As carbon (C), hydrogen (H), nitrogen (N), oxygen (O), sulfur (S), and phosphorus (P) are fundamental to human physiology, they naturally serve as the primary chemical foundation for the vast majority of therapeutic drugs [1]. However, exploring chemical diversity beyond this traditional group unlocks entirely new methods for drug design. Medicinal chemistry of boron stands out as a highly promising and rapidly growing field. Despite the fact that boron is not one of the elements typical of living systems, its unique ability to form specific coordination bonds and simulate key transition states in biochemical reactions allows to create drugs with new principles of action [2, 3]. Boron’s application in drug design is relatively new, and the biological behaviors of these molecules have mostly been identified in the last two decades [4]. For many years, boron-based compounds were disregarded in medicinal chemistry. This was largely due to their perceived toxicity, which originated from their application in ant control.

The previous fears have been dismissed, and boron compounds are now largely viewed as safe [5]. This is supported by the proven clinical track record and approval of boron-containing medications, as well as ongoing preclinical and clinical evaluations of new formulations [6]. This paper analyzes FDA-approved boron therapeutics, with a primary focus on their mechanisms of action. Significant focus is placed on evaluating the viability of amine-borane adducts, a subset of boron-based compounds, for the discovery and development of novel therapeutic agents in medicinal chemistry.

BORON-CONTAINING PREPARATIONS APPROVED FOR CLINICAL USE

In medicinal chemistry, organoboron compounds (fig. 1) such as boric acid derivatives are highly effective. Boronic acids (RB(OH)2) and boronate esters (RB(OR´)2 are the most prominent and successfully utilized examples [7].

To date, five approved therapeutic agents that contain boron and refer to boronic acid derivatives have been successfully integrated into clinical practice (fig. 2).

Approved by the FDA in 2005 [8] and Health Ministry of Canada in 2008 to treat multiple myeloma [9], bortezomib (Velcade®) made history as the first and most widely recognized medication containing boron. It serves as a temporary, bond-forming blocker of the 26S proteasome [10]. Functioning as a critical regulator of cellular homeostasis, this extensive protein assembly breaks down polyubiquitinated proteins [11]. Bortezomib specifically targets the catalytical β5-subunit of the proteasome (fig. 3), thereby suppressing its chymotrypsin-like function [10].

This action stops regulatory proteins from breaking down, which causes protein homeostasis disruption, triggers cell-death proteins, and shuts down the NF-kB pathway, ultimately killing the cancer cell [10]. Despite high effectiveness, especially when combined with other chemotherapeutic agents, bortezomib produces several adverse effects, with dose-dependent peripheral neuropathy being its most prominent and critical complication [12].

Ixazomib (Ninlaro®) was subsequently approved as the first oral, more selective second-generation proteasome inhibitor following the introduction of bortezomib [13]. The primary way it works mirrors bortezomib: it covalently but reversibly blocks the chymotrypsin-like activity of the β5-subunit inside the 26S proteasome [14]. Ixazomib (Ninlaro®) offers better pharmacokinetics than bortezomib primarily due to its shorter elimination period from the active center (about 18 min vs 110 min for bortezomib), which, along with the peroral way of administration results in a better profile of tolerability and decreased risk of dose-limiting toxicities like peripheral neuropathy [15].

Tavaborole (Keridin®), approved in 2014, is used to treat onychomycosis (fungal nail disease) [16]. Unlike cytotoxic proteasome inhibitors, tavaborole works through a completely different mechanism that targets a specific fungal metabolic pathway. It targets cytoplasmic leucyl-tRNA synthetase, an essential translation enzyme that attaches leucine to transport RNA [17]. By forming a stable tetrahedral adduct, tavaborole’s boron atom tightly locks into the editing site of the enzyme, blocking its normal catalytic function (fig. 4). Consequently, the 3’-end of the properly charged leucyl-tRNA becomes locked into the active site, creating an inactive, three-part enzyme-tRNA-tavaborole complex. By depleting the entire pool of leucyl-tRNA, this action induces an abrupt and total cessation of protein synthesis, ultimately resulting in fungal cell death [18]. The favorable safety profile of tavaborole stems from its exceptional selectivity (three orders of magnitude greater) for the fungal enzyme over human enzymes. This distinction arises from structural variations within their respective editing sites, resulting in an excellent safety profile [16].

Crisaborole (Eucrisa™), an approved boron containing compound, is utilized as a topical treatment for mild to moderate atopic dermatitis [19]. The therapeutic efficacy of this agent is driven by the pronounced inhibition of phosphodiesterase type 4 (PDE-4), a critical enzyme in the modulation of inflammatory pathway. The boron atom in the structure of crisaborole reversibly binds to the active center of PDE-4 [20].

The boron atom adopts a tetrahedral geometry as it interacts with the hydrophobic residues methionine (Met347) and leucine (Leu393) within the enzyme’s catalytic domain. This allows the crisaborole molecule to sterically block the substrate (cAMP) binding site, enabling it to physically halt the enzyme’s hydrolytic function [21]. Blocking the PDE-4 enzyme allows the signaling molecule cAMP to steadily build up inside major immune cells, specifically T-lymphocytes and macrophages. Elevated cAMP levels trigger protein kinase A (PKA), which inhibits pro-inflammatory gene expression. This process ultimately yields a sharp decrease in key atopic dermatitis cytokines, specifically interleukins IL-4 and IL-13, alongside tumor necrosis factor alpha (TNFa) [18, 19].

