The Rise of Boron-Containing Compounds: Advancements in Synthesis, Medicinal Chemistry, and Emerging Pharmacology.

Boron-containing compounds (BCC) have emerged as important pharmacophores. To date, five BCC drugs (including boronic acids and boroles) have been approved by the FDA for the treatment of cancer, infections, and atopic dermatitis, while some natural BCC are included in dietary supplements. Boron's Lewis acidity facilitates a mechanism of action via formation of reversible covalent bonds within the active site of target proteins. Boron has also been employed in the development of fluorophores, such as BODIPY for imaging, and in carboranes that are potential neutron capture therapy agents as well as novel agents in diagnostics and therapy. The utility of natural and synthetic BCC has become multifaceted, and the breadth of their applications continues to expand. This review covers the many uses and targets of boron in medicinal chemistry.

Tibolone Improves Memory and Decreases the Content of Amyloid-ß Peptides and Tau Protein in the Hippocampus of a Murine Model of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) affects women more than men and consequently has been associated with menopause. Tibolone (TIB) has been used as a hormone replacement therapy to alleviate climacteric symptoms. Neuroprotective effects of TIB have also been reported in some animal models. OBJECTIVE: This study aimed to assess the effect of TIB on memory and Aß peptides and tau protein content in the hippocampus and cerebellum of transgenic 3xTgAD ovariectomized mice. METHODS: Three-month-old female mice were ovariectomized. Ten days after surgery, animals were divided into four groups: wild-type (WT)+vehicle; WT+TIB (1 mg/kg); 3xTgAD+vehicle; and 3xTgAD+TIB (1 mg/kg). TIB was administered for three months, and memory was evaluated using the object-in-context recognition task. Subsequently, animals were decapitated, and the hippocampus and cerebellum were dissected. Using commercial ELISA kits, these brain structures were homogenized in a PBS buffer for quantifying Aß40 and Aß42 and phosphorylated and total tau.ResultsA long-term memory deficit was observed in the 3xTgAD+vehicle group. In contrast, TIB treatment improved long-term memory in the 3xTgAD+TIB group than those treated with vehicle (p < 0.05). Furthermore, TIB treatment decreased Aß and tau content in the hippocampus of 3xTgAD mice compared to vehicle-treated groups (p < 0.05). No significant changes were observed in the cerebellum. CONCLUSION: Chronic treatment with TIB showed neuroprotective effects and delayed AD neuropathology in the 3xTgAD mice. Our results support hormone replacement therapy with TIB in menopausal women for neuroprotection.

Identification and evaluation of boronic compounds ameliorating cognitive deficit in orchiectomized rats.

BACKGROUND: Boron is a trace element with increasing importance in drug design. In this sense, boronic acids are emerging as therapeutic agents for several diseases. METHODS: Herein, 3- and 4- acetamidophenylboronic acids and 4-acetamidophenylboronic acid pinacol ester were identified as potential inhibitors of acetylcholinesterase through docking assays on eel, rat, and human acetylcholinesterases indicating binding on the gorge region of the target enzymes. Then, these compounds were evaluated in vitro and in vivo. RESULTS: It was found these compounds showed ability to inhibit acetylcholinesterase as competitive and non-competitive inhibitors. But also, these compounds were non-toxic to PC12 cells at micromolar concentration, and they have the ability to protect those cells against damage by amyloid-beta. CONCLUSIONS: Noticeably, intraperitoneal administration of these boronic compounds to rats with the cognitive deficit induced by orchiectomy provided ameliorative effects on disrupted behavior and neuronal damage induced by hormonal deprivation. Additional approaches are required to evaluate the possibility of multiple mechanisms of action for the observed effects in the central nervous system.

Polyphenols as potential enhancers of stem cell therapy against neurodegeneration.

