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Boron in Medicinal Chemistry: From Synthesis to Therapeutic Applications
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Boron in Medicinal Chemistry: From Synthesis to Therapeutic Applications

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (25 February 2025) | Viewed by 10181

Special Issue Editors

Dr. Daniela Imperio

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy
Interests: carbohydrates; boronic acids; benzoxaboroles; boron clusters; BNCT
Prof. Dr. Luigi Panza

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy
Interests: carbohydrates; boronic acids; benzoxaboroles; boron clusters; BNCT

Special Issue Information

Dear colleagues,

In recent years, the interest in boron-based compounds for medical applications has grown significantly, bearing the development of new drugs, e.g., Velcade® (bortezomib), which is used in the treatment of multiple myeloma. This Special Issue is dedicated to all aspects of boron-based compounds with potential pharmaceutical interest, including clusters of boron (carboranes, metallaboranes, metallacarboranes, aminoboranes, etc.), organic and bio-organic boron conjugates (boronic acids and their complexes as well as derivatives, benzoxaboroles), and boron in materials (including polymers and dendrimers), that can have an impact on the medical field, with anticancer, bactericidal, antifungal, and anti-HIV activity, anti-rheumatoid arthritis activity, applications of boron in drug delivery and imaging for diagnosis, or compounds focused on boron neutron capture therapy.

It is a pleasure to invite you to submit a manuscript to this Special Issue; regular articles, communications, and reviews are all welcome.

Dr. Daniela Imperio
Prof. Dr. Luigi Panza
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • boronic acids
  • benzoxaboroles
  • boron clusters
  • carboranes
  • boron neutron capture therapy
  • boron-based drugs
  • drug design
  • boron delivery agents
  • medical applications
 
 
 
 
 
 

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Published Papers (6 papers)

