John S. Williamson

Hydroxamic Acids as Pharmacological Agents

A variety of hydroxamic acid derivatives have recently been touted for their potential use as inhibitors of hypertension, tumor growth, inflammation, infectious agents, asthma, arthritis, and more. Here we provide a comprehensive review of the basic medicinal chemistry and pharmacology of hydroxamic acid derivatives that have been examined as inhibitors of zinc metalloproteases, matrix metalloproteinases, leukotriene A(4) hydrolases, ureases, lipoxigenases, cyclooxygenases, as well as peptide deformilases.

Angiogenesis: new targets for the development of anticancer chemotherapies.

Angiogenesis is the process by which new blood vessels are formed from preexisting microvasculature. To ensure an adequate blood supply, tumor cells release angiogenic factors that are capable of promoting nearby blood vessels to extend vascular branches to the tumor. In addition, larger tumors have been shown to release angiogeneic inhibitory factors that prevent blood vessels from sending branches to smaller, more distant tumors that compete for oxygen and nutrients. Angiogenesis is a complex multistep biochemical process, and offers several potential molecular targets for non-cytotoxic anticancer therapies. Strategies for exploiting tumor angiogenesis for novel cancer drug discovery include: (i) inhibition of proteolytic enzymes that breakdown the extracellular matrix surrounding existing capillaries; (ii) inhibition of endothelial cell migration; (iii) inhibition of endothelial cell proliferation; (iv) enhancement of tumor endothelial cell apoptosis. There is also a host of miscellaneous agents that inhibit angiogenesis for which the specific mechanisms are not clear. Several methods have been developed for measuring antiangiogenic activity both in vitro and in vivo. Although there has been intensive research efforts focused at the phenomena of angiogenesis, as well as the search for antiangiogenic agents for more than two decades, many questions remain unanswered with regard to the overall biochemical mechanisms of the angiogenesis process and the potential therapeutic utility of angiogenic inhibitors. Nevertheless potent angiogenic inhibitors capable of blocking tumor growth have been discovered, and appear to have potential for development into novel anticancer therapeutics. However there are still hurdles to be overcome before these inhibitors become mainstream therapies.

SYNTHESIS, ANTITUBERCULAR ACTIVITY AND DOCKING STUDY OF NOVEL CYCLIC AZOLE SUBSTITUTED DIPHENYL ETHER DERIVATIVES

The re-emergence of tuberculosis (TB) as a global health problem over the past few decades, accompanied by the rise of drug-resistant strains of Mycobacterium tuberculosis, emphasizes the need for discovery of new therapeutic drugs against this disease. The emerging serious problem both in terms of TB control and clinical management prompted us to synthesize a novel series of heterocyclic o/m/p substituted diphenyl ether derivatives and determine their activity against H37Rv strain of Mycobacterium. All 10 compounds inhibited the growth of the H37Rv strain of mycobacterium at concentrations as low as 1 microg/mL. This level of activity was found comparable to the reference drugs rifampicin and isoniazid at the same concentration. Molecular modeling of the binding of the diphenyl ether derivatives on enoyl-ACP reductase, the molecular target site of triclosan, indicated that these compounds fit within the binding domain occupied by triclosan. Hence the diphenyl ether derivatives tested in this study were docked to ENR and the binding of the diphenyl ether derivatives was also estimated using a variety of scoring functions that have been compiled into the single consensus score. As the scores ranged from 47.27% to 65.81%, these bioactive compounds appear to have a novel mechanism of action against M. tuberculosis, and their structural features should be studied further for their potential use as new antitubercular drugs.

Transformation of Artemisinin by Cunninghamella elegans

Semi-synthetic derivatives of the anti-malarial drug artemisinin hold great promise in the search for an effective and economical treatment of chloroquine-resistant forms of malaria. Unfortunately, synthetic functionalization of the artemisinin skeleton is often tedious and/or impractical. We seek to utilize 7β-hydroxyartemisinin, obtained from microbial transformation, as a semi-synthetic precursor for the synthesis of novel 7β-substituted artemisinin anti-malarial agents. Here we employ liquid cultures of Cunninghamella elegans as a means for the rational and economical bioconversion of artemisinin to 7β-hydroxyartemisinin in 78.6% yield. In addition, there were three other bioconversion products: 7β-hydroxy-9α-artemisinin (6.0%), 4α-hydroxy-1-deoxoartemisinin (5.4%), and 6β-hydroxyartemisinin (6.5%).

