[Boronic Acid as a Promising Class of Chemical Entity for Development of Clinical Medicine for Targeted Therapy of Cancer].

The first medicine containing the boron element, bortezomib, was approved for clinical use just 18 years ago. The boronic acid substructure in bortezomib serves as an electrophilic functionality with high affinity for hydroxy groups, which are frequently found in catalytic sites of proteolytic enzymes, to create reversible covalent bonds with a slow dissociation rate. Today, boronic acid is considered an important molecule in the medicinal chemistry toolbox, which was promoted by the success of bortezomib and pioneering approaches to use boronic acid in the molecular design of serine protease inhibitors in the 1980s. In this review article, we first provide an overview of the development of bortezomib, and then summarize our achievements to construct boronic acid analogs of tyropeptin A, a naturally occurring proteasome inhibitor, with potent in vivo efficacy. Representative stereoselective synthetic methods of α-aminoboronic acid are also showcased.

[Design Strategy of Biologically Active Compounds Using Various Elements].

Almost all conventional drug discovery research has been based on hydrocarbon-based frameworks and common chemical elements such as nitrogen, oxygen, sulfur, and the halogens. However, triggered by the approval of bortezomib, a boronic acid-containing pharmaceutical agent, the incorporation of functionalities that are not native in biological systems has been intensively investigated. Several other boron-containing pharmaceuticals have also been marketed. Therefore, the inclusion of various elements is one of the most promising strategies for the development of novel and distinctive drug candidates. In this symposium review, the author focused on the 'elements chemistry' approaches for the structural development of biologically active compounds, particularly those involving silicon and phosphorus. The isosteric exchange of Si and C (Si/C-exchange) is one of the most-investigated forms of substituting elements. We revealed the detailed physicochemical impact of Si/C-exchange, and we proposed several applications of silyl functionalities other than the simple Si/C-exchange. Regarding phosphorus, we recently revealed that the P-B substructure can function as the isostere of C-C or Si-C substructures. In addition to these isosteric exchanges, the development of biologically active compounds bearing unique substructures such as carboranes, hydrophobic boron clusters, and ferrocene is introduced. These novel strategies provide several options for structural development, offering great potential for expanding the chemical space of medicinal chemistry.

Tuning isoform selectivity and bortezomib sensitivity with a new class of alkenyl indene PDI inhibitor.

Protein disulfide isomerase (PDI, PDIA1) is an emerging therapeutic target in oncology. PDI inhibitors have demonstrated a unique propensity to selectively induce apoptosis in cancer cells and overcome resistance to existing therapies, although drug candidates have not yet progressed to the stage of clinical development. We recently reported the discovery of lead indene compound E64FC26 as a potent pan-PDI inhibitor that enhances the cytotoxic effects of proteasome inhibitors in panels of Multiple Myeloma (MM) cells and MM mouse models. An extensive medicinal chemistry program has led to the generation of a diverse library of indene-containing molecules with varying degrees of proteasome inhibitor potentiating activity. These compounds were generated by a novel nucleophilic aromatic ring cyclization and dehydration reaction from the precursor ketones. The results provide detailed structure activity relationships (SAR) around this indene pharmacophore and show a high degree of correlation between potency of PDI inhibition and bortezomib (Btz) potentiation in MM cells. Inhibition of PDI leads to ER and oxidative stress characterized by the accumulation of misfolded poly-ubiquitinated proteins and the induction of UPR biomarkers ATF4, CHOP, and Nrf2. This work characterizes the synthesis and SAR of a new chemical class and further validates PDI as a therapeutic target in MM as a single agent and in combination with proteasome inhibitors.

A Sialylated-Bortezomib Prodrug Strategy Based on a Highly Expressed Selectin Target for the Treatment of Leukemia or Solid Tumors.

PURPOSE: This study aimed to explore the potential of sialic acid - related selectin targeting strategy in the treatment of leukemia and some solid tumors. We expected it could "actively" bind tumor cells and kill them, reducing non-specific toxicity to normal cells. METHODS: BOR-SA prodrug was synthesized by reacting an ortho-dihydroxy group in SA with a boronic acid group in BOR. Two kinds of leukemia cells (RAW264.7 and HL60 cells), one solid sarcoma cell model (S180 cells) and their corresponding normal cells (monocytes (MO), neutrophil (NE) and fibroblast (L929)) were selected for the in vitro cell experiments (cytotoxicity, cellular uptake, cell cycle and apoptosis experiments). The S180 tumor-bearing Kunming mice model was established for anti-tumor pharmacodynamic experiments. RESULTS: In vitro cell assay results showed that uptake of BOR-SA by HL60 and S180 cells were increased compared with the control group. BOR-SA induced a lower IC50, higher ratio of apoptosis and cell cycle arrest of tumor cells. In vivo anti-S180 tumor pharmacodynamics experiments showed that mice in the BOR-SA group had higher tumor inhibition rate, higher body weight and lower immune organ toxicity compared with the control group. CONCLUSIONS: sialic acid-mediated selectin targeting strategy may have great potential in the treatment of related tumors.

