Toxicology of a Boronated Porphyrin in Dogs

Among the most important characteristics of any therapeutic agent are efficacy and an acceptable toxicity. Prior to human use, toxicity studies are performed in both small and large animal models. Our laboratory has developed a new binary therapy agent, a boronated porphyrin (BOPP), with excellent potential efficacy. The purpose of this study is to examine the toxicology of this compound in dogs. Sixteen dogs were given 35 mg/kg of BOPP intravenously and evaluated for up to 28 days following administration. Clinical and pathologic responses were measured. BOPP was clinically well tolerated with some cases of weight loss, vomiting and mild photosensitivity. Adverse effects were limited primarily to thrombosis at the administration site in several subjects and three cases of mild, possibly transient, liver injury. Clinical pathologic tests found reversible changes in white blood cell counts and platelets, with neither change being clinically significant. The low toxicity associated with BOPP as shown in this study provides valuable evidence supporting the use of BOPP in binary therapy.     

A total synthesis of the antitumour macrolide rhizoxin D

An enantioselective synthesis of rhizoxin D, isolated from the plant pathogenic fungus Rhizopus chinensis, is described. The overall strategy is based on elaboration of the delta-lactone-substituted vinyl stannane and the phosphonate-substituted vinyl iodide, followed by their coupling to the core 16-membered macrolide via a sequential intermolecular Horner-Wadsworth-Emmons olefination, leading to (50), and by an intramolecular Stille reaction. The triene oxazole-containing side chain in rhizoxin D is then introduced using the phosphine oxide in an E-selective Horner-Wittig reaction with the macrolide aldehyde.     

Synthesis and evaluation of antitumour activity in vitro and in vivo of chrysin salicylate derivatives

A series of chrysin salicylate derivatives as potential antitumour agents were synthesised and evaluated their antitumour activities in vitro and in vivo. Most of the compounds exhibited moderate to good activities against MCF-7 cells, HepG2 cells, MGC-803cells and MFC cells. Among them, compound 3f showed the most potent activity against MGC-803 cells and MFC cells with IC₅₀ values of 23.83 ± 3.68 and 27.34 ± 5.21 μM, respectively. The flow cytometry assay reconfirmed that compound 3f promoted the occurrence of tumour cells’ G1/S block under the inhibiting effect of compound 3f. Compound 3f possessed higher antitumour efficacy in tumour-bearing mice, compared with the positive control 5-Fu and the blank control saline.     

2-Substituted thiazole-4-carboxamide derivatives as tiazofurin mimics: synthesis and in vitro antitumour activity

Tiazofurin analogues bearing a 5-hydroxymethyl-2-methyl-tetrahydrofuro[2,3-d][1,3]dioxol-6-ol moiety as a sugar mimic (2 and 3), and two novel thiazole-based acyclo-C-nucleosides 4 and 16 have been synthesized in multistep sequences starting from d-xylose (compounds 2 and 3) or from d-arabinose (compounds 4 and 16). All synthesized analogues showed potent in vitro antitumour activities against a panel of human tumour cell lines. Flow cytometry data suggest that cytotoxic effects of analogues 2–4 and 16 in the culture of K562 cells might be mediated by apoptosis. It was also found that these analogues induced changes in cell cycle distribution of K562 cells. Results of western blot analysis (upregulation of Bax and downregulation of Bcl-2, activation of caspase-3 and the presence of a PARP cleavage product) suggest that tiazofurin mimics (2–4 and 16) in K562 cells induced apoptosis in a caspase-dependent way.     

New antitumour active platinum compounds containing carboxylate ligands in trans geometry: synthesis, crystal structure and biological activity

New asymmetric trans-platinum(II) complexes, composed of an isopropylamine, an azole and two carboxylate leaving groups, are presented. The crystal and molecular structures of one of the complexes has been determined and the cytotoxicity and reactivity with 5'-guanosine monophosphate is reported. The complexes show a reduced reactivity, but no decrease in cytotoxic activity compared to their chloro-counterparts. Furthermore the complexes largely overcome cisplatin resistance, they therefore present an interesting class of antitumour active trans-platinum complexes.     

