Efficient Pathway for the Preparation of Aryl(isoquinoline)iodonium(III) Salts and Synthesis of Radiofluorinated Isoquinolines.

Iodonium compounds play a pivotal role in (18) F-fluorination of radiopharmaceuticals containing non-activated arenes. However, preparation of these species is limited to oxidation conditions or exchange with organometallics that are prepared from aryl halides. Herein we describe a novel "one-pot" process to assemble aryl(isoquinoline)iodonium salts in 40-94 % yields from mesoionic carbene silver complex and Aryl-I-Py2 (OTf)2 . The method is general, practical, and compatible with well-functionalized molecules as well as useful for the preparation of a wide range of (18) F-labeled isoquinolines resulting in up to 92 % radiochemical conversion. As proof of concept, a fluorinated isoquinoline alkaloid, (18) F-aspergillitine is prepared in 10 % isolated radiochemical yield from the corresponding phenyl(aspergillitine)iodonium salt.

An Efficient and Facile Method for the Synthesis of Benzimidazoisoquinoline Derivatives via a Multicomponent Reaction.

Two series of benzimidazoisoquinoline and fused benzimidazoisoquinoline-benzimidazole derivatives have been synthesized using an efficient one-pot procedure. This process involves an intramolecular nucleophilic substitution reaction and provides facile access to two series of complexes and potentially interesting biologically active scaffolds.

Modification of 3-arylisoquinolines into 3,4-diarylisoquinolines and assessment of their cytotoxicity and topoisomerase inhibition.

Inspired by the initial success of the monoarylisoquinolines and the quest to identify more potent and selective anticancer agents with topoisomerase (topo) inhibitory activity, series of diarylisoquinolines (3,4-diarylisoquinolones and 3,4-diarylisoquinolinamines) were designed and synthesized. Synthesis of these compounds primarily involved lithiated toluamide-benzonitrile cycloaddition, Suzuki coupling, and nucleophilic aromatic substitution reactions. Eight of the derivatives were selectively toxic against human ductal breast epithelial tumor cells (T47D), human prostate cancer cells (DU145), and human colorectal adenocarcinoma cells (HCT-15), but had no effect on normal human breast epithelial cells (MCF10A). The topo inhibitory activities of the diarylisoquinoline compounds were relatively dependent upon their chemical structure. 3,4-Diarylisoquinolones generally did not inhibit topo I and only showed moderate inhibition of topo II. In contrast, several 3,4-diarylisoquinolinamines showed superior topo I inhibitory activity. Isoquinolinamine derivatives had greater affinity for topo I than for topo II. Topo inhibition by 3,4-diarylisoquinolines was further supported by docking models showing intercalative and/or H-bond interactions between these compounds and the DNA/topo(s). An analysis of the correlation between the cytotoxicity and topo inhibition of these compounds indicated that the primary biological target of derivatives with potent cytotoxicity was topo, which in turn establishes diaryl-substituted isoquinolines as a novel class of potential anticancer drugs.

Rapid two-step synthesis of benzimidazo[1',2':1,5]pyrrolo[2,3-c]isoquinolines by a three-component coupling reaction.

A two-step, three-component coupling reaction on ionic liquid supported 2-cyanomethylbenzimidazoles, methyl 2-formylbenzoate, and isocyanides under microwave activation is explored. Knoevenagel condensation of 2-cyanomethylbenzimidazole with methyl-2-formylbenzoate in the presence of piperidine catalyst is followed by [4+1] cycloaddition with an isocyanide in the next step. Consequent intramolecular δ-lactam formation allows rapid construction of novel aza-pentacycles, benzimidazo[1',2':1,5]pyrrolo[2,3-c]isoquinolines.

A simple and effective approach to the synthesis of isoquinoline derivatives under solvent-free conditions.

An efficient synthesis of dialkyl pyrrolo[2,1-a]isoquinoline-2,3-dicarboxylates, pyrrolo[1,2-a]quinoline-1,2- dicarboxylates and indolizines is described via one-pot reactions of isoquinoline, quinoline or pyridine and phenacyl bromids with dialkyl acetylenedicarboxylates or diaryloylacetylene under solvent-free conditions at 50°C. The mild reaction conditions and high yields of the products exhibit the good synthetic advantage of these methods.

Assessment of the intraocular pressure-lowering activity of bicyclic derivatives of 1-substituted benzyloctahydroisoquinoline.

In our study of IOP-lowering agents, we have synthesized several bicyclic analogs of 1-benzyloctahydroisoquinoline. The target molecules were synthesized in an eleven-step process. Structures were proved through spectrometry, elemental analysis and, in selected cases, high resolution mass spectrometry. The final products were secondary or tertiary amines containing a 1-benzyl moiety substituted at the p-position with a methoxy, methyl or chloro group. All target molecules were analyzed in 1% solution in distilled water in normotensive rabbits. After topical administration, IOP was monitored in both eyes for up to seven hours. The 1-p-methoxybenzyl molecule 2 was the most active, and caused a maximal IOP drop of 8.8 +/- 1.9 (n = 7) mm Hg in the ipsilateral eye at 4 hours post-administration, with only partial recovery at seven hours. All other compounds tested either showed very weak activity (3-6) or were inactive (1). All compounds produced a contralateral effect, and 5 induced rebound ocular hypertension. We conclude that selected tertiary bicyclic 1-p-methoxybenzyl-octahydroisoquinolines, particularly N-methylated structures, exhibit a significant IOP-lowering effect in normotensive rabbits.

Assessment of substitution in the second pharmacophore of Dmt-Tic analogues.

The Dmt-Tic pharmacophore exhibits potent delta-opioid receptor antagonism. Analogues with substitutions in the second pharmacophore with (1, 1') or without a COOH function (2-9) were synthesized: several had high delta affinity (1', 2, 7, and 9), but exhibited low to non-selectivity toward mu receptors similar to H-Dmt-Tic-amide and H-Dmt-Tic-ol. Functional bioactivity indicated high delta antagonism (pA2 7.4-7.9) (1', 2, and 9) and modest mu agonism, pEC50 (6.1-6.3) (1', 2, 8, and 9), but with Emax values analogous to dermorphin. These Dmt-Tic analogues with mixed delta antagonist/mu agonist properties would appear to be better candidates as analgesics than pure mu agonists.

Assessment of the in vivo and in vitro opioid activity of bridged hexahydroaporphine and isoquinoline molecules.

Four novel racemic bridged hexahydroaporphine (1 and 2) and isoquinoline (3 and 4) analogues have been synthesized in an attempt to generate bicyclic derivatives of the morphinan ring system. The opioid activity of these analogues has been assessed through membrane-binding studies, in vitro studies in isolated guinea pig ileum and mouse vas deferens, and in vivo studies utilizing the mouse hot plate technique. The bridged isoquinoline precursor molecules were inactive as antinociceptives. Both the racemic phenolic hexahydroaporphine 1 and its 10-methoxy congener 2 demonstrated dose-dependent, albeit weak, antinociceptive activity when administered icv, but they induced lethal convulsions when given subcutaneously. The antinociception elicited by 1 appeared to show very weak opioid character while that caused by 2 was totally nonopioid.