Boron in drug design: Recent advances in the development of new therapeutic agents.

Advances in the field of boron chemistry have expanded the application of this element in Medicinal Chemistry. Boron-containing compounds represent a new class for medicinal chemists to use in their drug designs. Bortezomib (Velcade®), a dipeptide boronic acid approved by the FDA in 2003 for treatment of multiple myeloma, paved the way for the discovery of new boron-containing compounds. After its approval, two other boron-containing compounds have been approved, tavaborole (Kerydin®) for the treatment of onychomicosis and crisaborole (Eucrisa®) for the treatment of mild to moderate atopic dermatitis. A number of boron-containing compounds have been described and evaluated for a plethora of therapeutic applications. The present review is intended to highlight the recent advances related to boron-containing compounds and their therapeutic applications. Here, we focused only in those most biologically active compounds with proven in vitro and/or in vivo efficacy in the therapeutic area published in the last years.

Bortezomib-loaded solid lipid nanoparticles: preparation, characterization, and intestinal permeability investigation.

Bortezomib (BTZ), a proteasome inhibitor, is clinically used for the treatment of multiple myeloma and mantle cell lymphoma via intravenous or subcutaneous administration. Since BTZ has limited intestinal permeability, in this study, solid lipid nanoparticles (SLNs) were selected as lipid carrier to improve the intestinal permeability of BTZ. The nanoparticles were prepared by hot oil-in-water emulsification method and characterized for physicochemical properties. Moreover, in situ single-pass intestinal perfusion technique was used for intestinal permeability studies. Mean particle size of the BTZ-loaded solid lipid nanoparticles (BTZ-SLNs) was 94.6 ± 0.66 nm with a negative surface charge of -18 ± 11 mV. The entrapment efficiency of the BTZ-SLNs was 68.3 ± 3.7% with a drug loading value of 0.8 ± 0.05%. Cumulative drug release (%) over 48 h, indicated a slow release pattern for nanoparticles. Moreover, the SEM image showed a spherical shape and uniform size distribution for nanoparticles. Also, FTIR analysis indicated that BTZ was successfully loaded in the SLNs. The results of the intestinal perfusion studies revealed an improved effective permeability for BTZ-SLNs with a Peff value of about threefold higher than plain BTZ solution.

Discovery of novel 20S proteasome inhibitors by rational topology-based scaffold hopping of bortezomib.

A series of structurally novel proteasome inhibitors 1-12 have been developed based rational topology-based scaffold hopping of bortezomib. Among these novel proteasome inhibitors, compound 10 represents an important advance due to the comparable proteasome-inhibitory activity (IC50 = 9.7 nM) to bortezomib (IC50 = 8.3 nM), the remarkably higher BEI and SEI values and the effectiveness in metabolic stability. Therefore, compound 10 provides an excellent lead suitable for further optimization.

Bortezomib Enhances the Antitumor Effects of Interferon-ß Gene Transfer on Melanoma Cells.

BACKGROUND: Malignant melanoma is a fast growing form of skin cancer with increasing global incidence. Clinically, canine malignant melanoma and human melanoma share comparable treatment-resistances, metastatic phenotypes and site selectivity. OBJECTIVE: Both interferon-ß (IFNß) and bortezomib (BTZ) display inhibitory activities on melanoma cells. Here, we evaluated the cytotoxic effects of the combination of BTZ and IFNß gene lipofection on cultured melanoma cell lines. METHOD: Cell viability determined by the acid phosphatase method, cell migration mesasured by the wound healing assay, DNA fragmentation and cell cycle by flow cytometry after propidium iodide staining and reactive oxygen species (ROS) production by H2DCF-DA fluorescence. RESULTS: Four canine mucosal (Ak, Br, Bk and Ol) and two human dermal (A375 and SB2) melanoma cell lines were assayed. BTZ sub-pharmacological concentrations (5 nM) enhanced the cytotoxic effects of IFNß transgene expression on melanoma cells monolayers and spheroids. The combination was also more effective than the single treatments when assayed for clonogenic survival and cell migration. The combined treatment produced a significant raise of apoptosis evidenced by DNA fragmentation as compared to either BTZ or IFNß gene lipofection single treatments. Furthermore, BTZ significantly increased the intracellular ROS generation induced by IFNß gene transfer in melanoma cells, an effect that was reversed by the addition of the ROS inhibitor N-acetyl-L-cystein. CONCLUSION: The present work encourages further studies about the potential of the combination of interferon gene transfer with proteasome inhibitors as a new combined therapy for malignant melanoma, both in veterinary and/or human clinical settings.