Charles J. Kelley

Time course of recovery of cytochrome p450 3A function after single doses of grapefruit juice

Components of grapefruit juice may impair the activity of intestinal cytochrome P450 (CYP) 3A enzymes, sometimes resulting in clinically important drug interactions. The time course of recovery from CYP3A inhibition after a single exposure to grapefruit juice is not clearly established.

Macamides and their synthetic analogs: evaluation of in vitro FAAH inhibition.

Maca (Lepidium meyenii), a traditional food crop of the Peruvian Andes is now widely touted as a dietary supplement. Among the various chemical constituents isolated from the plant are a unique series of non-polar, long-chain fatty acid N-benzylamides known as macamides. We have synthesized 11 of the 19 reported macamides and have tested each as potential inhibitors of the human enzyme, fatty acid amide hydrolase (FAAH). The five most potent macamides were FAAH inhibitors (IC50=10-17μM). These amides were derivatives of oleic, linoleic and linolenic acids and benzylamine or 3-methoxybenzylamine. Of the three compounds evaluated in a pre-incubation time study, two macamides were not irreversible inhibitors of FAAH. The third, a carbamate structurally related to macamides, was shown to be an irreversible inhibitor of FAAH (IC50=0.153μM).

Electronic absorption and emission spectral data and fluorescence quantum yields of bridgedp-oligophenylenes, bi- to deciphenyls, and related furans and carbazoles

Absorption and fluorescence emission spectral data, as well as fluorescence quantum yields (Φf), were determined for 41p-oligophenylene compounds containing 2–6, 8, and 10 benzene rings. Of 29 compounds containing carbon-bridged rings (fluorenes), 28 were dialkylated on each bridge for improved solubility and photostability. Absorption maxima for oligophenylenes were observed at wavelengths as long as 366 nm, emission maxima to 437 nm, and molar extinction coefficients (ɛ) as large as 153,000 L/mol-cm; all three exceeded predicted maximum values for the corresponding unbridged oligophenylenes. The substitution of furan for benzene or carbazole for a fluorene (two examples each) bathochromically shifted absorption and emission maxima. Dialkylated carbon bridges bathochromically shifted absorption and emission maxima, and lowered Φf in biphenyl and in one terphenyl analogue, but appeared to cause no diminution of Φf in higher oligophenylenes. Bis(2-methoxyethyl) substitution on the bridges, incorporated to provide solubility in polar solvents, lowered Φf in all examples. Tertiary alkyl substituents on terminal rings bathochromically shifted the absorption and emission maxima and generally increased Φf. The “loose bolt” effect, which lowers Φf in mononuclear substituted benzenes, may operate in 9,9-dialkylfluorenes, but not in 2,7-di-t-butylfluorene or in higher oligophenylenes. Cyclic ether and methoxy substituents as auxofluors on terminal rings generally bathochromically shifted absorption and emission maxima and increased ɛ and Φf. Cyano substituents bathochromically shifted absorption and emission maxima, and increased ɛ, but lowered Φf slightly.

Lenticellarine, a molluscicidal alkaloid from Dysoxylum lenticellare

Abstract A new, homoerythrina-derived alkaloid with molluscicidal activity, lenticellarine, was isolated from the leaves of Dysoxylum lenticellare and its structure was determined by spectroscopic methods.

Bridged quaterphenyls as flashlamp-pumpable laser dyes

Partial bridging of the o,o′ positions of the aromatic rings in quaterphenyl gave superior flashlamp-pumpable laser dyes. Alkyl-substituted carbon bridges gave superior dyes to those containing oxygen or alkyl-substituted nitrogen or silicon bridges. Dyes lasing in the 365–390 nm region with improved energy output, lifetime and solubility were discovered.

Cyclic Ether Auxofluors on Oligophenylene Laser Dyes

Laser dyes with terphenyl and quaterphenyl as the fluorophors and with acyclic ether auxofluors were improved when the ether groups were made cyclic. Dyes containing cyclic ethers in 5- and 6-membered rings were observed to lase in the 360–400 nm region with better lifetime and/or solubility than their acyclic analogs. In one case the laser output wavelength of a quaterphenyl fitted with cyclic ether auxofluors was red-shifted enough to match the wavelength of a sexiphenyl without auxofluors.

Unsymmetrical selenides from selenocyanates and methyl Grignard

Abstract The addition of methyl Grignard to diethyl acetamido(cyanoselenobenzyl)malonates 3 and 4 at −78° followed by hydrolysis yields the 3-(4-and 3-methylselenophenyl)alanines 1 and 2.

Synthesis of Bridged Oligophenylenes from Fluorene. Part 1. Ter- and Quater-phenyls

Alkylation and halogenation of fluorene give halogenated 9,9-dialkylfluorenes, which are converted by Pd-catalysed coupling with aryl Grignard reagents into a series of ter- and quater-phenyls exhibiting strongly efficient fluorescence, useful solubility and photochemical stability.

Ferrubietolide: X-ray crystal structure of a novel bis-diterpene from Dysoxylum Ienticellare

Spectroscopic and X-ray diffraction analyses have established the structure and stereochemistry of ferrubietolide, a new bis-diterpene isolated from Dysoxylum Ienticellare, which apparently arises as the result of a Diels–Alder condensation of two dissimilar diterpenes.

Investigating effect of water of hydration on active pharmaceutical ingredients in a water-sensitive dosage form

BackgroundPreparation of mini buccal tablets incorporating either of the Alzheimer’s drugs, rivastigmine tartrate or donepezil hydrochloride, were developed for patients who have difficulty swallowing as a source of effervescence, by pairing the less commonly used malic acid with sodium bicarbonate in an experimentally determined (1:2) stochiometirc ratio.MethodsTo avoid premature reaction of the acid and the base during compounding, the tablet ingredients were mixed in the following order: acid, sweetener, binder, drug, preservative, base, and anti-adherent/lubricant.ResultsAn accelerated thermal stability study at 40 °C and 25% relative humidity showed that the integrity of the effervescent tablets containing rivastigmine tartrate were superior to that of donepezil HCl tablets. FT-IR spectrometry confirmed the presence of water of hydrate in donepezil HCl crystals. This water was absent in the IR after one-month storage at accelerated thermal stability, but was present at room temperature. This behavior was not observed in the tablet made from rivastigmine tartrate powder. Differential scanning calorimetry of donepezil hydrochloride showed two thermal events: the first was associated with the loss of the water, and the second, at much higher temperature, was the melting of theanhydrous drug. Such behavior was not observed in the rivastigmine tartrate powder.ConclusionsHidden water which may function as catalyst to induce premature effervescence during storage.