Christina L. L. Chai

Structure-Activity Relationship Studies of Phenanthridine-Based Bcl-XL Inhibitors

Despite their structural similarities, the natural products chelerythrine ( 5) and sanguinarine ( 6) target different binding sites on the pro-survival Bcl-X L protein. This paper details the synthesis of phenanthridine-based analogues of the natural products that were used to probe this difference in binding profiles. The inhibitory constants for these compounds were then measured in a fluorescence polarization assay against Bcl-X L and the tagged Bak-BH3 peptide. The results led to structure-activity relationship studies, which identified the structural motifs required for binding-site specificity as well as inhibitory activity. We also identified synthetic analogues of the natural products that display similar binding modes but with more potent IC 50 values.

Inactivation of Rabbit Muscle Creatine Kinase by Reversible Formation of an Internal Disulfide Bond Induced by the Fungal Toxin Gliotoxin

The biological activity of gliotoxin is dependent on the presence of a strained disulfide bond that can react with accessible cysteine residues on proteins. Rabbit muscle creatine kinase contains 4 cysteines per 42-kDa subunit and is active in solution as a dimer. Only Cys-282 has been identified as essential for activity. Modification of this residue results in loss of activity of the enzyme. Treatment of creatine kinase with gliotoxin resulted in a time-dependent loss of activity abrogated in the presence of reducing agents. Activity was restored when the inactivated enzyme was treated with reducing agents. Inactivation of creatine kinase by gliotoxin was accompanied by the formation of a 37-kDa form of the enzyme. This oxidized form of creatine kinase was rapidly reconverted to the 42-kDa species by the addition of reducing agents concomitant with restoration of activity. A 1:1 mixture of the oxidized and reduced monomer forms of creatine kinase as shown on polyacrylamide gel electrophoresis was equivalent to the activity of the fully reduced form of the enzyme consistent with only one reduced monomer of the dimer necessary for complete activity. Conversion of the second monomeric species of the dimer to the oxidized form by gliotoxin correlated with loss of activity. Our data are consistent with gliotoxin inducing the formation of an internal disulfide bond in creatine kinase by initially binding and possibly activating a cysteine residue on the protein, followed by reaction with a second neighboring thiol. The recently published crystal structure of creatine kinase suggests the disulfide is formed between Cys-282 and Cys-73.

Copper-Catalyzed Diacetoxylation of Olefins using PhI(OAc)2 as Oxidant

Copper(I) or -(II) salts with weakly coordinating anions catalyze the diacetoxylation of olefins efficiently in the presence of PhI(OAc)(2) as the oxidant under mild conditions. The reaction is effective for aryl, aryl alkyl, as well as aliphatic terminal and internal olefins forming the corresponding vicinal diacetoxy compounds in 70-85% yields and dr (syn/anti) of up to 5.2. Under these conditions, homoallylic alcohols formed the corresponding tetrahydrofuran derivatives in high yields.

Efficient Formal Synthesis of Oseltamivir Phosphate (Tamiflu) with Inexpensive d-Ribose as the Starting Material

An efficient formal synthesis of oseltamivir phosphate (Tamiflu) has been achieved in 12 steps with use of the inexpensive and highly abundant D-ribose as the starting material. This concise alternative route does not utilize protecting groups and features the introduction of 3-pentylidene ketal as the latent 3-pentyl ether, the use of a highly efficient RCM reaction to form the Tamiflu skeleton, and selective functional group manipulations.

Highly enantioselective titanium-catalyzed cyanation of imines at room temperature.

A highly active and enantioselective titanium-catalyzed cyanation of imines at room temperature is described. The catalyst used is a partially hydrolyzed titanium alkoxide (PHTA) precatalyst together with a readily available N-salicyl-beta-aminoalcohol ligand. Up to 98% ee was obtained with quantitative yields in 15 min of reaction time using 5 mol % of the catalyst. Various N-protecting groups such as benzyl, benzhydryl, Boc, and PMP are tolerated.

