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The Suzuki-Miyaura cross-coupling reaction provides a useful method for the synthesis of methyl 2-(2-chloropyridyl or 2-methoxypyridyl)phenylacetates. The 2-chloropyridyl or 2-methoxypyridyl ring system can be readily elaborated to N-substituted (OH, Me, CH[F.sub.2], H) 1,2-dihydropyrid-2-one ring systems that are useful synthons for use in bioorganic and medicinal chemistry applications. Key words: Suzuki-Miyaura cross-coupling reaction, 1,2-dihydropyrid-2-ones, cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibition. La reaction de couplage croise de Suzuki-Miyaura est une methode utile pour la synthese d'esters 2-(2-chloropyridyl)- ou de 2-(methoxypyridyl)phenylacetates. Ce systeme cyclique, portant des groupes 2-chloropyridyle ou 2-methoxypyridyle, peut facilement etre transforme en systemes cycliques a base de 1,2-dihydropyrid-2-one N-substituee (OH, Me, CH[F.sub.2], H), des synthons utiles dans des applications de chimie bioorganique ou medicinale. Mots-cles : reaction de couplage croise de Suzuki-Miyaura, 1,2-dihydropyrid-2-ones, inhibition de la cycclooxygenase (COX) et de la 5-lipoxygenase (5-LOX)., Introduction Biotransformation of arachidonic acid gives rise to prostaglandin and leukotriene inflammatory mediators that are produced via their respective cyclooxygenase (COX) and lipoxygenase (LOX) pathways. (1) Dual inhibition of the [...]

Prolongation of the QT interval has been observed during treatment with olanzapine, a thienobenzodiazepine antipsychotic agent. Our objectives were 1) to characterize the effects of olanzapine on cardiac repolarization and 2) to evaluate effects of olanzapine on the major time-dependent outward potassium current involved in cardiac repolarization, namely [I.sub.Kr] ([I.sub.Kr]: rapid component of the delayed rectifier potassium current). Isolated, buffer-perfused guinea pig hearts (n = 40) were stimulated at different pacing cycle lengths (150-250 msec) and exposed to olanzapine at concentrations ranging from 1 to 100 µM. Olanzapine increased monophasic action potential duration measured at 90% repolarization (MAP[D.sub.90]) in a concentration-dependent manner by 6.7 ± 0.7 msec at 3µM but by 26.0 ± 4.3 msec at 100 µM (250 msec cycle length). Increase in MAP[D.sub.90] was also reverse frequency dependent; 30 µM olanzapine increased MAP[D.sub.90] by 28.0 ± 6.2 msec at a pacing cycle length of 250 msec but by only 18.9 ± 2.2 msec at a pacing cycle length of 150 msec. Experiments in HERG-transfected (HERG: human ether-a-gogo-related gene) HEK293 cells (n = 36) demonstrated concentration-dependent block of the rapid component ([I.sub.Kr]) of the delayed rectifier potassium current: tail current was decreased 50% at olanzapine 3.8µM. Olanzapine possesses direct cardiac electrophysiological effects similar to those of class III anti-arrhythmic drugs. These effects were observed at concentrations that can be measured in patients under conditions of impaired drug elimination such as renal or hepatic insufficiency, during co-administration of other CYP1A2 substrates/inhibitors or after drug overdose. These results offer a new potential explanation for QT prolonging effects observed during olanzapine treatment in patients. Keywords antipsychotics, drug-induced long QT syndrome, potassium channel, torsades de pointes, arrhythmia, Introduction Olanzapine is an atypical antipsychotic of the thienobenzodiazepine class that shows high affinity for the serotonin 5-H[T.sub.2A/C] receptor. Although structurally and functionally related to clozapine, it possesses a more [...]

A group of 4-[l-(2-deoxy-[beta]-D-ribofuranosyl)]-derivatives of 5-fluoroaniline possessing a variety of aryl C-2 substituents (6a R = H, 6b R = F, 6c R = Me) were synthesized. Accordingly, a Heck-type coupling reaction of the .4-iodoaniline derivatives (13a--c) with the bis(tert-butyldimethylsilyl)glycal (11) in the presence of Pd[(OAc).sub.2] and P[h.sub.3]As, followed by removal of the tert-betyldimethylsilyl protection groups using n-B[u.sub.4][N.sup.+] [F.sup.-], yielded the corresponding 4-([beta]-D-glycero-pentofuran-3-ulos-1-yl) aniline derivatives (14a-c) having a C-3 C=O in the sugar ring. Reduction of the C-3 C=O compounds (14a-c) using NaB[(OAc).sub.3]H afforded the target 4-[l-(2-deoxy-[beta]-D-ribofuranosyl)]-derivatives of the respective 2-substituted-5-fluoroaniline (6a-c). The deoxycytidine mimic, 3-fluoro-4-[1-(2-deoxy-[beta]-D-ribofuranosyl)]aniline (6a), in which the cytosine ring of deoxycytidine is replaced by a 4-(3-fluoroaniline) ring system, was inactive as an anticancer agent against a variety of tumor cell lines, and as an antihuman immunodeficiency virus (HIV-l, HIV-2) agent. The failure of this unnatural deoxycytidine mimic (6a) to exhibit anticancer-antiviral activity may be due to its inability to undergo phosphorylation by host cell- and virus-induced kinases. Key words: fluoroanilines, deoxycytidine mimics, anticancer-antihuman immunodeficiency virus (HIV) evaluation.

L-thymidine (L-TdR) a substrate for herpes simplex virus type 1 thymidine kinase (HSV-1 TK), reduces HSV-1 multiplication in HeLa cells. HSV-1 TK phosphorylates the L and D enantiomers of TdR to their corresponding monophosphates (MPs) with identical efficacy.