Evaluation of the interaction between hydroxyapatite and bisphosphonate by nonlinear capillary electrochromatography

Bisphosphonates are a class of chemical compounds used to treat diseases caused by increased bone resorption. Zoledronate is a third‐generation bisphosphonate drug. Hydroxyapatite is main mineral constituent of bones, which can be bound by bisphosphonates in vivo. In this work, we report a method of nonlinear capillary electrochromatography for study on the interaction between hydroxyapatite and bisphosphonate. Hydroxyapatite was modified on the inner wall of capillary by a biomimetic‐mineralization method. Then nonlinear chromatography was used to fit and analyze the interaction between zoledronate and hydroxyapatite. The association rate constants of zoledronate in hydroxyapatite‐modified capillary and bare capillary are 642.3 and 195/M/min, respectively. This indicates that there is strong binding interactions and affinity between zoledronate and hydroxyapatite. Besides, the interaction between zoledronate and hydroxyapatite was confirmed further by ultraviolet spectroscopy. The method of nonlinear capillary electrochromatography provides a fast and effect approach for studying of bone metabolism disease by evaluation of interaction between hydroxyapatite and bisphosphonates.     

Potentiality of vanadium compounds as anti-parasitic agents

Research efforts on the medicinal chemistry of vanadium have been mainly focused whether on improving biodistribution and tolerability of the vanadium insulin-enhancing core or on developing potential anti-tumor compounds. Despite the fact that the World Health Organization statistics show that parasitic diseases are among the most prevalent illnesses worldwide, work on vanadium compounds for the potential treatment of some of these diseases has only recently arisen. This review focuses on recent attempts to develop vanadium-based potential anti-parasitic agents, mainly active against the parasites causing American trypanosomiasis (Chagas disease), leishmaniasis and amoebiasis. In addition, the search for new therapeutic uses of some previously known bioactive vanadium compounds is included.     

Zoledronic acid: pharmacologic profile of a potent bisphosphonate

Bisphosphonates are an important class of osteotropic compounds that are effective in treating benign and malignant skeletal diseases characterized by enhanced osteoclast-mediated bone resorption (i.e., osteoporosis, Paget’s disease, and tumor-induced osteolysis). The evolution of bisphosphonates has led to compounds with ever-increasing potency. First-generation bisphosphonates, including etidronate and clodronate, contained simple side chains and were relatively weak inhibitors of bone resorption. Second-generation compounds, including pamidronate, alendronate, and ibandronate, have an aliphatic R² side chain containing a single nitrogen atom. These nitrogen-containing bisphosphonates (N-BPs) are up to 100-fold more potent than the first-generation compounds. Zoledronic acid, a novel N-BP with an imidazole substituent, has demonstrated more potent inhibition of osteoclast-mediated bone resorption than all other bisphosphonates in both in vitro and in vivo preclinical models. Recent data suggest that N-BPs inhibit farnesyl diphosphate (FPP) synthase, an enzyme in the mevalonate biosynthetic pathway that is critical for protein prenylation and activation of important signaling molecules. Inhibition of FPP synthase also leads to production of triphosphoric acid 1-adenosin-5′yl ester 3-[3-methylbut-3-enyl] ester (ApppI), which induces apoptosis of osteoclasts and tumor cells. Our current knowledge of the pharmacology of N-BPs at the molecular level largely explains their observed effects on bone metabolism and tumor growth in animal models and their clinical activity in the treatment of benign and malignant bone diseases.     

Organoboron Compounds: Effective Antibacterial and Antiparasitic Agents

The unique electron deficiency and coordination property of boron led to a wide range of applications in chemistry, energy research, materials science and the life sciences. The use of boron-containing compounds as pharmaceutical agents has a long history, and recent developments have produced encouraging strides. Boron agents have been used for both radiotherapy and chemotherapy. In radiotherapy, boron neutron capture therapy (BNCT) has been investigated to treat various types of tumors, such as glioblastoma multiforme (GBM) of brain, head and neck tumors, etc. Boron agents playing essential roles in such treatments and other well-established areas have been discussed elsewhere. Organoboron compounds used to treat various diseases besides tumor treatments through BNCT technology have also marked an important milestone. Following the clinical introduction of bortezomib as an anti-cancer agent, benzoxaborole drugs, tavaborole and crisaborole, have been approved for clinical use in the treatments of onychomycosis and atopic dermatitis. Some heterocyclic organoboron compounds represent potentially promising candidates for anti-infective drugs. This review highlights the clinical applications and perspectives of organoboron compounds with the natural boron atoms in disease treatments without neutron irradiation. The main topic focuses on the therapeutic applications of organoboron compounds in the diseases of tuberculosis and antifungal activity, malaria, neglected tropical diseases and cryptosporidiosis and toxoplasmosis.     

