Infections caused by resistant organisms: Could organic arsenic compounds be an effective treatment?

Without question one of the most important medicinal chemistry discoveries of the 20th century was made by Paul Ehrlich and his colleagues, chemist, Alfred Bertheim and bacteriologist, Sahachiro Hata. They ushered in the age of targeted chemotherapy in 1910 with the discovery of the anti-syphilitic organic arsenic agent, arsphenamine or Salvarsan (also known as 606). It was the clinical compound of choice for treating syphilis until penicillin and other antibiotics were introduced clinically in the 1940s. Yet now, more than 100years after its discovery, the precise biochemical mechanism by which this compound eliminates the syphilis spirochete in vivo from humans and animals remains unknown. Other organic arsenic compounds such as melarsoprol and roxarson have been used to treat parasitic infections. More recently, arsenic trioxide has been shown effective in producing remissions and possibly cures in a high percentage of patients with acute promyelocytic leukemia. However, the exact biochemical mechanism by which this clinical result is manifested remains to be determined. The purpose of this publication is to propose a possible mechanism, by which these apparently diverse arsenic compounds function to produce their clinical results and to suggest their potential for the treatment of infections caused by resistant organisms.

Possible chemical initiators of cognitive dysfunction in phenylketonuria, Parkinson's disease and Alzheimer's disease.

Though a great deal is known of the pathophysiology of phenylketonuria (PKU), Parkinson's disease (PD) and Alzheimer's disease (AD) very little is known regarding possible chemical species responsible for initiating the cascade of events that ultimately cause cognitive dysfunction. Can these be viewed as inborn errors in metabolism, occurring at various stages in the life cycle, analogous to adult onset diabetes? One major deficiency in understanding such conditions is the paucity of information regarding the total metabolic pathway for various amino acids that may be implicated in their causation. For example in PKU, its etiology was reported in 1934 and dietary restriction of phenylalanine proved effective for individuals with unsatisfactory metabolism of phenylalanine. Yet, current phenylalanine metabolism does not take into account fully the multiple biochemical pathways operating whose role is preventing burdensome accumulations of intermediates that can contribute to morbidity and toxicity. The same may apply for metabolism of tyrosine in PD and methionine in AD. Especially important, are the presence of labile and reactive chemical species which may be causative agents in protein alteration, misfolding and the creation of prions in neurodegenerative diseases, thereby preventing normal protein catabolism and excretion. Though genetic or epigenetic factors must be responsible, the question remains how are these translated into the chemical structures responsible for disease initiation? The purpose of this presentation is to explore potential labile metabolites in those biochemical pathways, which may be contributing factors. Finally it is worth noting, that drug development has been increasingly designed based upon targeting genetic deficiencies. The effectiveness of this approach for the treatment of these neurodegenerative illnesses will be determined in the future.

Potential role of reactive metabolites of addictive drugs at the receptor: a novel hypothesis.

The central nervous system (CNS) stimulants to CNS depressants such as morphine, cocaine, methamphetamine and nicotine each have the capacity for inducing chemical dependence with an enormous impact on human behavior. Because of the difficulties in isolation, the role of the reactive metabolites as a modulating factor in the receptor activation and related addiction of these drugs is not studied. The chemical transformations of these compounds to their metabolites at the receptors have been proposed. There is the distinct possibility that irreversible binding of N-hydroxy, N-formyl or related metabolites of morphine, cocaine, methamphetamine, or nicotine with the respective receptors can occur. This unique role of highly reactive molecular species is postulated. In this way, the synaptic glutaminergic and or dopaminergic transmission can be compromised. On repeated exposure of the drug, the receptor reserve may decrease. More drug is needed to activate the residual receptor to maintain the reward in addiction.

Macular degeneration: a possible biochemical mechanism.

The possible role of labile endogenous metabolites in the cause of various chronic debilitating diseases such as macular degeneration has not been adequately explored. In the metabolism of the various retinoids, namely retinal (vitamin A aldehyde), retinol (vitamin A alcohol) and retinoic acid, each has the potential for generating labile intermediates, such as their corresponding 5,6-epoxides by the action of various cytochrome P(450)s. Such retinoid epoxides may well have the capacity for acting as toxins upon the neurons in the macula unless they are rapidly hydrolyzed by epoxide hydrolases. Since the cytochrome P(450)s responsible for epoxide formation and the various epoxide hydrolases involved in their hydrolysis are determined genetically, this may serve to explain a genetic component being involved in the causation of age-related macular degeneration.

Potential endogenous epoxides of steroid hormones: initiators of breast and other malignancies?

The metabolism of steroid hormones has the potential for generating labile and reactive intermediates that may themselves be mutagenic and/or carcinogenic. Epoxides, derived from the cytochrome P450s, offer that potential and the concept is derived from extensive metabolic knowledge of PAHs and other compounds. In the case of the estrogens, possible epoxides have been proposed as metabolic precursors in the formation of the catechol estrogens. One of these compounds is the first structure shown below that has been demonstrated to be as carcinogenic as 3-methylcholanthrene. Increasingly, there is evidence that some, of these epoxides are intermediates in estrogen metabolism. If that were the case, individuals could be screened for their proclivity to produce such carcinogens and therapies may be designed to inhibit their formation.