Photophysics and Intracellular Distribution of a Boronated Porphyrin Phototherapeutic Agent

Abstract— The absorption and emission spectra, fluorescence quantum yields and lifetimes and triplet state properties of a boronated porphyrin, the tetrakiscarborane carboxylate ester of 2,4-(α,β-dihydroxyethyl) deuteroporphyrin IX (BOPP), have been determined. This compound is an alternative photodynamic therapy (PDT) agent that exhibits highly selective tumor localization, with the potential to be used in conjunction with boron neutron capture therapy. The photophysical characteristics of BOPP are similar to other porphyrins and it exhibits marked aggregation and acid-base speciation under typical physiological conditions. In particular, protonation of the porphyrin imino (-N=) nitrogens occurs in the pH 5–7 region and influences the photophysical properties. Time-resolved confocal fluorescence imaging of the intracellular distribution of BOPP in C6 glioma cells indicates distinct subcellular localization and heterogeneity of emission. The results are interpreted and discussed in terms of the possible mechanisms for cellular uptake and localization.     

Ferrocene-modified amino acids: synthesis and in vivo bioeffects on hippocampus

Russian Chemical Bulletin - A method for the ferrocene modification of amino acids of natural and synthetic origin has been developed. In the in vivo studies, the hippocampal electrical activity...     

Boronated (co)polystyrene: monomer reactivity ratios,thermal behavior and flammability

Chemical modification based on incorporation of flame retardants (FR) into the polymer backbone was used in order to reduce polystyrene flammability. Boronated styrenes such as 4‐vinylphenylboronic acid (StB(OH)₂) and 6‐methyl‐2‐(4‐vinylphenyl)‐1,3,6,2‐dioxazaborocane‐4,8‐dione (StBcyclo) were applied as reactive FR. Homo‐ and copolymers of boronated styrenes and styrene (St) were synthesized with different feed ratios using free radical polymerization. It yielded in series of (co)polymers with various amounts of StB(OH)₂ and StBcyclo (5–20% mol/mol of St). Copolymer compositions were determined by ¹H NMR. The relative reactivity ratios of system St‐StBcyclo were determined by applying the Jaacks method. Glass transition temperature and thermal stability of obtained (co)polymers were determined from DSC and TGA analysis, respectively. The pyrolysis combustion flow calorimeter was applied as a tool for assessing the flammability of the synthesized (co)polymers. Copyright © 2014 John Wiley & Sons, Ltd.     

Novel N-heterocyclic ylideneamine gold(I) complexes: synthesis, characterisation and screening for antitumour and antimalarial activity

Ylideneamine functionalised heterocyclic ligands, 1,3-dimethyl-1,3-dihydro-benzimidazol-2-ylideneamine (I), 3-methyl-3H-benzothiazol-2-ylideneamine (II) or 3,4-dimethyl-3H-thiazol-2-ylideneamine (III), were employed in the preparation of a series of both charged and neutral gold(I) complexes consisting either of a Au(C(6)F(5)) fragment (1-3), a [Au(PPh(3))](+) unit (4-6) or a [Au(NHC)](+) unit (7) coordinated to the imine nitrogen of the neutral ylideneamine ligand. These complexes were fully characterised by various techniques including X-ray diffraction. In addition, the antitumour and antimalarial potential of selected compounds were assessed in a preliminary study aimed at determining the medicinal value of such compounds. Complexation of the azol-2-ylideneamine ligands with [Au(PPh(3))](+) increases their antitumour as well as antimalarial activity.     

Boronated enynes as versatile sources of stereodefined and skeletally diverse molecules

[reaction: see text] The application of a one-pot palladium-catalyzed cycloisomerization of enynes 1/Diels-Alder cycloaddition/allylboration sequence efficiently generates tricyclic structures with complete control of the four stereogenic centers. Ruthenium and platinum catalysts perform distinct transformations providing other isomeric boron-substituted cyclic compounds.     

In vitro and in vivo antitumour studies of a new thiosemicarbazide derivative and its complexes with 3d-metal ions

A new ligand, 1-(2-furanthiocarbo)-3-thiosemicarbazide (H₂ftsc), prepared from thiosemicarbazide and carboxymethyl-2-furandithioate, forms complexes [Mn(ftsc)(H₂O)₂], [Pd(ftsc)] · 2H₂O, [M(Hftsc)(acac)₂] (M=Co^III or Cr^III), [M(Hftsc)₂(acac)] (M=Mn^III or Fe^III) and [Zn(Hftsc)₂] · 2H₂O, which were characterized by elemental analyses, magnetic susceptibility, i.r., electronic and n.m.r. spectral data. The Mössbauer spectra of [Fe(Hftsc)₂(acac)] at 298K and 80K suggest the presence of high-spin iron(III) with an S=5/2 state. In vivo and in vitro antitumour activity of the ligand and the complexes have been screened towards several tumour cell-lines.     

