Monitoring of total type ii pyrethroid pesticides in citrus oils and water by converting to a common product 3-phenoxybenzoic acid.

Pyrethroids are a class of insecticides that are becoming increasingly popular in agricultural and home use applications. Sensitive assays for pyrethroid insecticides in complex matrices are difficult with both instrumental and immunochemical methods. Environmental analysis of the pyrethroids by immunoassay requires either knowing which pyrethroids contaminate the source or the use of nonspecific antibodies with cross-reactivities to a class of compounds. We describe an alternative method that converts the type II pyrethroids to a common chemical product, 3-phenoxybenzoic acid (3-PBA), prior to analysis. This method is much more sensitive than detecting the parent compound, and it is much easier to detect a single compound rather than an entire class of compounds. This is useful in screening for pyrethroids as a class or in situations where a single type of pyrethroid is used. We demonstrated this technique in both citrus oils and environmental water samples with conversion rates of the pyrethroid to 3-PBA that range from 45 to 75% and methods that require no extraction steps for either the immunoassay or the liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques. Limits of detection for this technique applied to orange oil are 5 nM, 2 µM, and 0.8 µM when detected by LC-MS/MS, gas chromatography-mass spectrometry, and immunoassay, respectively. The limit of detection for pyrethroids in water when detected by immunoassay was 2 nM.

Isosteric ramatroban analogs: selective and potent CRTH-2 antagonists.

The chemoattractant receptor-homologous molecule expressed on T(H)2 cells (CRTH-2), also found on eosinophils and basophils, is a prostaglandin D2 receptor involved in the recruitment of these cell types during an inflammatory response. In this report, we describe the synthesis and optimization of a ramatroban isostere that is a selective and potent antagonist of CRTH-2 which may be useful in the treatment of certain diseases.

The identification and optimization of a N-hydroxy urea series of flap endonuclease 1 inhibitors.

Flap endonuclease-1 (FEN1) is a key enzyme involved in base excision repair (BER), a primary pathway utilized by mammalian cells to repair DNA damage. Sensitization to DNA damaging agents is a potential method for the improvement of the therapeutic window of traditional chemotherapeutics. In this paper, we describe the identification and SAR of a series of low nanomolar FEN1 inhibitors. Over 1000-fold specificity was achieved against a related endonuclease, xeroderma pigmentosum G (XPG). Two compounds from this series significantly potentiate the action of methyl methanesulfonate (MMS) and temozolamide in a bladder cancer cell line (T24). To our knowledge, these are the most potent endonuclease inhibitors reported to date.

A versatile prodrug approach for liposomal core-loading of water-insoluble camptothecin anticancer drugs.

We describe a versatile prodrug strategy for loading the liposomal lumen with water-insoluble camptothecins. The procedure involves conversion of an active camptothecin analogue to a 20-OR omega-aminoalkanoanic ester prodrug in which R = CO[CH(2)](n)()NH(2) and n = 1-3. The basic amino group of the prodrug serves three roles. First, at pH ranges of 3-5, the amine enhances aqueous solubility. Second, it enhances responsiveness to a transmembrane ammonium sulfate gradient across the liposomal bilayer, thereby facilitating active loading of the agent into the liposomal aqueous core. Third, at a physiological pH of 7 or above (the pH to be encountered following drug release at the tumor site), the nucleophilicity of the amine manifests itself and cyclization to the C-21 carbonyl carbon occurs. This cyclization triggers a rapid and convenient nonenzymatic decomposition process that releases active camptothecin. Accordingly, this novel liposomal approach offers a potential system for tumor-targeting prodrugs of many water-insoluble camptothecins, including the highly lipophilic and clinically attractive analogues SN-38, 9-nitrocamptothecin and DB-67. The rate of formation of the active agent at the tumor site can be controlled through the selection of n (the length of the alkyl spacer group).