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Research

17 pages, 3398 KiB  
Article
Enhancing Boron Neutron Capture Therapy (BNCT) with Materials Based on COSAN-Functionalized Nanoparticles
by Albert Ferrer-Ugalde, Amanda Muñoz-Juan, Anna Laromaine, Paula Curotto, Susana Nievas, María Alejandra Dagrosa, Marcos Couto and Rosario Núñez
Pharmaceuticals 2025, 18(4), 466; https://doi.org/10.3390/ph18040466 - 26 Mar 2025
Viewed by 617
Abstract
Background/Objectives: Boron neutron capture therapy (BNCT) is a promising approach for selectively targeting and destroying malignant cells using 10B isotopes. A significant challenge in BNCT lies in the development of efficient boron delivery systems that ensure adequate boron accumulation within tumor [...] Read more.
Background/Objectives: Boron neutron capture therapy (BNCT) is a promising approach for selectively targeting and destroying malignant cells using 10B isotopes. A significant challenge in BNCT lies in the development of efficient boron delivery systems that ensure adequate boron accumulation within tumor cells. This study aims to synthesize, characterize, and evaluate COSAN-functionalized nanoparticles (NP@I-COSAN) as a potential boron carrier for BNCT. Methods: Hybrid nanoparticles were synthesized by conjugating monoiodinated cobaltabisdicarbollides (I-COSAN) to commercially available acrylic polymer-based nanoparticles. Functionalization and cellular uptake were confirmed through FTIR, TGA, UV-Vis spectroscopy, and TEM/EDX analyses. Biocompatibility was evaluated by assessing cytotoxicity in HeLa cells and C. elegans as an in vivo model. Intracellular boron uptake was quantified using ICP-MS, with results compared to those obtained with 4-borono-L-phenylalanine conjugated to fructose (f-BPA). An in vitro BNCT proof-of-concept assay was also performed to evaluate therapeutic efficacy. Results: NP@I-COSAN demonstrated low cytotoxicity and efficient internalization in cells. ICP-MS analysis revealed stable boron retention, comparable to traditional boron agents. The BNCT assay further showed that NP@I-COSAN was effective in inducing tumor cell apoptosis, even at lower boron concentrations than conventional treatments. Conclusions: These results underscore the potential of NP@I-COSAN as an effective boron delivery system for BNCT, offering a promising strategy to enhance boron accumulation within tumor cells and improve treatment efficacy. Full article
(This article belongs to the Special Issue Boron in Medicinal Chemistry: From Synthesis to Therapeutic Applications)
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16 pages, 2593 KiB  
Article
Boronic Acid-Containing 3H- pyrazolo[4,3-f]quinoline Compounds as Dual CLK/ROCK Inhibitors with Anticancer Properties
by Neetu Dayal, Riddhi Chaudhuri, Kofi Simpa Yeboah, Nickolas R. Brauer and Herman O. Sintim
Pharmaceuticals 2024, 17(12), 1660; https://doi.org/10.3390/ph17121660 - 10 Dec 2024
Viewed by 1254
Abstract
Background: The protein kinases CLK and ROCK play key roles in cell growth and migration, respectively, and are potential anticancer targets. ROCK inhibitors have been approved by the FDA for various diseases and CLK inhibitors are currently being trialed in the clinic as [...] Read more.
Background: The protein kinases CLK and ROCK play key roles in cell growth and migration, respectively, and are potential anticancer targets. ROCK inhibitors have been approved by the FDA for various diseases and CLK inhibitors are currently being trialed in the clinic as anticancer agents. Compounds with polypharmacology are desired, especially in oncology, due to the potential for high efficacy as well as addressing resistance issues. In this report, we have identified and characterized novel, boron-containing dual CLK/ROCK inhibitors with promising anticancer properties. Methods: A library of boronic acid-based CLK/ROCKi was synthesized via Povarov/Doebner-type multicomponent reactions. Kinase inhibition screening and cancer cell viability assays were performed to identify the hit compounds. To gain insights into the probable binding modes of the compounds to the kinases, docking studies were performed. Cell cycle analysis, qPCR and immunoblotting were carried out to further characterize the mode(s) of action of the lead candidates. Results: At 25 nM, the top compounds HSD1400 and HSD1791 inhibited CLK1 and 2 and ROCK2 at greater than 70%. While HSD1400 also inhibited CLK4, the C1 methylated analog HSD1791 did not inhibit CLK4. Antitumor effects of the top compounds were evaluated and dose–response analysis indicated potent inhibition of renal cancer and leukemia cell growth. Immunoblotting results indicated that the top compounds induce DNA damage via upregulation of p-H2AX. Moreover, flow cytometry results demonstrated that the top compounds promote cell cycle arrest in the renal cancer cell line, Caki-1. qPCR and immunoblotting analysis upon HSD1791 dosing indicated suppression of cyclin D/Rb oncogenic pathway upon compound treatment. Conclusions: Novel boronic acid-containing pyrazolo[4,3-f]quinoline-based dual CLK/ROCK inhibitors were identified. The so-called “magic methylation” design approach was used to tune CLK selectivity. Additionally, the findings demonstrate potent in vitro anticancer activity of the lead candidates against renal cancer and leukemia. This adds to the growing list of boron-containing compounds that display biological activities. Full article
(This article belongs to the Special Issue Boron in Medicinal Chemistry: From Synthesis to Therapeutic Applications)