The potential of polyphenols for treating chronic-degenerative diseases (particularly neurodegenerative diseases) is attractive. However, the selection of the best polyphenol for each treatment, the mechanisms by which they act, and their efficacy are frequently discussed. In this review, the basics and the advances in the field, as well as suggestions for using natural and synthetic polyphenols alone or in a combinatorial strategy with stem cell assays, are compiled and discussed. Thus, stem cells exhibit several responses when polyphenols are added to their environment, which could provide us with knowledge for advancing the elucidation of the origin of neurodegeneration. But also, polyphenols are being included in the innovative strategies of novel therapies for treating neurodegenerative diseases as well as metabolic diseases related to neurodegeneration. In this regard, flavonoid compounds are suggested as the best natural polyphenols due to their several mechanisms for acting in ameliorative effects; but increasing reports are involving other polyphenols. Even if some facts limiting bioactivity prevent them from conventional use, some natural polyphenols and derivatives hold the promise for being improved compounds, judged by their induced effects. The current results suggest polyphenols as enhancers of stem cell therapy against the targeted diseases.

Effects of boron-containing compounds on immune responses: review and patenting trends.

INTRODUCTION: Boron-containing compounds induce effects on immune responses. Such effects are interesting to the biomedical field for the development of therapeutic tools to modulate the immune system. AREAS COVERED: The scope of BCC use to modify immune responses is expanding, mainly with regard to inflammatory diseases. The information was organized to demonstrate the breadth of reported effects. BCCs act as modulators of innate and adaptive immunity, with the former including regulation of cluster differentiation and cytokine production. In addition, BCCs exert effects on inflammation induced by infectious and noninfectious agents, and there are also reports regarding their effects on mechanisms involving hypersensitivity and transplants. Finally, the authors discuss the beneficial effects of BCCs on pathologies involving various targets and mechanisms. EXPERT OPINION: Some BCCs are currently used as drugs in humans. The mechanisms by which these BCCs modulate immune responses, as well as the required structure-activity relationship for each observed mechanism of action, should be clarified. The former will allow for the development of improved immunomodulatory drugs with extensive applications in medicine. Patenting trends involve claims concerning the synthesis and actions of identified molecules with a defined profile regarding cytokines, cell differentiation, proliferation, and antibody production.

Turning Fear of Boron Toxicity into Boron-containing Drug Design.

BACKGROUND: Despite the historical employment of boron-containing compounds (BCCs) with medicinal purposes, the reported cases of BCC toxicity in humans during the twentieth-century drived us towards a "boron-withdrawal" period. Fortunately, the use of boric acid for specific purposes remains, and the discovery of natural BCCs with biological action attractive for therapeutic purposes as well as the introduction of some new BCCs for clinical use has reactivated the interest in studying the properties of these BCCs. METHODS: We carried out a structured search of bibliographic databases for scientific peerreviewed research literature regarding boron toxicity and linked that information to that of BCCs in drug design and development. A deductive qualitative content analysis methodology was applied to analyse the interventions and findings of the included studies using a theoretical outline. RESULTS: This review recapitulates the following on a timeline: the boron uses in medicine, the data known about the toxicological profiles of some BCCs, the pharmacological properties of some BCCs that are employed in cancer and infectious disease therapies, and the known properties of BCCs recently introduced into clinical assays as well as the identification of their structure-activity relationships for toxicity and therapeutic use. Then, we discuss the use of new approaches taking advantage of some toxicological data to identify potent and efficient BCCs for prevention and therapy while limiting their toxic effects. CONCLUSION: Data for boron toxicity can be strategically used for boron-containing drug design.

Several effects of boron are induced by uncoupling steroid hormones from their transporters in blood.