Electrospray ionization mass spectrometry coupled to reversed-phase ion-pair high-performance liquid chromatography for quantitation of sodium borocaptate and application to pharmacokinetic analysis.

We have developed a quantitative assay using electrospray ionization mass spectrometry coupled to reversed-phase ion-pair liquid chromatography (LC/MS) for quantitation of sodium borocaptate (BSH) in human plasma. The assay was developed using a Micromass Q-TOF II mass spectrometer equipped with an orthogonal electrospray source. The mobile phase was a 1:1 solution of methanol and 5 mM aqueous tetrabutylammonium acetate flowing at 0.2 mL/min, and the chromatography was performed using a Machery-Nagel Nucleosil C18 column. Plasma samples from patients who had received an intravenous infusion of sodium borocaptate (Na2B12H11SH), frequently referred to as BSH, were prepared for analysis by precipitation with acetonitrile. Following this, the supernatants were collected, and 40 microL was injected onto the column for analysis. The LC/MS assay was linear over a BSH plasma concentration range of 20-0.5 microg/mL with acceptable variability for both intra- and interassay precision. The LC/MS assay was used to generate pilot pharmacokinetic data for the plasma disposition of BSH in humans. The disposition of BSH was found to be consistent with a two-compartment model with first-order elimination from the central compartment. The mean total body plasma clearance was 95.7 +/- 30.8 m/min and the harmonic mean terminal half-life was 3.6 h.

S-alkylation and S-amination of methyl thioethers--derivatives of closo-[B(12)H(12)](2-). synthesis of a boronated phosphonate, gem-bisphosphonates, and dodecaborane-ortho-carborane oligomers.

A variety of S-alkylated products was prepared by alkylation of methyl thioethers [MeSB(12)H(11)](2-) (5), [1-(MeS)-2(7,12)-(Me(2)S)B(12)H(10)](-) (6-8), and [1,2(7,12)-(MeS)(2)B(12)H(10)](2-) (9-11) with alkyl halides and tosylates in acetonitrile. Since these methyl thioethers can be prepared easily in B-10-enriched form on a large scale and due to their chemical versatility, they are potentially very attractive boron entities for the design and synthesis of therapeutics for boron neutron capture therapy of cancer. It was found that alkylation of 6-8 can be complicated by an equilibrium which establishes between, on the one hand, one of the former species and, on the other hand, 1,2(7,12)-(Me(2)S)(2)B(12)H(10) (2-4) and [1,2(7,12)-(MeS)(2)B(12)H(10)](2-) (9-11). A boronated phosphonate 1-(MeS(CH(2))(4)P(O)(OEt)(2))-7-(Me(2)S)B(12)H(10) (14g) and a gem-bisphosphonate 1-(MeS(CH(2))(3)CH[P(O)(OEt)(2)](2))-7-(Me(2)S)B(12)H(10) (14h) were prepared from thioether 7 and the corresponding iodide and tosylate, respectively, and subsequently converted to their sodium salts. The propargyl sulfonium salts obtained by alkylation of thioethers 7, 8, 10, and 11 with propargyl bromide have been further converted to two- and three-cage oligomers containing both ortho-carborane and dodecaborane moieties. Methyl thioethers derived from closo-[B(12)H(12)](2-) are excellent participants in Michael addition reactions in the presence of a strong acid. The sulfonium salts with tertiary alkyl and vinyl substituents have been prepared by this method. Methyl thioethers 5-11 react with hydroxylamine-O-sulfonate yielding the corresponding aminosulfonium salts, albeit in lower yields as compared to those in the alkylation reactions. Several derivatives of methyl thioethers 5-11 have been characterized by single-crystal X-ray diffraction.

Linkage of boronated polylysine to glycoside moieties of polyclonal antibody; boronated antibodies as potential delivery agents for neutron capture therapy.

Among the ways to deliver comparatively large amounts of boron to cells in vitro for boron neutron capture studies is the linkage of a boronated macromolecule such as polylysine to an antibody. In order to reduce interference with immunoreactivity, boronated polylysine (BPL) was linked to oligosaccharide moieties on the IgG molecule distant from the antibody combining sites. The resultant bioconjugate was chromatographically separated from free BPL and unconjugated antibody using a Sephacryl S300 column. The total measured boron per BPL-IgG conjugate, determined by direct current plasma atomic emission spectroscopy, was estimated to be approximately 6 x 10(3) atoms. This, together with molecular weight estimations, indicated conjugation of about 3 polylysines to each IgG molecule. Immunoreactivity of the conjugate was found to be the same as that of the unconjugated polyclonal antibody. This was based on its concentration dependent interference with immunometric reactions for an antigen (TSH), whereas heat inactivated or non-specific antibody had no such inhibitory effects. The results support the hypothesis that the binding affinity of the conjugate for antigen was preserved after its linkage to BPL under the conditions described. The methodology described in this report may have applicability for the preparation of boronated antibodies as delivery agents for BNCT.