The Synthesis and Evaluation of Quaternary Pyridinium Bisphosphonates as Potent Anti-Resorptives

Abstract

Several novel quaternary pyridinium bisphosphonates have been synthesised and their efficacy as potential anti-resorptive bone agents have been tested in Dictyostelium discoideum. This assay has been shown to accurately reflect the potency of a bisphosphonic acid as an anti-resorptive compound. All the quaternary bisphosphonates are very potent growth inhibitors but results indicate that the more potent compounds are those containing hydrophobic, bulky groups.     

The interaction of cationic polymers and their bisphosphonate derivatives with hydroxyapatite

Conjugating proteins with bisphosphonates (BPs), a class of molecules with exceptional affinity to hydroxyapatite (HA), is a feasible means to impart bone affinity to protein-based therapeutic agents. To increase the targeting effectiveness while minimizing protein modification, a polymeric linker containing multiple copies of BPs could be constructed for protein conjugation and targeting to bone. Towards this goal, poly(L-lysine) (PLL) and poly(ethylenimine) (PEI) were utilized as the polymeric backbones to incorporate a BP, namely 2-(3-mercaptopropylsulfanyl)-ethyl-1,1-bisphosphonic acid (thiolBP), by using N-hydroxysuccinimidyl polyethylene glycol maleimide and succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate, respectively. In vitro and in vivo mineral affinity of the polymer-BP conjugates were determined in comparison with the unmodified polymers. The in vitro results indicated strong binding of the cationic polymers to HA in their unmodified form. BP conjugation did not enhance the inherent mineral affinity of the polymers; in contrast, certain modifications negatively affected the polymers' binding to the HA. In vivo results from a subcutaneous implant model in rats also showed no significant difference in mineral affinity of the BP modified and unmodified PEI. We conclude that thiolBP conjugation to the cationic polymers PLL and PEI was not beneficial for increasing the mineral affinity of the polymeric molecules. The strong interaction between the cationic polymers and HA may make the polymers suitable for imparting mineral affinity to bone-acting therapeutics.     

Comparative studies on 99mTc-pyrophosphate and 85Sr-chloride for skeletal imaging

In order to know the potential merits of 99mTc-pyrophosphate (99mTc-PYP) skeletal imaging, a comparative study was carried out by administering to the rabbit 85Sr-chloride (85Sr), classical bone-seeking agent, and 99mTc-PY simultaneously. Radioisotopic distribution was investigated as regards their deposition in the pelvic bones, and sharpness of the skeletal scintigrams, too. Both agents were remarkably affinitive to the skeletal system and there were remarkably differences in their temporal deposition pattern. Marked deposition was observed of either agent in the metaphyses. With 99mTc-PYP, the vertebral and costal systems were delineated symmetrically and each vertebral body was distinctly depicted as such 99mTc-PYP many possess the following merits over 85Sr; (1) owing to its physical properties, sufficiently large radioactivity of 99mTc-can be administered; (2) body burden of radiation absorption is reduced; (3) skeletal scintigrams of high quality are obtainable in a short period of time.     

An effective method for bisphosphonate moiety inserting into O–H bond of carboxylic acids by Cu (II) catalyst

In this study we developed a novel copper-catalyzed O–H insertion of tetraethyl diphosphonodiazomethane into carboxylic acids, providing a simple method to link bisphosphonates to compounds containing carboxyl group. Moreover, a novel bone-targeting prodrug of naproxen was synthesized according to this new methodology, and the preliminary evaluation indicated that the prodrug exhibited excellent bone affinity in vitro.     

