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.

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.

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.

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.

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.

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.

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).

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.