Reductive Amination with Zinc Borohydride. Efficient, Safe Route to Fluorinated Benzylamines

Abstract Abstract: Fluorinated benzylamines are synthesized in high yields by reductive alkylation of secondary amines with appropriate fluoroaldehydes using a combination of zinc chloride and zinc borohydride. The present method offers an alternative to toxic sodium cyanoborohydride and is adaptable to multigram-scale preparations.

Design and Synthesis of Heterocyclic Hydroxamic Acid Derivatives as Inhibitors of Helicobacter pylori Urease

Abstract Helicobacter pylori produces ammonia to help counter the acidic environment in the human stomach. The production of ammonia, essential for the microorganisms survival and virulence, is the product of enzymatic conversion of urea by the H. pyloris urease. Inhibition of urease activity by dipeptide hydroxamic acids has previously been demonstrated using a variety of fluorides, thiols and hydroxamic acids. Studies employing computer-aided drug design techniques have been utilized to suggest a novel series of heterocyclic hydroxamic acid derivatives as potential as urease inhibitors. The heterocyclic compounds 7a,b, 10b, 12b, 16b, and 19b have been designed, synthesized, and preliminarily tested as dipeptide mimics which offer a structure that is more biologically stable than that of the reported dipeptide inhibitors.

Synthesis of N-methyl secondary amines

Abstract A diverse set of N-methyl secondary amines are obtained in high yields by an expedient reductive alkylation of commercially available methanolic methylamine.

Biotransformation of 10-deoxoartemisinin to its 7β-hydroxy derivative by Mucor ramannianus

Abstract10-Deoxoartemisinin at 0.2 mg ml−1 medium was transformed to 7β-hydroxy deoxoartemisinin by Mucor ramannianus growing on sucrose, 20 g l−1, and peptone, 10 g l−1, at pH 4 and 26 °C. The yield of product was increased from 16% to 45% by selecting optimal culture conditions using a 25−2 factorial design.

Ultra-performance liquid chromatography-tandem mass spectrometric method for the determination of Artemisinin in rat serum and its application in pharmacokinetics

A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to quantify artemisinin in rat serum. The lower limit of quantification (LLOQ) was 4 ng/mL. The calibration curve was linear from 4 ng/mL to 10,000 ng/mL (R=0.998). The assay was based on the selected reaction monitoring (SRM) transitions at m/z 305.4-151.10 for artemisinin and m/z 335.2-163.10 for arteether (internal standard). The artemisinin and internal standard can be separated from endogenous interferences in rat serum. Inter- and intra-day assay variation was less than 15%. The extraction recoveries ranged from 80.0 to 107.3% at the three concentrations (5000, 2000, and 200 ng/mL). This method was successfully applied to pharmacokinetic studies of artemisinin after intravenous and oral administration to rats.

Molecular Modeling, Synthesis And Biological Evaluation of Heterocyclic Hydroxamic Acids Designed as Helicobacter Pylori Urease Inhibitors

Abstract: A computer-generated homology model of the antimicrobial target Helicobacter pylori urease was derived, using the x-ray crystal structure of Klebsiellaaerogenes as a template, in order to design novel urease inhibitors. Based on thesecomputational studies, several heterocyclic hydroxamic acid derivatives have beendesigned, synthesized, and examined for their ability to inhibit urease activity. Keywords: Helicobacter pylori , antimicrobial, urease, hydroxamic acids. INTRODUCTION Almost 90% of the human population is believedinfected with the spiral-shaped, Gram-negative bacterium Helicobacter pylori ( H. pylori ) , making it one of the mostinfectious agents known [1]. After numerous studies on thepathogenic role of this bacterium, it is now widely acceptedthat H. pylori is a major causative factor in peptic ulcerdiseases [2]. Antibiotic eradication therapies in the clinichave been shown to heal gastritis, provide a cure for manypatients suffering from peptic ulcers, and even generate aremission of MALT carcinomas. While the majority of