Synthesis of 188 Re-labelled long chain alkyl diaminedithiol for therapy of liver cancer.

Radioisotope-labelled lipiodol has been used in the therapy of liver cancer. Recently a lipiodol solution of 188Re-labelled diaminedithiol (DD) has been reported to show a high uptake in the liver cancer. We synthesized long-chain alkyl DD derivatives to improve their uptake and retention in tissue. As the length of the alkyl chain increased, tissue uptake and retention also increased due to hydrophobic interaction with lipiodol. Among the synthesized compounds, the lipiodol solution of 188Re-HDD, the DD derivative with the longest side chain (C16), is a promising agent for therapy of liver cancer.

Simultaneous determination of loxoprofen and its diastereomeric alcohol metabolites in human plasma and urine by a simple HPLC-UV detection method.

A simple, reliable HPLC-UV detection method was developed for the simultaneous determination of loxoprofen and its metabolites (i.e. trans- and cis-alcohol metabolites), in human plasma and urine samples. The method involves the addition of a ketoprofen (internal standard) solution in methanol, zinc sulfate solution and acetonitrile to plasma and urine samples, followed by centrifugation. An aliquot of the supernatant was evaporated to dryness, and the residue reconstituted in a mobile phase (acetonitrile:water=35:65 v/v, pH 3.0). An aliquot of the solution was then directly injected into the HPLC system. Separations were performed on octadecylsilica column (250x4.5 mm, 5 microm) with a guard column (3.2x1.5 cm, 7 microm) at ambient temperature. Loxoprofen and the metabolites in the eluent were monitored at 220 nm (a.u.f.s. 0.005). Coefficients of variations (CV%) and recoveries for loxoprofen and its metabolites were below 10 and over 96%, respectively, in the 200 approximately 15000 ng ml(-1) range for plasma and 500 approximately 50000 ng ml(-1) range for urine. Calibration curves for all the compounds in the plasma and urine were linear over the above-mentioned concentration ranges with a common correlation coefficient of 0.999. The detection limit of the present method was 100 ng for all the compounds. These results indicate that the present method is very simple and readily applicable to routine bioavailability studies of these compounds with an acceptable sensitivity.

Pimarane cyclooxygenase 2 (COX-2) inhibitor and its structure-activity relationship.

The structure-activity relationship and molecular modelings of a novel pimarane COX-2 inhibitor are reported. Particularly, a series of linker extended analogues designed on the basis of these studies exhibited significantly enhanced COX-2 inhibitory activities and selectivities.

Isolation of a potent anti-MRSA sesquiterpenoid quinone from Ulmus davidiana var. japonica.

A highly potent anti-MRSA sesquiterpenoid has been isolated from Ulmus davidiana var. japonica, which has been traditionally used to treat infectious diseases in Korea. This naturally occurring antibiotic was identified as mansonone F (1). This compound has been found to be highly active specifically against MRSA and showed an MIC range of 0.39-3.13 microg/ml which is comparable to that of vancomycin.

Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances.

Capsaicin, a pungent ingredient of hot peppers, causes excitation of small sensory neurons, and thereby produces severe pain. A nonselective cation channel activated by capsaicin has been identified in sensory neurons and a cDNA encoding the channel has been cloned recently. However, an endogenous activator of the receptor has not yet been found. In this study, we show that several products of lipoxygenases directly activate the capsaicin-activated channel in isolated membrane patches of sensory neurons. Among them, 12- and 15-(S)-hydroperoxyeicosatetraenoic acids, 5- and 15-(S)-hydroxyeicosatetraenoic acids, and leukotriene B(4) possessed the highest potency. The eicosanoids also activated the cloned capsaicin receptor (VR1) expressed in HEK cells. Prostaglandins and unsaturated fatty acids failed to activate the channel. These results suggest a novel signaling mechanism underlying the pain sensory transduction.

Total synthesis of sufentanil.

Sufentanil, a potent anilidopiperidine analgesic, was synthesized from a simple thiophenylethylamine via six step sequence. The key parts of this synthesis involved an efficient construction of thiophenylethylpiperidone by aminomethano desilylation-cyclization followed by Swern oxidation and a direct regioselective N-nucleophilic spiral epoxide cleavage with aniline promoted by Lewis acids.

Total synthesis of fentanyl.

Fentanyl of a potent anilidopiperidine analgesic has been synthesized from a simple phenylethylamine by four step sequence. The key part of this synthesis involves an efficient construction of phenylethylpiperidone skeleton via aminomethano desilyltion-cyclization followed by Swern oxidation.

Selective mono-Claisen rearrangement of carbohydrate glycals. A chemical consequence of the vinylogous anomeric effect.

The mono-Claisen rearrangement of carbohydrate glycals is demonstrated to be a synthetically useful and mechanistically significant reaction. Addition of per-O-acetyl glycal-tert-butyldimethylchlorosilane mixture to lithium diisopropylamide generated a bis (or tris)ketenesilylacetal which, upon heating, underwent smooth mono-Claisen rearrangement to provide a C-glycosyl compound after methylation. A second apparently similar Claisen rearrangement required significantly higher temperatures in all cases. Thus, similar hydroxy groups were differentiated without resort to selective protection. A stereoelectronic rationale based on the newly-introduced vinylogous anomeric effect (VAE) is put forth to explain the accelerated Claisen rearrangements of these glycals. Molecular orbital and resonance descriptions of the VAE are included, and the VAE is also used to rationalize ground-state conformational preferences of carbohydrate glycals. The C-glycosyl compounds produced by mono-Claisen rearrangement were suitable for Pd(0)-catalyzed allylic alkylations, providing an unusually facile entry into the pseudomonic acid-ring systems. A nine-step synthesis of a known precursor of pseudomonic acid C is reported.