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12 pages, 577 KiB  
Article
Cobaltabis(Dicarbollide) [o-COSAN]− for Boron Neutron Capture Therapy of Head and Neck Cancer: Biodistribution and Irradiation Studies in an Experimental Oral Cancer Model
by Mónica A. Palmieri, Andrea Monti Hughes, Verónica A. Trivillin, Marcela A. Garabalino, Paula S. Ramos, Silvia I. Thorp, Paula Curotto, Emiliano C. C. Pozzi, Miquel Nuez Martínez, Francesc Teixidor, Clara Viñas and Amanda E. Schwint
Pharmaceuticals 2024, 17(10), 1367; https://doi.org/10.3390/ph17101367 - 14 Oct 2024
Cited by 3 | Viewed by 1276
Abstract
Background: Boron neutron capture therapy (BNCT) is a tumor-selective particle radiotherapy that combines preferential boron accumulation in tumors and neutron irradiation. Based on previous studies in tumor-bearing mice, this study evaluated the biodistribution of the sodium salt of cobaltabis(dicarbollide) (Na[3,3′-Co(C2B9 [...] Read more.
Background: Boron neutron capture therapy (BNCT) is a tumor-selective particle radiotherapy that combines preferential boron accumulation in tumors and neutron irradiation. Based on previous studies in tumor-bearing mice, this study evaluated the biodistribution of the sodium salt of cobaltabis(dicarbollide) (Na[3,3′-Co(C2B9H11)2], abbreviated as Na[o-COSAN]) in the hamster cheek pouch oral cancer model and the Na[o-COSAN]/BNCT therapeutic effect on tumors and induced radiotoxicity. The synthesis and comprehensive characterization of 10B-enriched trimethylammonium salt of nido-[7,8-C210B9H12]−o-carborane, along with the cesium and sodium salts of [o-10COSAN] cobaltabis(dicarbollide) are reported here for the first time. Methods: Hamsters bearing tumors were injected with Na[o-COSAN] (7.5 mg B/kg) and euthanized at different time-points after injection (30 min, 2, 3, 5, and 18 h post-administration) to evaluate boron uptake in different tissues/organs. Based on these results, tumor-bearing animals were treated with Na[10B-o-COSAN]/BNCT (7.5 mg B/kg b.w., 3 h), prescribing 5 Gy total in absorbed dose to the precancerous tissue surrounding tumors, i.e., the dose-limiting tissue. Results: Na[o-10COSAN] exhibited no toxicity. Although biodistribution studies employing Na[o-COSAN] have shown low absolute boron concentration in the tumor (approx. 11 ppm), Na[o-10COSAN]/BNCT induced a high and significant therapeutic effect on tumors versus the control group (cancerized, untreated animals). Moreover, only half of the animals exhibited severe mucositis in the precancerous dose-limiting tissue after BNCT, which resolved completely at 21 days after irradiation. Conclusions: Na[o-10COSAN] would be potentially useful to treat head and neck cancer with BNCT. Full article
(This article belongs to the Special Issue Boron in Medicinal Chemistry: From Synthesis to Therapeutic Applications)
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15 pages, 3671 KiB  
Article
One-Step Synthesis, Crystallography, and Acute Toxicity of Two Boron–Carbohydrate Adducts That Induce Sedation in Mice
by Ricardo Ivan Cordova-Chávez, José G. Trujillo-Ferrara, Itzia I. Padilla-Martínez, Héctor González-Espinosa, Antonio Abad-García, Eunice D. Farfán-García, Clara Ortega-Camarillo, Alejandra Contreras-Ramos and Marvin A. Soriano-Ursúa
Pharmaceuticals 2024, 17(6), 781; https://doi.org/10.3390/ph17060781 - 14 Jun 2024
Viewed by 2125
Abstract
Boronic acids form diester bonds with cis-hydroxyl groups in carbohydrates. The formation of these adducts could impair the physical and chemical properties of precursors, even their biological activity. Two carbohydrate derivatives from d-fructose and d-arabinose and phenylboronic acid were synthesized in [...] Read more.
Boronic acids form diester bonds with cis-hydroxyl groups in carbohydrates. The formation of these adducts could impair the physical and chemical properties of precursors, even their biological activity. Two carbohydrate derivatives from d-fructose and d-arabinose and phenylboronic acid were synthesized in a straightforward one-step procedure and chemically characterized via spectroscopy and X-ray diffraction crystallography. Additionally, an acute toxicity test was performed to determine their lethal dose 50 (LD50) values by using Lorke’s method. Analytical chemistry assays confirmed the formation of adducts by the generation of diester bonds with the β-d-pyranose of carbohydrates, including signals corresponding to the formation of new bonds, such as the stretching of B–O bonds. NMR spectra yielded information about the stereoselectivity in the synthesis reaction: Just one signal was found in the range for the anomeric carbon in the 13C NMR spectra of both adducts. The acute toxicity tests showed that the LD50 value for both compounds was 1265 mg/kg, while the effective dose 50 (ED50) for sedation was 531 mg/kg. However, differences were found in the onset and lapse of sedation. For example, the arabinose derivative induced sedation for more than 48 h at 600 mg/kg, while the fructose derivative induced sedation for less than 6 h at the same dose without the death of the mice. Thus, we report for the first time two boron-containing carbohydrate derivatives inducing sedation after intraperitoneal administration. They are bioactive and highly safe agents. Further biological evaluation is desirable to explore their medical applications. Full article
(This article belongs to the Special Issue Boron in Medicinal Chemistry: From Synthesis to Therapeutic Applications)
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Figure 1