The Antimicrobial efficacy of Elaeis guineensis: characterization, in vitro and in vivo studies

The urgent need to treat multi-drug resistant pathogenic microorganisms in chronically infected patients has given rise to the development of new antimicrobials from natural resources. We have tested Elaeis guineensis Jacq (Arecaceae) methanol extract against a variety of bacterial, fungal and yeast strains associated with infections. Our studies have demonstrated that E. guineensis exhibits excellent antimicrobial activity in vitro and in vivo against the bacterial and fungal strains tested. A marked inhibitory effect of the E. guineensis extracts was observed against C. albicans whereby E. guineensis extract at ?, 1, or 2 times the MIC significantly inhibited C. albicans growth with a noticeable drop in optical density (OD) of the bacterial culture. This finding confirmed the anticandidal activity of the extract on C. albicans. Imaging using scanning (SEM) and transmission (TEM) electron microscopy was done to determine the major alterations in the microstructure of the extract-treated C. albicans. The main abnormalities noted via SEM and TEM studies were the alteration in morphology of the yeast cells. In vivo antimicrobial activity was studies in mice that had been inoculated with C. albicans and exhibited good anticandidal activity. The authors conclude that the extract may be used as a candidate for the development of anticandidal agent.     

Fluorinated photosensitizers: synthesis, photophysical, electrochemical, intracellular localization, in vitro photosensitizing efficacy and determination of tumor-uptake by F in vivo NMR spectroscopy

For in vivo NMR studies, starting from pyrroles, a series of fluorinated porphyrins were synthesized by following the MacDonald reaction conditions. Upon reaction with osmium tetroxide, a fluorinated porphyrin containing four trifluoromethyl groups (12 fluorine units) was converted into the related chlorin and bacteriochlorin which exhibited long-wavelength absorptions at 652 and 720 nm, respectively. All compounds produced good singlet oxygen production efficiency. A comparative study of nine porphyrins with and without fluorine substituents indicated no adverse effects of the presence of fluorinated groups in the photophysical properties of the porphyrins, chlorins or bacteriochlorins. The first and second one-electron reduction potentials (vs SCE) of the investigated compounds range between −1.29 and −1.49 V and between −1.66 and −1.84 V in PhCN containing 0.1 M TBAP. UV-visible spectroelectrochemical data suggested the formation of π-anion and π-cation radicals upon the first reduction and first oxidation. The in vivo ¹⁹F MR study of a representative fluorine labeled compound with twelve equivalent fluorines confirmed the presence of the fluorine labeled sensitizer in mouse (C3H/HeJ) implanted with RIF tumors on mouse foot dorsum by inoculating 2×10⁵ cells (the studies were repeated on four tumored mice to confirm the feasibility and reproducibility). All fluorinated compounds were found to be quite effective in vitro. In a comparative intracellular localization study with Rhodamine-123 in RIF tumor cells, the most soluble porphyrin containing two propionic ester side chains was found to localize in mitochondria as well as the related chlorin and bacteriochlorin.     

Synthesis and Characterization of a Boronated Metallophthalocyanine for Boron Neutron Capture Therapy

Synthesis of the first fully characterized, water-soluble boronated phthalocyanine is reported. Reaction of 4-nitrophthalonitrile with dimethyl malonate in the presence of base yielded dimethyl (3,4-dicyanophenyl)malonate which was converted into dimethyl (3,4-dicyanophenyl)propargylmalonate by sequential treatment with potassium hydroxide and propargyl bromide. Formation of the o-carborane cage was accomplished by reaction of the alkyne with decaborane in acetonitrile at reflux. High-temperature solid state condensation of the resulting o-carboranylphthalonitrile with cobalt(II) chloride followed by ester deprotection and cation exchange provided the water-soluble closo-carbonylphthalocyanine product. The product contains 40 boron atoms (27% boron by weight) and may be useful as a tumor-seeking boron delivery agent for boron neutron capture therapy of cancer.     

Studies on the synthesis of a hindered analogue of the antitumour agent CC-1065

Studies on the synthesis of a sterically congested analogue of CC-1065 (2) are described. Interesting steric effects in the reactivity of intermediates and the rare predominance of keto tautomers in some phenols were observed.     