Pentacyclic Triterpenoids with Nitrogen-Containing Heterocyclic Moiety,Privileged Hybrids in Anticancer Drug Discovery

Pentacyclic triterpenoids are well-known phytochemicals with various biological activities commonly found in plants as secondary metabolites. The wide range of biological activities exhibited by triterpenoids has made them the most valuable sources of pharmacological agents. A number of novel triterpenoid derivatives with many skeletal modifications have been developed. The most important modifications are the formation of analogues or derivatives with nitrogen-containing heterocyclic scaffolds. The derivatives with nitrogen-containing heterocyclic compounds are among the most promising candidate for the development of novel therapeutic drugs. About 75% of FDA-approved drugs are nitrogen-containing heterocyclic moieties. The unique properties of heterocyclic compounds have encouraged many researchers to develop new triterpenoid analogous with pharmacological activities. In this review, we discuss recent advances of nitrogen-containing heterocyclic triterpenoids as potential therapeutic agents. This comprehensive review will assist medicinal chemists to understand new strategies that can result in the development of compounds with potential therapeutic efficacy.     

Adsorption-Desorption Properties of Bisphosphonates

Abstract

Aminobisphosphonates have generated substantial interest recently for the treatment of bone diseases and as plant growth regulators, both alone and as a carrier for other drugs, because of the high affinity to the hydroxyapatite (HAP). We are investigating the drug delivery action of bisphosphonates for the treatment of osteoporosis and other bone diseases. Current studies include analysis of the adsorption-desorption processes of bisphosphonate drug carriers to bone mineral, as well as the design and synthesis of new bisphosphonate derivatives. The HAP adsorption data of aminomethylenebis-phosphonate (M P) (1). alendronate (2), and the prostaglandin derivative of bisphosphonate (PGE,-BP) (3) is shown on the graph.     

Anti-Osteoporotic activity of metal complexes of amine carboxyboranes

Metal complexes of trimethylamine carboxyborane successfully suppressed calcium flux from both paired pup calvaria bones and rat UMR-106 osteosarcoma cultured cells over a 48 h period. These agents increased uptake of calcium into the cell cultures and accelerated [³H]proline incorporation into collagen. Copper and iron complexes of the trimethylamine carboxyborane were more potent compared with the cobalt and chromium complexes. The agents effectively reduced Iysosomal enzyme activity and also proteolytic enzyme activities of macrophages. Since macrophages invade the bone surface and assist in the demineralization and digestion of collagen, those agents may be potentially useful to retard diseases involving bone reconstruction. Influx of white blood cells and macrophages to sites of degradation most probably would be inhibited by the agents, based on sponge test observations in mice. Osteoporosis induced by ovariectomy was minimized by injections of tetrakis[u-(trimethylamine-boranecarboxylato)-bis(trimethylamine-carboxyborane)dicopper(II)] into rats at 3.5 mg kg^?1 day^?1 for 14 days. Bone volume, density, weight and calcium content returned to normal baseline control values. In addition, the copper complex returned serum calcium, serum parathyroid hormone (PTH) and vitamin D₃ values to normal levels. One possible mode of action of these derivatives is the regulation of the production and release of chemical mediators initiating bone loss, e.g. tumor necrosis factor, TNF α and interleukins 11 or 11-2.     

A Comprehensive Review on the Benefits and Problems of Curcumin with Respect to Human Health

Curcumin is the most important active component in turmeric extracts. Curcumin, a natural monomer from plants has received a considerable attention as a dietary supplement, exhibiting evident activity in a wide range of human pathological conditions. In general, curcumin is beneficial to human health, demonstrating pharmacological activities of anti-inflammation and antioxidation, as well as antitumor and immune regulation activities. Curcumin also presents therapeutic potential in neurodegenerative, cardiovascular and cerebrovascular diseases. In this review article, we summarize the advancements made in recent years with respect to curcumin as a biologically active agent in malignant tumors, Alzheimer’s disease (AD), hematological diseases and viral infectious diseases. We also focus on problems associated with curcumin from basic research to clinical translation, such as its low solubility, leading to poor bioavailability, as well as the controversy surrounding the association between curcumin purity and effect. Through a review and summary of the clinical research on curcumin and case reports of adverse effects, we found that the clinical transformation of curcumin is not successful, and excessive intake of curcumin may have adverse effects on the kidneys, heart, liver, blood and immune system, which leads us to warn that curcumin has a long way to go from basic research to application transformation.     

The Design and Synthesis of Bone-Active Phosphinic Acid Analogues: 1. The Pyridylaminomethane Phosphonoalkylphosphinates

Abstract

The bisphosphonic acids and their salts, the bisphosphonates, have been the subject of study by a number of research groups for their marked ability to modulate bone metabolism. From a recent study of phosphinic acid isosteres, we have designed a novel related class of bone active agents, the pyridylaminomethane phosphonoaikylphosphinates I.     

