Michael Eissenstat

C-ATTACHED AMINOALKYLINDOLES : POTENT CANNABINOID MIMETICS

Abstract Aminoalkylindoles (AAIs) with potent cannabinoid agonist activity have been synthesized where the aminoalkyl chain is attached to the indole ring via a carbon atom of the cyclic amine.

Morpholinoalkylindenes as antinociceptive agents: Novel cannabinoid receptor agonists

Abstract Indence analogs of pravadoline exhibited antinociceptive activity in several animal models. The inhibition of prostaglandin (PG) synthesis in mouse brain microsomes was diminished in these pravadoline analogs, but they were potent in inhibiting electrically stimulated contractions in the mouse vas deferens (MVD) preparations. Binding studies with ligand WIN 55212-2 have aided to demonstrate that the morpholinoalkyl-indene binding site is functionally equivalent with cannabinoid binding site. The antinociceptive activity of the indene derivatives appears to be mediated by increased affinity for the cannabinoid receptor.

3-BENZYL-QUINOLONES: NOVEL, POTENT INHIBITORS OF MAMMALIAN TOPOISOMERASE II

Abstract Replacement of the 3-carboxy group of quinolone topoisomerase II inhibitors by hydroxy substituted benzyl groups resulted in potent topoisomerase II inhibitors. The 2,6-dihydroxybenzyl analog, Win 64593, had a topo II EC 50 of 96 nM and had potent in vitro cytotoxicity as well as murine antitumor activity.

HIV Protease as a Target for the Design of Antiviral Agents for AIDS

Publisher Summary This chapter discusses the key biological and structural features of HIV protease (HIV PR) that define its usefulness as an antiviral target. HIV proteases have proven to be valuable instructional targets for the design of mechanism- and structure-based drugs, and for providing novel strategies for designing antiviral therapeutics. The introduction of PR inhibitors to the armamentarium of AIDS drugs has had a profoundly successful impact on the AIDS community where these drugs are prolonging life and providing new hope for the long-term maintenance of relatively good health until such time as a more effective cure or vaccine becomes available. The chapter presents a brief review as well as an update on efforts to discover and design inhibitors of HIV PR inhibitors. The problem of drug resistance to HIV PR inhibitors is discussed with an emphasis on viral strategies for resistance and on implications for future drug discovery efforts in this area.

Cyanide mediated decarboxylation of 1-substituted-4-oxoquinoline and 4-oxo-1,8-naphthyridine-3-carboxylic acids

Abstract Electron deficient 3-quinolinecarboxylic acids undergo ready decarboxylation in the presence of cyanide ion. This reaction most likely requires the addition of CN − to the 2-position of the quinoline (or naphthyridine) nucleus to provide a β-keto acid intermediate that rapidly decarboxylates to give the 3-H substituted product.

Potent mammalian topoisomerase II inhibitors: 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-substituted-quinolines

A series of novel 4-substituted-1,4-dihydro-quinolines 3 were prepared and found to exhibit moderate to excellent mammalian topo II inhibitory activity. Among the compounds prepared, in general, the nitrogen analogues are the most active compounds and the sulfur analogue is the least active one.

Transfer of activation from indoles to alcohols A new method for the synthesis of aminoethylindoles

Abstract Transfer of a sulfonyl group from an indole nitrogen to a β-amino alkoxide generates an indole anion and an aminoethylsulfonate which react to give aminoethylindoles.

Relationship of structure of bridged (2,6-dimethyl-4-pyridinyl)quinolones to mammalian topoisomerase II inhibition☆

Abstract Several enantiomerically pure (2,6-dimethyl-4-pyridinyl)quinolones, previously shown to be potent inhibitors of bacterial DNA gyrase, exhibit topoisomerase II inhibitory activity. Among these and other analogues, topoisomerase II inhibitory potency was found to be a sensitive function of the size and substitution of the bridge spanning the 1- and 8-positions of the quinoline ring. The 6-fluoro group was required for activity.

A novel base-promoted oxidative rearrangement of 2-methyl-4-substituted phenols to 1,2-(methylenedioxy)-4-substituted benzenes

Abstract Several 2-methyl-4-substituted phenols 5 were oxidatively rearranged to 1,2-(methylenedioxy)-4-substituted benzenes 6 in the presence of base and air. A mechanism was proposed.