Metalloenzymatic radical polymerization using alkyl halides as initiators

A novel initiation strategy for enzyme-induced radical polymerization that makes use of alkyl halides is reported here. The approach is remarkably versatile and can be applied to emulsion polymerization as well as surface-initiated polymerization. The molecular weights of the polymers can be effectively regulated with either irreversible (i.e., L-cysteine) or reversible (i.e., 2-cyano-2-propyl dithiobenzoate) chain transfer agents, the latter resulting in a well-controlled, RAFT-type polymerization process.

Clinical utility of neuroprotective agents in neurodegenerative diseases: current status of drug development for Alzheimer's, Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis

Introduction: According to the definition of the Committee to Identify Neuroprotective Agents in Parkinsons Disease (CINAPS), “neuroprotection would be any intervention that favourably influences the disease process or underlying pathogenesis to produce enduring benefits for patients” [Meissner W, et al. Trends Pharmacol Sci 2004;25:249-253]. Preferably, neuroprotective agents should be used before or eventually during the prodromal phase of the diseases that could start decades before the appearance of symptoms. Although several symptomatic drugs are available, a disease-modifying agent is still elusive. Areas covered: The aim of the present review is to give an overview of neuroprotective agents being currently investigated for the treatment of AD, PD, HD and ALS in clinical phases. Expert opinion: Development of effective neuroprotective therapies resulting in clinically meaningful results is hampered by several factors in all research stages, both conceptual and methodological. Novel solutions might be offered by evaluation of new targets throughout clinical studies, therapies emerging from drug repositioning approaches, multi-target approaches and network pharmacology.

Transparent, flexible and highly conductive ion gels from ionic liquid compatible cyclic carbonate network

Transparent, flexible, self-standing and highly ion conductive ion gels have been synthesised from novel ionic liquid compatible cyclic carbonate (CC) network polymer. The use of dual functional cyclic carbonate methacrylate (CCMA) monomer for the synthesis has enabled versatile and operationally simple routes to such type of ion gels.

A Class of Pantothenic Acid Analogs Inhibits Plasmodium falciparum Pantothenate Kinase and Represses the Proliferation of Malaria Parasites

ABSTRACT The growth and proliferation of the human malaria parasite Plasmodium falciparum are dependent on the parasites ability to obtain essential nutrients. One nutrient for which the parasite has an absolute requirement is the water-soluble vitamin pantothenic acid (vitamin B5). In this study, a series of pantothenic acid analogs which retain the 2,4-dihydroxy-3,3-dimethylbutyramide core of pantothenic acid but deviate in structure from one another and from pantothenic acid in the nature of the substituent attached to the amide nitrogen were synthesized using an efficient single-step synthetic route. Eight of 10 analogs tested inhibited the proliferation of intraerythrocytic P. falciparum parasites in vitro, doing so with 50% inhibitory concentrations between 15 and 200 μM. The compounds were generally selective, inhibiting the proliferation of a human cell line (the Jurkat cell line) only at concentrations severalfold higher than those required for inhibition of parasite growth. It was demonstrated that compounds in this series inhibited the phosphorylation of pantothenic acid by pantothenate kinase, the first step in the parasites biosynthesis of the essential enzyme cofactor coenzyme A, doing so competitively, with Ki values in the nanomolar range.

Hybocarpone, a novel cytotoxic naphthazarin derivative from mycobiont cultures of the lichen Lecanora hybocarpa

Abstract Hybocarpone ( 1 ), a novel pentacyclic naphthazarin-derived dimer has been isolated from mycobiont cultures derived from the lichen Lecanora hybocarpa . The structure of hybocarpone ( 1 ) was established on the basis of 1D and 2D NMR spectroscopy. Its relative stereochemistry was predicted with the use of molecular modelling and confirmed by X-ray crystallographic analysis. Hybocarpone ( 1 ) was found to be a potent cytotoxin (IC 50 c 0.27 μM), active against the murine P815 mastocytoma cell line.