Preferential crystallization of (±)-pinenyllithium·TMEDA.

(±)-Pinenyllithium·TMEDA or (tetramethylethylenediamine-κN,N')(η-6,6-dimethyl-2-methylenebicyclo[3.1.1]heptyl)lithium, [Li(CH)(CHN)], is readily prepared from β-pinene, butyllithium and TMEDA, and the racemic material preferentially crystallizes even from 96:4 (92% ee) mixtures of (-)- and (+)-β-pinene, respectively.

A quantitative study of vapor diffusions for crystallizations: rates and solvent parameter changes.

Vapor diffusion crystallizations are among the most versatile methods for growing X-ray quality crystals. While many experimental sections describe the successful use of various solvent combinations, the literature has been entirely lacking in quantitative data (rates, measures of solvent strength changes) that might allow more informed planning rather than simple trial-and-error approaches. We here report the diffusion-induced volume changes for 44 solvent combinations over the first 60 h under standardized conditions, plus six more combinations that exhibit little or no volume changes.

Kinetic studies of the epimerization of diastereomeric pyrylium salts.

Chiral pyrylium salts are almost unknown in the literature, and none that are epimerizable have been reported prior to our work. Herein, we report two new epimerizable pyryliums and the kinetics of the diastereomeric equilibration of these and one other example. All of these required a careful analysis of the (1)H NMR spectrum to identify the stereoisomers, particularly for one of them.

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).

Combretastatin dinitrogen-substituted stilbene analogues as tubulin-binding and vascular-disrupting agents.

Several stilbenoid compounds having structural similarity to the combretastatin group of natural products and characterized by the incorporation of two nitrogen-bearing groups (amine, nitro, serinamide) have been prepared by chemical synthesis and evaluated in terms of biochemical and biological activity. The 2',3'-diamino B-ring analogue 17 demonstrated remarkable cytotoxicity against selected human cancer cell lines in vitro (average GI 50 = 13.9 nM) and also showed good activity in regard to inhibition of tubulin assembly (IC 50 = 2.

Design, synthesis, and biological evaluation of combretastatin nitrogen-containing derivatives as inhibitors of tubulin assembly and vascular disrupting agents.

A series of analogs with nitro or serinamide substituents at the C-2'-, C-5'-, or C-6'-position of the combretastatin A-4 (CA4) B-ring was synthesized and evaluated for cytotoxic effects against heart endothelioma cells, blood flow reduction to tumors in SCID mice, and as inhibitors of tubulin polymerization. The synthesis of these analogs typically featured a Wittig reaction between a suitably functionalized arylaldehyde and an arylphosphonium salt followed by separation of the resultant E- and Z-isomers. Several of these nitrogen-modified CA4 derivatives (both amino and nitro) demonstrate significant inhibition of tubulin assembly as well as cytotoxicity and in vivo blood flow reduction.

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.

Oxi4503, a novel vascular targeting agent: effects on blood flow and antitumor activity in comparison to combretastatin A-4 phosphate.

Oxi4503, which is the diphosphate prodrug of combretastatin A1, is a novel vascular targeting agent from the combretastatin family. Another member of this family, Combretastatin A-4 phosphate (CA4P), is a well-characterized vascular targeting agent already being evaluated in clinical trials. The potential for tumor vascular targeting by Oxi4503 was assessed in a mouse system.

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..