Galbofloxacin: a xenometal-antibiotic with potent in vitro and in vivo efficacy against S. aureus

Siderophore-antibiotic drug conjugates are considered potent tools to deliver and potentiate the antibacterial activity of antibiotics, but only few have seen preclinical and clinical success. Here, we introduce the gallium(iii) complex of a ciprofloxacin-functionalized linear desferrichrome, Galbofloxacin, with a cleavable serine linker as a potent therapeutic for S. aureus bacterial infections. We employed characterization using in vitro inhibitory assays, radiochemical, tracer-based uptake and pharmacokinetic assessment of our lead compound, culminating in in vivo efficacy studies in a soft tissue model of infection. Galbofloxacin exhibits a minimum inhibitory concentration of (MIC₉₈) 93 nM in wt S. aureus, exceeding the potency of the parent antibiotic ciprofloxacin (0.9 μM). Galbofloxacin is a protease substrate that can release the antibiotic payload in the bacterial cytoplasm. Radiochemical experiments with wt bacterial strains reveal that ⁶⁷Galbofloxacin is taken up efficiently using siderophore mediated, active uptake. Biodistribution of ⁶⁷Galbofloxacin in a mouse model of intramuscular S. aureus infection revealed renal clearance and enhanced uptake in infected muscle when compared to ⁶⁷Ga-citrate, which showed no selectivity. A subsequent in vivo drug therapy study reveals efficient reduction in S. aureus infection burden and sustained survival with Galbofloxacin for 7 days. Ciprofloxacin had no treatment efficacy at identical molecular dose (9.3 μmol kg⁻¹) and resulted in death of all study animals in <24 hours. Taken together, the favorable bacterial growth inhibitory, pharmacokinetic and in vivo efficacy properties qualify Galbofloxacin as the first rationally designed Ga-coordination complex for the management of S. aureus bacterial infections.

Galbofloxacin, a novel theranostic xenosiderophore antibiotic, exhibits unparalleled potency in combating S. aureus infections in vivo.     

Organotin gibberellates: Synthesis,spectroscopic characterization and antitumour activity

The synthesis and characterization of di-n-butyl-, tri-n-butyl- and triphenyltin gibberellates are reported. Their antitumour activities in vitro against a panel of seven human tumour cell lines are given and compared with those of drugs used clinically. Copyright © 1998 John Wiley & Sons, Ltd.     

Identification and characterization of in vitro and in vivo fidarestat metabolites: Toxicity and efficacy evaluation of metabolites

The progression of diabetic complications can be prevented by inhibition of aldose reductase and fidarestat considered to be highly potent. To date, metabolites of the fidarestat, toxicity, and efficacy are unknown. Therefore, the present study on characterization of hitherto unknown in vitro and in vivo metabolites of fidarestat using liquid chromatography–electrospray ionization tandem mass spectrometry (LC/ESI/MS/MS) is undertaken. In vitro and in vivo metabolites of fidarestat have been identified and characterized by using LC/ESI/MS/MS and accurate mass measurements. To identify in vivo metabolites, plasma, urine, and feces samples were collected after oral administration of fidarestat to Sprague–Dawley rats, whereas for in vitro metabolites, fidarestat was incubated in human S9 fraction, human liver microsomes, and rat liver microsomes. Furthermore, in silico toxicity and efficacy of the identified metabolites were evaluated. Eighteen metabolites have been identified. The main in vitro phase I metabolites of fidarestat are oxidative deamination, oxidative deamination and hydroxylation, reductive defluroniation, and trihydroxylation. Phase II metabolites are methylation, acetylation, glycosylation, cysteamination, and glucuronidation. Docking studies suggest that oxidative deaminated metabolite has better docking energy and conformation that keeps consensus with fidarestat whereas the rest of the metabolites do not give satisfactory results. Aldose reductase activity has been determined for oxidative deaminated metabolite (F‐1), and it shows an IC50 value of 0.44 μM. The major metabolite, oxidative deaminated, did not show any cytotoxicity in H9C2, HEK, HEPG2, and Panc1 cell lines. However, in silico toxicity, the predication result showed toxicity in skin irritation and ocular irritancy SEV/MOD versus MLD/NON (v5.1) model for fidarestat and its all metabolites. In drug discovery and development research, it is distinctly the case that the potential for pharmacologically active metabolites must be considered. Thus, the active metabolites of fidarestat may have an advantage as drug candidates as many drugs were initially observed as metabolites.