Charles M. Garner

Combretastatin family member OXI4503 induces tumor vascular collapse through the induction of endothelial apoptosis

The mechanism of tumor cell killing by OXI4503 was investigated by studying vascular functional and morphological changes post drug administration. SCID mice bearing MHEC5‐T hemangioendothelioma were given a single dose of OXI4503 at 100 mg/kg. Tumor blood flow, measured by microsphere fluorescence, was reduced by 50% at 1 hr, and reached a maximum level 6–24 hr post drug treatment. Tumor vascular permeability, measured by Evans blue and hemoglobin, increased significantly from 3 hr and peaked at 18 hr. The elevated tumor vessel permeability was accompanied by an increase in vascular endothelial growth factor (VEGF) from 1 hr post drug treatment. Immunohistochemical staining for CD31 and laminin showed that tumor blood vessels were affected as early as 3 hr but more prominent from 6 hr. From 12 hr, the vessel structure was completely destroyed. Histopathological and double immunohistochemical staining showed morphological change and induction of apoptosis in endothelial cells at 1–3 hr, followed by tumor cell necrosis from 6–72 hr. There were no statistically significant changes of Evans blue and hemoglobin contents in liver tissue over the time course. These results suggest that OXI4503 selectively targets tumor blood vessels, and induces blood flow shutdown while it enhances tumor blood vessel permeability. The early induction of endothelial cell apoptosis leads to functional changes of tumor blood vessels and finally to the collapse of tumor vasculature, resulting in massive tumor cell necrosis. The time course of the tumor vascular response observed with OXI4503 treatment supports this drug for development as a stand alone therapy, and also lends support for the use of the drug in combination with other cancer therapies.

Thermoreversible gelation of organic liquids by arylcyclohexanol derivatives Synthesis and characterisation of the gels

A variety of organic liquids can be immobilised using certain 4-tert-butyl-1-arylcyclohexanol derivatives (BACOl). Only the isomers with axial aryl groups are active as gelling agents. The BACOl–hydrocarbon systems have been characterised with respect to their rheological properties under shear. The gels are viscoelastic solids with high elastic shear moduli (G′≈70350 Pa at C≈2.2 wt.% in dodecane) and high yield stresses (σ≈620 Pa). A 3D network with high cohesive energy and long lifetimes of the related structures is in thermal equilibrium with the surrounding solution. Diffraction experiments have characterised the crystallinity of the gel networks made up of assemblies of bimolecular BACOl associations (d≈14.3 A). Xerogels exhibit a mesomorphic organisation with a 76 A repeating unit. Phase diagrams have been determined as a function of the solvent and gelator types and the related thermodynamic parameters were deduced. IR spectroscopy has demonstrated that H-bonding is responsible for the aggregation of the BACOl molecules.

Synthesis of a 2-aryl-3-aroyl indole salt (OXi8007) resembling combretastatin A-4 with application as a vascular disrupting agent

The natural products colchicine and combretastatin A-4 are potent inhibitors of tubulin assembly, and they have inspired the design and synthesis of a large number of small-molecule, potential anticancer agents. The indole-based molecular scaffold is prominent among these SAR modifications, leading to a rapidly increasing number of agents. The water-soluble phosphate prodrug 33 (OXi8007) of 2-aryl-3-aroylindole-based phenol 8 (OXi8006) was prepared by chemical synthesis and found to be strongly cytotoxic against selected human cancer cell lines (GI₅₀ = 36 nM against DU-145 cells, for example). The free phenol, 8 (OXi8006), was a strong inhibitor (IC₅₀ = 1.1 μM) of tubulin assembly. The corresponding phosphate prodrug 33 (OXi8007) also demonstrated pronounced interference with tumor vasculature in a preliminary in vivo study utilizing a SCID mouse model bearing an orthotopic PC-3 (prostate) tumor as imaged by color Doppler ultrasound. The combination of these results provides evidence that the indole-based phosphate prodrug 33 (OXi8007) functions as a vascular disrupting agent that may prove useful for the treatment of cancer.

An improved synthesis of tetramethylcyclopentadiene

Abstract A two-step synthesis of tetramethylcyclopentadiene, immediate precursor to substituted cyclopentadienyl ligands, has been developed based on a cyclodehydration reaction, providing this material rapidly and in relatively high yield.

The epimerization of α-chiral hydrazones: Menthonetosylhydrazone

Abstract The first preparation of (−)-menthonetosylhydrazone (2) in diastereomerically pure form is reported. Kinetic studies show that 2 is far more susceptible to acid-catalyzed epimerization (∼150x) than is the parent ketone, (−)-menthone (1), a relationship which has not been generally recognized. Conversion of 2 to 1-menthenyllithium (3) using excess butyllithium occurs without detectable epimerization, as determined by analysis of the 1-iodomenthene 5 obtained by treatment of 3 with iodine in-situ.

Synthesis of methoxy and hydroxy containing tetralones: versatile intermediates for the preparation of biologically relevant molecules

Abstract The synthesis of 5-hydroxy-6-methoxy-1-tetralone and the 7-hydroxy regioisomer along with the corresponding 5,7-dihydroxy analog has been achieved using an efficient directed metallation procedure followed by a regioselective methylene oxidation. This methodology represents a general synthetic route for the preparation of highly oxygenated tetralone analogs which are versatile building blocks for the construction of molecules of biological interest.

2-(3-tert-Butyldimethylsiloxy-4-methoxyphenyl)-6-methoxy-3-(3,4,5-trimethoxybenzoyl)indole

In the crystal structure of the title compound, C(32)H(39)NO(7)Si, all geometric parameters fall within experimental error of expected values. The analysis of molecular-packing plots reveals an infinite two-dimensional linear array running parallel to the b axis, formed by one N[bond]H...O intermolecular hydrogen-bonding interaction. Several potential C[bond]H...O interactions are also present.

Menthyldichlorophosphate: A chiral derivatizing agent for symmetrical diols

Abstract Menthyldichlorophosphate reacts readily with a variety of C 2 -chiral and meso diols to yield phosphate esters that exhibit useful diastereomeric differences in the 31 P NMR spectra. Meso and d,l diols are easily differentiated with this reagent.

Rearrangement of methylenecamphor during electrophilic bromination: remarkably clean access to the unnatural fenchyl (1,3,3-trimethylbicyclo[2.2.1]heptane) system

Treatment of (+)-methylenecamphor (2) with NBS in the presence of pyridine resulted in a rapid and remarkably clean rearrangement to yield a brominated (+)-methylenefenchone (3) in high yield and purity (>96%). The structure of the product was established by X-ray crystallography and the stereochemistry confirmed by both polarimetric and chiral GC analyses. Two transformations of the product were also performed to elucidate the structure.

Electronic effects in asymmetric hydroboration

Abstract To determine whether electronic effects are operative in asymmetric hydroboration, a series of para -substituted 2-aryl-1-propenes were prepared and reacted with four asymmetric borane reagents. A significant correlation between the electronic nature of the para -substituent and the degree of asymmetric induction was observed only for a chloroborane–ether complex, not for any of several simple alkylboranes. A quantitative analysis of the relative reactivities is also given.