords: 1H-1,2,3-triazole; CD25; T cells; boswellic acid; β-AKBA.