Vaborbactam is a boron-based β-lactamase inhibitor (βLI) that lacks intrinsic antibacterial properties [22]. The clinical significance of this agent is its capacity to bypass a major resistance pathway in Gram-negative bacteria. Combined with the carbapenem antibiotic meropenem, vaborbactam (Vabomer™) is approved to manage severe bacterial illnesses such as complicated urinary tract infections (cUTI), complex intra-abdominal infections (cIAI), and both hospital-acquired and ventilator-associated pneumonia (HAP/VAP) [23].

Vaborbactam inhibits class A and C beta-lactamase antibiotics that hydrolyze the beta-lactam ring ensuring resistance to penicillins, cephalosporins, and carbapenems. The boron atom is fundamental to the molecule’s cyclic borate ester. It forms a reversible covalent bond with the nucleophilic serine residue in the active center of β-lactamase, simulating the transition state of the hydrolysis reaction. This effectively and competitively blocks the enzyme. Consequently, the beta-lactamase is deactivated, which protects the respective antibiotics (meropenem) from being destroyed and allows it to effectively kill bacteria [18, 23].

STRUCTURE OF AMINE-BORANE ADDUCTS

Boron readily formsa wide diversity of boron hydrides, known as boranes. Over 50 neutral borane compounds have been identified so far. Boranes primarily stand out for their capacity to produce adducts, which are molecules formed through donor-acceptor bonding [24]. A prime illustration is the reaction involving amines, which yields amine-borane adducts characterized by the formula R3N→BX3, with R and X representing either organic substituents or hydrogen atoms [25].

The Boron-Nitrogen bond in these compounds acts as a donor-acceptor (coordination) bond, where pπ-interaction occurs between a nitrogen lone pair and boron’s empty orbital. This interaction leads to pyramidalization of the borane fragment shifting boron’s hybridization from sp2 to sp3 and changing its molecular geometry to tetrahedral. This type of binding is denoted as R3N→BX3 or R3N+ – B–X3. Despite the adduct having no net charge, differing electronegativities create localized partial charges: a positive one on the nitrogen and a negative one on the boron [26]

The strength of the B–N bond in amine-borane adducts (R3N→BX3) is determined by several factors. The fundamental interaction potential is dictated by the acid-base characteristics of the components (BX3 Lewis acid and NR3 Lewis base). However, bond dissociation energies are highly specific to the individual reagent pair and do not consistently correlate with these general properties. Substituents, electron-donating groups — like alkyl chains — on the nitrogen atom heighten its basic characteristics and improve bond integrity. Conversely, incorporating identical substituents at the boron atom reduces its electrophilic character, which destabilizes the resulting adduct. Steric factors have a significant impact. The complex becomes less stable when large functional groups are attached to both the boron and nitrogen atoms. Spatial barriers cause this by disrupting the ideal donor-acceptor alignment, preventing the boron atom from easily shifting from sp2 to sp3 hybridization [26].

AMINE-BORANE ADDUCTS IN MEDICINAL CHEMISTRY

Amine-boranes are a largely overlooked group of molecules in medicinal chemistry. It features borane complexes of aliphatic, aromatic, and heterocyclic amines, along with nucleosides and alpha-amino acids. Furthermore, the boron atom can be substituted with various functional groups, such as cyano, carboxy, or carbomethoxy. Research confirms that amine-boranes are highly effective as analgesics, antiviral, antibacterial, antifungal and antitumor agents [7, 27, 28].

The biological activity of a series of borane adducts with α-amino acids was studied in paper [29] (fig. 5).

In in vivo testing on the Ehrlich ascites carcinoma model, three compounds such as 1-Gly (89 %), 7-Tyr (81 %) and 11-Val (87 %) significantly suppressed tumor growth by over 80 %. 4-Leu (77 %), 5-Ile (74 %), 13-Ile (77 %) and 15-Met (75 %) exhibited high activity. 3-Val, 6-Ser, 9-Gly-Gly and 10-Gly demonstrated moderate activity, while the lowest growth suppression was observed for 8-Met (44 %), 12-Leu (46 %) and 14-Ser (52 %).