Boron is increasingly added to food supplements due to multiple effects that have been reported in mammals after boric acid administration. Among these effects are inflammatory process control, bone and muscle strength enhancement, protein expression regulation, and a decreased risk of developing some pathologies in which these processes are key, such as osteoporosis, dermatological inflammatory non-infectious maladies and diseases affecting the central nervous system. Experimental data have suggested that steroid hormone levels in plasma change after boric acid administration, but a clear mechanism behind these variations has not been established. We analyzed possibilities for these changes and hypothesized that boric acid disrupts the interactions between steroid hormones and several carriers in plasma. In particular, we proposed that there is an uncoupling of the interactions between sex hormone binding globulin (SHBG) and estrogens and testosterone and that there are alterations in the binding of hydrophobic ligands by other carrier proteins in plasma. Further experimental and computational studies are required to support the hypothesis that boric acid and probably other boron-containing compounds can displace steroid hormones from their plasma carriers. If such phenomena are confirmed, boron administration with a clear mechanism could be employed as a therapeutic agent in several diseases or physiological events that require modulation of steroid hormone levels in plasma.

Boron-containing compounds: chemico-biological properties and expanding medicinal potential in prevention, diagnosis and therapy.

INTRODUCTION: Although the medicinal use of boron-containing compounds (BCCs) had long been limited to antiseptics, in the last few decades, these compounds have been used as antibiotics or chemotherapeutic agents. In the last few years, boron has been included in the moieties of many known drugs to improve their capacity in binding to their respective target receptors. AREAS COVERED: The current review focuses on research and patent literature of the last decade related to the development of BCCs as preventive, diagnostic and therapeutic tools. It explores the possible mechanisms of action of these compounds as well as the advantageous features of their structure and chemico-pharmacological properties. EXPERT OPINION: Although uncertainties exist about the mechanism of action of BCCs, increasing evidence about their toxicological profile strongly suggests that many can be safely administered to humans. Even stronger evidence exists regarding the capacity of BCCs to reach multiple targets that are involved in the treatment of common diseases. It seems fair to say that some BCCs will reach the market for medicinal use in the near future, not only for targeting microbial or neoplastic systems but also for acting on cell-signaling processes involved in many other disorders.

Cell-based and in-silico studies on the high intrinsic activity of two boron-containing salbutamol derivatives at the human ß2-adrenoceptor.

Salbutamol is a well-known ß(2) adrenoceptor (ß(2)AR) partial agonist. We synthesized two boron-containing salbutamol derivatives (BCSDs) with greater potency and efficacy, compared to salbutamol, for inducing ß(2)AR-mediated smooth-muscle relaxation in guinea-pig tracheal rings. However, the mechanism involved in this pharmacological effect remains unclear. In order to gain insight, we carried out binding and functional assays for BCSDs in HEK-293T cells transfected with the human ß(2)AR (hß(2)AR). The transfected hß(2)AR showed similar affinity for BCSDs and salbutamol, but adenosine 3',5'-cyclic phosphate (cAMP) accumulation induced by both BCSDs was similar to that elicited by isoproterenol and greater than that induced by salbutamol. The boron-containing precursors (boric and phenylboronic acids, 100 µM) had no significant effect on salbutamol binding or salbutamol-induced cAMP accumulation. These experimental results are in agreement with theoretical docking simulations on lipid bilayer membrane-embedded hß(2)AR structures. These receptors showed slightly higher affinity for BCSDs than for salbutamol. An essential change between putative active and inactive conformational states depended on the interaction of the tested ligands with the fifth, sixth and seventh transmembrane domains. Overall, these data suggest that BCSDs induce and stabilize conformational states of the hß(2)AR that are highly capable of stimulating cAMP production.

Theoretical study of 3-D molecular similarity and ligand binding modes of orthologous human and rat D2 dopamine receptors.

The D(2) dopamine receptor (D(2)DR) is an important target for the treatment of some central nervous system disorders, such as Parkinson disease, schizophrenia and drug-dependence. In this work, we built 3-D models of the long form of human and rat D(2)DRs by considering data from the crystallized D3 dopamine receptor, ß2 adrenoceptor and A2a adenosine receptor as templates. Then, docking was performed with ligand and protein residue flexibility. These results were used to analyze ligand recognition and estimate binding affinity. Our results show that the predicted ligand affinity correlates with experimental data, and binding modes are very similar between the D(2)DRs of these two species.