13 pages, 5228 KiB  
Article
PK Modeling of L-4-Boronophenylalanine and Development of Bayesian Predictive Platform for L-4-Boronophenylalanine PKs for Boron Neutron Capture Therapy
by Woohyoung Kim, Ji Yeong Won, Jungyu Yi, Seung Chan Choi, Sang Min Lee, Kyungran Mun and Hyeong-Seok Lim
Pharmaceuticals 2024, 17(3), 301; https://doi.org/10.3390/ph17030301 - 26 Feb 2024
Cited by 1 | Viewed by 1508
Abstract
L-4-[(10B)]Boronophenylalanine (BPA) is an amino acid analogue with a boron-10 moiety. It is most widely used as a boron carrier in boron neutron capture therapy. In this study, a Bayesian predictive platform of blood boron concentration based on a BPA pharmacokinetic [...] Read more.
L-4-[(10B)]Boronophenylalanine (BPA) is an amino acid analogue with a boron-10 moiety. It is most widely used as a boron carrier in boron neutron capture therapy. In this study, a Bayesian predictive platform of blood boron concentration based on a BPA pharmacokinetic (PK) model was developed. This platform is user-friendly and can predict the individual boron PK and optimal time window for boron neutron capture therapy in a simple way. The present study aimed to establish a PK model of L-4-boronophenylalanine and develop a Bayesian predictive platform for blood boron PKs for user-friendly estimation of boron concentration during neutron irradiation of neutron capture therapy. Whole blood boron concentrations from seven previous reports were graphically extracted and analyzed using the nonlinear mixed-effects modeling (NONMEM) approach. Model robustness was assessed using nonparametric bootstrap and visual predictive check approaches. The visual predictive check indicated that the final PK model is able to adequately predict observed concentrations. The Shiny package was used to input real-time blood boron concentration data, and during the following irradiation session blood boron was estimated with an acceptably short calculation time for the determination of irradiation time. Finally, a user-friendly Bayesian estimation platform for BPA PKs was developed to optimize individualized therapy for patients undergoing BNCT. Full article
(This article belongs to the Special Issue Boron in Medicinal Chemistry: From Synthesis to Therapeutic Applications)
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12 pages, 1162 KiB  
Article
Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin
by Svetlana Paskas, Philipp Stockmann, Sanja Mijatović, Lydia Kuhnert, Walther Honscha, Evamarie Hey-Hawkins and Danijela Maksimović-Ivanić
Pharmaceuticals 2023, 16(11), 1582; https://doi.org/10.3390/ph16111582 - 9 Nov 2023
Viewed by 1848
Abstract
The ABCG2 transporter protein, as part of several known mechanisms involved in multidrug resistance, has the ability to transport a broad spectrum of substrates out of the cell and is, therefore, considered as a potential target to improve cancer therapies or as an [...] Read more.
The ABCG2 transporter protein, as part of several known mechanisms involved in multidrug resistance, has the ability to transport a broad spectrum of substrates out of the cell and is, therefore, considered as a potential target to improve cancer therapies or as an approach to combat drug resistance in cancer. We have previously reported carborane-functionalized quinazoline derivatives as potent inhibitors of human ABCG2 which effectively reversed breast cancer resistance protein (BCRP)-mediated mitoxantrone resistance. In this work, we present the evaluation of our most promising carboranyl BCRP inhibitors regarding their toxicity towards ABCG2-expressing cancer cell lines (MCF-7, doxorubicin-resistant MCF-7 or MCF-7 Doxo, HT29, and SW480) and, consequently, with the co-administration of an inhibitor and therapeutic agent, their ability to increase the efficacy of therapeutics with the successful inhibition of ABCG2. The results obtained revealed synergistic effects of several inhibitors in combination with doxorubicin or cisplatin. Compounds DMQCa, DMQCc, and DMQCd showed a decrease in IC50 value in ABCB1- and ABCG2-expressing SW480 cells, suggesting a possible targeting of both transporters. In an HT29 cell line, with the highest expression of ABCG2 among the tested cell lines, using co-treatment of doxorubicin and DMQCd, the effective inhibitory concentration of the antineoplastic agent could be reduced by half. Interestingly, co-treatment of compound QCe with cisplatin, which is not an ABCG2 substrate, showed synergistic effects in MCF-7 Doxo and HT29 cells (IC50 values halved or reduced by 20%, respectively). However, a literature-known upregulation of cisplatin-effluxing ABC transporters and their effective inhibition by the carborane derivatives emerges as a possible reason. Full article
(This article belongs to the Special Issue Boron in Medicinal Chemistry: From Synthesis to Therapeutic Applications)
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