ABSTRACT
The chemistry of organic polycyclic cage compounds has intrigued medicinal chemists for over 50 years, yet little is published about their pharmacological profiles. Polycyclic cage compounds have important pharmaceutical applications, ranging from the symptomatic and proposed curative treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's disease (e.g., amantadine and memantine), to use as anti-viral agents against influenza and the immunodeficiency virus (HIV). The polycyclic cage appears to be a useful scaffold to yield drugs with a wide scope of applications, and can be used also to modify and improve the pharmacokinetic and pharmacodynamic properties of drugs in current use. This review attempts to summarize the pharmacological profiles of polycyclic cage compounds with an emphasis on the lesser known pentacycloundecanes, homocubanes, and trishomocubanes.
Subject(s)
Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/pharmacology , HIV/drug effects , Models, Molecular , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Orthomyxoviridae/drug effects , Structure-Activity RelationshipABSTRACT
Electrospray ionization mass spectrometry (ESI-MS) is used to evaluate the metal binding selectivities of an array of novel caged macrocycles for silver, gold, copper, nickel, zinc, iron, lead, manganese and alkali metal ions. It is found that five of the new compounds display silver selectivity, and their relative affinities for various metals depend on the type, number, and arrangement of heteroatoms (N, O), the cavity size, and the presence of aromatic substituents. Alkali metal cation binding studies are used to evaluate the size-selectivities of the cavities of the macrocycles. Electronic structure calculation by B3LYP density function theory methods were used to model the metal complexes. The presence of nitrogen atoms in the macrocyclic ring is essential for silver selectivity over other transition metals and alkali metal ions, and the presence of aromatic groups also enhances silver avidity. Macrocycle 3, a triaza-18-crown-6 analog modified with two phenyl groups and a cage group, is capable of selective extraction of Ag+ from aqueous solutions in the presence of other transition metal ions and the most common alkali and alkaline earth metal ions.
Subject(s)
Environmental Pollutants/analysis , Silver/analysis , Crown Ethers , Ion-Selective Electrodes , Metals, Alkali/analysis , Metals, Heavy/analysis , Spectrometry, Mass, Electrospray Ionization/methodsABSTRACT
In the present study, electrospray ionization mass spectrometry is used to evaluate the metal-binding selectivities of an array of novel caged macrocycles for mercury(II), lead(II), cadmium(II), and zinc(II) ions. In homogeneous methanol/chloroform solutions as well as extractions of metals from aqueous solution by macrocycles in chloroform, it is found that the type of heteroatom (S, O, N), cavity size, and presence of other substituents influence the metal selectivities. Several of the macrocycles in this study bind mercury ion very selectively and efficiently in the presence of many other metal ions and have an avidity toward mercury that was tunable by the size and combination of heteroatoms in the macrocycle ring and the number of cage groups attached. The extraction mechanism was further investigated by determining the variation in extraction selectivity as a function of the counterions of the mercury salts.
Subject(s)
Ethers, Cyclic/chemistry , Metals, Heavy/isolation & purification , Organometallic Compounds/analysis , Spectrometry, Mass, Electrospray Ionization/methods , Cadmium/chemistry , Cadmium/isolation & purification , Environmental Pollutants/isolation & purification , Ethers, Cyclic/analysis , Lead/chemistry , Lead/isolation & purification , Mercury/chemistry , Mercury/isolation & purification , Metals, Heavy/chemistry , Organometallic Compounds/chemistry , Zinc/chemistry , Zinc/isolation & purificationABSTRACT
pi-Facial diastereoselectivities in Diels-Alder reactions that involve pi-facially differentiated cyclohexa-1,3-dienes, i.e., 3-substituted or 3-10-disubstituted hexacyclo-[10.2.1.0.(2,11)0.(4,9)0.(4,14)0(9,13)]pentadeca-5,7-dienes have been investigated. Two types of reactions have been examined experimentally and theoretically: (i) reactions of cage-annulated, pi-facially differentiated cyclohexa-1,3-dienes with pi-facially symmetric dienophiles and (ii) reactions of pi-facially symmetric dienes with cage-annulated, pi-facially differentiated dienophiles.
ABSTRACT
Reaction of N-(ethoxycarbonyl)-3-(bromomethyl)-3-chloroazetidine (3) with DBU results in the formation of two haloalkenes, i.e., N-(ethoxycarbonyl)-3-(bromomethylene)azetidine and N-(ethoxycarbonyl)-3-(chloromethylene)azetidine (4a and 4b, respectively). The results of control experiments suggest that Cl(-) is capable of promoting nucleophilic displacement of bromine in the CH(2)Br groups of both 3 and N-(ethoxycarbonyl)-3-bromo-3-(bromomethyl)azetidine (8), but Br(-) is incapable of displacing chlorine in the CH(2)Cl groups of both N-(ethoxycarbonyl)-3-chloro-3-(chloromethyl)azetidine (7) and N-carbethoxy-3-bromo-3-(chloromethyl)azetidine (10). Thus, it is suggested that the formation of 4b via reaction of 3 with DBU is a result of DBU-promoted elimination of HCl from 7, a key reaction intermediate. The observations reported herein can be explained without invoking the intermediacy of any bridged halonium ion.
