A new series of imidazolyl nitrones spin traps has been synthesized and evaluated pharmacologically. The salient structural feature of these molecules is the presence of an imidazole moiety substituted by aromatic or heteroaromatic cycles. This connectivity imparts to the nitrone superior neuroprotective properties in vivo and in parallel reduced side effects and toxicity. Thus compound 6a (a 2-phenylimidazolyl nitrone) administered intraperitoneally protects (80%) mice from lethality induced by an intracerebroventricular administration of tert-butyl hydroperoxide (t-BHP) an oxidant capable of inducing neurodegenerative processes. Administration of the archetypal nitrone phenyl-tert-butyl nitrone (PBN) at an equimolar dose also affords some protection (60%) in this test. However, this activity is accompanied by hypothermia, whereas no such effect is apparent for 6a. Moreover, previously prepared nonsubstituted or alkyl-substituted imidazolyl nitrones were shown to be extremely toxic to rats in contrast to the compounds prepared in this study. The observed activities in vivo correlate well with the calculated partition coefficients (ClogP) and HOMO energy level.
A series of 36 purine and purine analog derivatives have been synthesized and tested for their ability to modulate multidrug resistance in vitro (P388/VCR-20 and KB-A1 cells) and in vivo (P388/VCR leukemia). Compounds were compared to S9788, a triazine derivative which has already shown some activity during phase 1 clinical trials and also a limiting cardiovascular side effect possibly linked to its calcium channel affinity. The fact that active compounds increase adriamycin accumulation in the resistant KB-A1 cells, and not in the sensitive KB-3-1 cells, suggests they act predominantly by inhibiting the P-glycoprotein-catalyzed efflux of cytotoxic agents. No direct relation was found between the affinity for the phenylalkylamine binding site of the calcium channel and in vitro sensitization of resistant cells. In vivo, when administered po in association with vincristine (0.25 mg/kg), five compounds (3, 4, 9, 25, and 26), of very differing calcium channel affinities (Ki from 5 to 560 nM), fully restored (T/V > or = 1.4) the sensitivity of P388/VCR leukemia to vincristine.
SUMMARYThe synthesis of [I4 C ] Zolpidem, a new hypnotic agent having a non-benzodiazepine structure, is described. This compound was synthesised in a 64% overall radiochemical yield from potassium ["C]cyanide and with a specific radioactivity of 56 mCi/mmol. I t was used for pharmacokinetic and drug metabolism studies.
Zolpidem is a novel hypnotic agent possessing a substituted imidazo [l, 2-g] pyridine structure. The synthesis of the tritium labelled compound with a specific activity of 6 0 . 5 Ci/mol is described. This new radioligand w a s initially used to establish and characterize the binding properties of Zolpidem in the rat brain.
Among the newer and promising weapons against cancer are Farnesyl Transferase Inhibitors (FTI). Indeed it is known that the enzyme Farnesyl Transferase (FT), catalyses the prenylation of cysteine residues of several proteins associated with cancer progression, including oncogenic forms of Ras.FTI could alter tumour progression. Exploration of our corporate structural database, based on concepts of diversity and similarity, brought forward a quinazoline-2,4-dione possessing weak farnesyl transferase inhibitory properties. A systematic modulation of structural parameters allowed the elaboration of a series of analogs out of which the most potent compound (21b) exhibited an IC(50) of 19 nM on FT, an excellent cellular activity on the oncogenic H-Ras-transfected cell line Ras #1, as well as selectivity (ratio of IC(50) on parental RAT2 cells/ IC(50) on Ras#1 cells > 2000). Moreover this compound also showed encouraging "in vivo" activity. The synthesis of these new chemical entities as well as the structure activity relationships found following pharmacological testing, is described.
A Flexible Radical Approach to 5-Substituted 4,5-Dihydro-3H-pyrido[4,3-b]azepin-2-ones. Some Mechanistic Observations on the Radical Cyclization-Aromatization Process. -A convenient two-step sequence allows the synthesis of the title compounds via radical addition of xanthates to substrate (I) followed by radical cyclization onto the pyridine ring. -(PETIT, L.; BOTEZ, I.; TIZOT, A.; ZARD*, S. Z.; Tetrahedron Lett. 53 (2012) 26, 3220-3224, http://dx.
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