Out of the compounds tested in vitro for toxicity against L1210 lymphoid leukemia cells, the top performers were 6-Ser (ED50 = 1.98 μg/ml), 10-Gly (1.40 μg/ml) and 11-Val (3.44 μg/ml). 7-Tyr, 9-Gly-Gly, 12-Leu and 15-Met also showed low Ed50 values. Compounds 3-Val (12.62 mcg/ml) and 13-Ile (14.70 mcg/ml) demonstrated the lowest cytotoxicity. [29]

Compounds 4-Leu (7.0 mg/kg), 5-Ile (7.8 mg/kg) and 12-Leu (8.1 mg/kg) showed the best results in assessing anti-inflammatory activity. At the same time, they remained less active than the standard drug indomethacin (IC50 = 5.4 mg/kg). Compounds 3-Val, 6-Ser, 7-Tyr, 11-Val, 13-Ile, 14-Ser, and 15-Met showed moderate activity (IC50 in the range of 9.8–11.8 mg/kg), while compounds 1-Gly, 2-Ala, and 8-Met, 9-Gly-Gly and 10-Gly (IC50 from 13.2 to 29.0 mg/kg) had the least anti-inflammatory activity [29]. Thus, among the studied compounds, several promising structures can be identified that combine high antitumor, cytotoxic and/or anti-inflammatory activity, which makes them interesting objects for further research.

In addition, the compounds were tested for lipid-lowering activity in mice. Evaluations of lipid-lowering properties in murine models demonstrated that every studied compound produced a hypocholesterolemic effect after a 16-day intraperitoneal dosing period. Compounds 1-Gly, 8-Met, 12-Leu, and 14-Ser showed the strongest cholesterol-lowering effects, reducing levels by over 40 % relative to the control group. Compounds 3-Val, 7-Tyr, 12-Leu, and 14-Ser were found to be the most active in reducing triglyceride levels. According to the data presented, the studied compounds are superior in lipid-lowering activity to the standard drug clofibrate (Atromide-C®).

Borane-nucleoside adducts (fig. 6) exhibited highly significant biological effects during in vivo pharmacological testing at an 8 mg/kg. Compound 17 reduced the development of edema by 50–60 % in mice and rats in Winter’s test. Compounds 18 and 19 showed slightly lower, but also significant activity. In the tail-twitch assay, the test substances prolonged reaction times, demonstrating a centrally mediated pain-relieving property comparable to that of morphine. The maximum effect (130 % of the control) was recorded for compound 18, whereas compound 17 showed 100 %, and compound 19 showed 108 %. [30] In the pleurisy model, a key test for evaluating the ability of compounds to suppress inflammatory exudation (the release of fluid and proteins from blood vessels into tissues), compounds 17–19 showed varying efficacy. Compound 17 demonstrated the most pronounced activity, providing 53.1 % protection (i. e., a reduction in exudate volume by more than half compared with the control group). Compound 18 showed moderate activity with 42.2 % protection. Compound 19 turned out to be the least active in this model, showing only 12.2 % protection. [30]

The cytotoxicity of a number of amine-borane adducts in vitro was studied in [24] and [25] (fig. 7, table).

Adducts 23 and 26 have the widest and most effective profile of cytotoxic activity in vitro among the 19 compounds studied. They demonstrated activity against murine lymphoid leukemia L1210 cell lines, as well as human Tmolt3, Hela-S3, and glioma lines. A detailed analysis of how they work showed they block the creation of DNA, RNA, and proteins. Studies demonstrated that compounds 23 and 26 effectively suppress three enzymes critical for nucleotide synthesis: thymidylate synthetase, carbamoyl phosphate synthetase, and aspartate  aminotransferase. This suggests that their main target is the purine synthesis pathway. Thus, these heterocyclic amine-borane adducts act as antimetabolites capable of being incorporated into DNA as false bases, which causes structural stress and subsequent breaks in the DNA chain, leading to the death of the tumor cell [27, 28].

Evaluating the other compounds in this series reveals key structure-activity relationships. In particular, all adducts can be divided into two groups: those with saturated and unsaturated heterocyclic fragments. It is shown that the saturation of the cycle significantly affects the activity profile. For instance, compounds 32–38 (with an unsaturated heterocycle) exhibit significantly higher activity against the growth of bronchogenic lung carcinoma (HLB) than their saturated counterparts 30–31, while compounds 20–29 are inactive in this screening. Various representatives demonstrate selective activity against specific types of tumors. Thus, adducts 20–23, 36, and 38 are most effective against human osteosarcoma; 27, 28, and 30 are used in screening for lymphocytic leukemia in mice P388; 20 and 36 are used against colon adenocarcinoma SW480.

Activity against other lines, such as human glioma, nasopharyngeal carcinoma KB, and Lewis lung carcinoma, also varies depending on the specific structure of the adduct [27, 28]

CONCLUSION

Amine-borane adducts represent a promising, but still insufficiently studied class of boron-containing compounds with a wide range of biological activity, including antitumor, anti-inflammatory, hypolipidemic and analgesic effects. Because select variants within this structural class demonstrate a capacity to bind to specific biological targets and selectively disrupt vital enzymes, they exhibit significant promise for the formulation of novel therapeutics. However, for the successful translation of these results into clinical practice, the issue of the stability of amine-borane adducts in the body remains fundamentally important [31–33]. The foundational B–N coordination bond varies considerably in strength, as it is primarily governed by the steric and electronic characteristics of the attached substituents. This feature determines not only the activity, but also the stability of the compound under physiological conditions. Despite the known stability of some classes of organoborane compounds (for example, boronic acids) in vivo, the behavior of amine-borane adducts proper, especially under conditions of possible hydrolysis, oxidative stress, or interaction with biological nucleophiles, requires separate and careful study.