Synthetic Strategies for Fused Benzothiazoles: Past,Present, and Future

Benzothiazole is used as a building block in organic synthesis, which serves as a key template for the development of various therapeutic agents and shows a wide spectrum of activities. The attractive application of benzothiazole in organic synthesis is undoubtedly due to the highly reactive C-2 amino group, which is responsible for the change in its bioactivity. The construction of a poly-heterocyclic compound with the fused hetero-systems has attracted increasing attention because of the diverse range of potential therapeutic activities. Significant efforts have been undertaken to exploit different synthetic routes to these compounds. This article gives a comprehensive account of the synthetic utility of benzothiazole employed in the design and synthesis of different types of compounds containing fused heterocyclic rings with greater emphasis on recent literature.     

Progress in Targeted Alpha-Particle-Emitting Radiopharmaceuticals as Treatments for Prostate Cancer Patients with Bone Metastases

Bone metastasis remains a major cause of death in cancer patients, and current therapies for bone metastatic disease are mainly palliative. Bone metastases arise after cancer cells have colonized the bone and co-opted the normal bone remodeling process. In addition to bone-targeted therapies (e.g., bisphosphonate and denosumab), hormone therapy, chemotherapy, external beam radiation therapy, and surgical intervention, attempts have been made to use systemic radiotherapy as a means of delivering cytocidal radiation to every bone metastatic lesion. Initially, several bone-seeking beta-minus-particle-emitting radiopharmaceuticals were incorporated into the treatment for bone metastases, but they failed to extend the overall survival in patients. However, recent clinical trials indicate that radium-223 dichloride (²²³RaCl₂), an alpha-particle-emitting radiopharmaceutical, improves the overall survival of prostate cancer patients with bone metastases. This success has renewed interest in targeted alpha-particle therapy development for visceral and bone metastasis. This review will discuss (i) the biology of bone metastasis, especially focusing on the vicious cycle of bone metastasis, (ii) how bone remodeling has been exploited to administer systemic radiotherapies, and (iii) targeted radiotherapy development and progress in the development of targeted alpha-particle therapy for the treatment of prostate cancer bone metastasis.     

Metabolic activities affect femur and lumbar vertebrae remodeling,and anti-resorptive risedronate disturbs femoral cortical bone remodeling

Metabolic activities are closely correlated with bone remodeling and long-term anti-resorptive bisphosphonate treatment frequently causes atypical femoral fractures through unclear mechanisms. To explore whether metabolic alterations affect bone remodeling in femurs and lumbar vertebrae and whether anti-osteoporotic bisphosphonates perturb their reconstruction, we studied three mouse strains with different fat and lean body masses (BALB/c, C57BL6, and C3H mice). These mice displayed variable physical activity, food and drink intake, energy expenditure, and respiratory quotients. Following intraperitoneal calcein injection, double calcein labeling of the femoral diaphysis, as well as serum levels of the bone-formation marker procollagen type-I N-terminal propeptide and the bone-resorption marker C-terminal telopeptide of type-I collagen, revealed increased bone turnover in mice in the following order: C3H > BALB/c ≥ C57BL6 mice. In addition, bone reconstitution in femurs was distinct from that in lumbar vertebrae in both healthy control and estrogen-deficient osteoporotic mice with metabolic perturbation, particularly in terms of femoral trabecular and cortical bone remodeling in CH3 mice. Interestingly, subcutaneous administration of bisphosphonate risedronate to C3H mice with normal femoral bone density led to enlarged femoral cortical bones with a low bone mineral density, resulting in bone fragility; however, this phenomenon was not observed in mice with ovariectomy-induced femoral cortical bone loss. Together, these results suggest that diverse metabolic activities support various forms of bone remodeling and that femur remodeling differs from lumbar vertebra remodeling. Moreover, our findings imply that the adverse effect of bisphosphonate agents on femoral cortical bone remodeling should be considered when prescribing them to osteoporotic patients.Subject terms: Bone, Bone quality and biomechanics     

Solid-state NMR, crystallographic, and computational investigation of bisphosphonates and farnesyl diphosphate synthase-bisphosphonate complexes

Bisphosphonates are a class of molecules in widespread use in treating bone resorption diseases and are also of interest as immunomodulators and anti-infectives. They function by inhibiting the enzyme farnesyl diphosphate synthase (FPPS), but the details of how these molecules bind are not fully understood. Here, we report the results of a solid-state (13)C, (15)N, and (31)P magic-angle sample spinning (MAS) NMR and quantum chemical investigation of several bisphosphonates, both as pure compounds and when bound to FPPS, to provide information about side-chain and phosphonate backbone protonation states when bound to the enzyme. We then used computational docking methods (with the charges assigned by NMR) to predict how several bisphosphonates bind to FPPS. Finally, we used X-ray crystallography to determine the structures of two potent bisphosphonate inhibitors, finding good agreement with the computational results, opening up the possibility of using the combination of NMR, quantum chemistry and molecular docking to facilitate the design of other, novel prenytransferase inhibitors.     

Medicinal Use of Testosterone and Related Steroids Revisited

Testosterone derivatives and related compounds (such as anabolic-androgenic steroids—AAS) are frequently misused by athletes (both professional and amateur) wishing to promote muscle development and strength or to cover AAS misuse. Even though these agents are vastly regarded as abusive material, they have important pharmacological activities that cannot be easily replaced by other drugs and have therapeutic potential in a range of conditions (e.g., wasting syndromes, severe burns, muscle and bone injuries, anemia, hereditary angioedema). Testosterone and related steroids have been in some countries treated as controlled substances, which may affect the availability of these agents for patients who need them for therapeutic reasons in a given country. Although these agents are currently regarded as rather older generation drugs and their use may lead to serious side-effects, they still have medicinal value as androgenic, anabolic, and even anti-androgenic agents. This review summarizes and revisits the medicinal use of compounds based on the structure and biological activity of testosterone, with examples of specific compounds. Additionally, some of the newer androgenic-anabolic compounds are discussed such as selective androgen receptor modulators, the efficacy/adverse-effect profiles of which have not been sufficiently established and which may pose a greater risk than conventional androgenic-anabolic agents.     

Propolis: Its Role and Efficacy in Human Health and Diseases

With technological advancements in the medicinal and pharmaceutical industries, numerous research studies have focused on the propolis produced by stingless bees (Meliponini tribe) and Apis mellifera honeybees as alternative complementary medicines for the potential treatment of various acute and chronic diseases. Propolis can be found in tropical and subtropical forests throughout the world. The composition of phytochemical constituents in propolis varies depending on the bee species, geographical location, botanical source, and environmental conditions. Typically, propolis contains lipid, beeswax, essential oils, pollen, and organic components. The latter include flavonoids, phenolic compounds, polyphenols, terpenes, terpenoids, coumarins, steroids, amino acids, and aromatic acids. The biologically active constituents of propolis, which include countless organic compounds such as artepillin C, caffeic acid, caffeic acid phenethyl ester, apigenin, chrysin, galangin, kaempferol, luteolin, genistein, naringin, pinocembrin, coumaric acid, and quercetin, have a broad spectrum of biological and therapeutic properties such as antidiabetic, anti-inflammatory, antioxidant, anticancer, rheumatoid arthritis, chronic obstruct pulmonary disorders, cardiovascular diseases, respiratory tract-related diseases, gastrointestinal disorders, as well as neuroprotective, immunomodulatory, and immuno-inflammatory agents. Therefore, this review aims to provide a summary of recent studies on the role of propolis, its constituents, its biologically active compounds, and their efficacy in the medicinal and pharmaceutical treatment of chronic diseases.     

具有生理活性的甾体酰胺类化合物

在甾体的甾核或支链上引入不同的官能团后可得到不同生理活性的化合物,它们有可能会成为人类治疗不同疾病的药物,因此甾体药物除了作为传统激素类药物使用外,在抗肿瘤药物、抗炎药物中的应用也成为甾体的重要研究内容之一。含有酰胺官能团的甾体化合物具有很好的生物活性。本文按照酰胺基团在甾体酰胺化合物中的位置进行分类,同时结合本课题组在甾体酰胺化合物的合成和生理活性研究方面所取得的一些成果,概述了近几年来新合成及发现的甾体酰胺类化合物及其衍生物的生理活性及研究进展,包括作为抗肿瘤药物的甾体酰胺化合物的设计、筛选、对5α-还原酶的抑制作用、抑制肿瘤细胞生长增殖活性及抗菌作用,并对此方面的发展趋势、应用前景作了展望。