Polycyclic Cage Compounds Research Articles

Calcium Modulating Effect of Polycyclic Cages: A Suitable Therapeutic Approach Against Excitotoxic-induced Neurodegeneration.

Neurodegenerative disorders pose a significant challenge to global healthcare systems due to their progressive nature and the resulting loss of neuronal cells and functions. Excitotoxicity, characterized by calcium overload, plays a critical role in the pathophysiology of these disorders. In this review article, we explore the involvement of calcium dysregulation in neurodegeneration and neurodegenerative disorders. A promising therapeutic strategy to counter calcium dysregulation involves the use of calcium modulators, particularly polycyclic cage compounds. These compounds, structurally related to amantadine and memantine, exhibit neuroprotective properties by attenuating calcium influx into neuronal cells. Notably, the pentacycloundecylamine NGP1-01, a cage-like structure, has shown efficacy in inhibiting both N-methyl-D-aspartate (NMDA) receptors and voltage- gated calcium channels (VGCCs), making it a potential candidate for neuroprotection against excitotoxic-induced neurodegenerative disorders. The structure-activity relationship of polycyclic cage compounds is discussed in detail, highlighting their calcium-inhibitory activities. Various closed, open, and rearranged cage compounds have demonstrated inhibitory effects on calcium influx through NMDA receptors and VGCCs. Additionally, these compounds have exhibited neuroprotective properties, including free radical scavenging, attenuation of neurotoxicities, and reduction of neuroinflammation. Although the calcium modulatory activities of polycyclic cage compounds have been extensively studied, apart from amantadine and memantine, none have undergone clinical trials. Further in vitro and in vivo studies and subsequent clinical trials are required to establish the efficacy and safety of these compounds. The development of polycyclic cages as potential multifunctional agents for treating complex neurodegenerative diseases holds great promise.

1,3-Bishomocubane: a kinetic rock, a thermodynamic powerhouse and a compelling chiral synthetic scaffold.

Over the last several decades, saturated polycyclic cage compounds have remained a point of interest for organic chemists because of their unique characteristics and reactivity. For the first time, a detailed analysis of the synthesis, properties and transformations of 1,3-bishomocubanes, which fall under the rare category of chiral cage compounds, is provided in this article. This review which also includes the authors' work in this area over the last decade is expected to serve as a valuable resource for chemists interested in the fascinating chemistry and properties of polycyclic cage compounds.

Diels-Alder reactions between cyclopentadiene analogs and benzoquinone in water and their application in the synthesis of polycyclic cage compounds.

Diels–Alder reactions between cyclopentadiene analogs and p-benzoquinone were explored in water and yielded 83–97% product, higher than the results reported in water with a catalyst or cetrimonium bromide (CTAB) micelles. The novel adduct 10 was synthesized and further used to synthesize the bi-cage hydrocarbon 4,4′-spirobi[pentacyclo[5.4.0.02,6.03,10.05,9]undecane], which has a high density (1.2663 g cm−3) and a high volumetric heat of combustion (53.353 MJ L−1). Four novel bi-cage hydrocarbon compounds were synthesized in water using this method starting from 2,2′-bi(p-benzoquinone) and cyclopentadiene analogs.

Synthesis and Biological Evaluations of NO-Donating Oxa- and Aza-Pentacycloundecane Derivatives as Potential Neuroprotective Candidates.

In order to utilize the neuroprotective properties of polycyclic cage compounds, and explore the NO-donating ability of nitrophenyl groups, an array of compounds was synthesized where the different nitrophenyl groups were appended on oxa and aza-bridged cage derivatives. Biological evaluations of the compounds were done for cytotoxicity, neuroprotective abilities, the inhibition of N-methyl-d-aspartate (NMDA)-mediated Ca2+ influx, the inhibition of voltage-mediated Ca2+ influx, and S-nitrosylation abilities. All of the compounds showed low toxicity. With a few exceptions, most of the compounds displayed good neuroprotection and showed inhibitory activity for NMDA-mediated and voltage-gated calcium influx, ranging from high (>70%) to low (20–39%) inhibition. In the S-nitrosylation assay, the compounds with the nitro moiety as the NO-donating group exhibited low to good nitrosylation potency compared to the positive controls. From the biological evaluation of the tested compounds, it was not possible to obtain a simple correlation that could explain the results across all of the biological study domains. This can be ascribed to the independent processes evaluated in the different assays, which reiterate that neuroprotection is a result of multifactorial biochemical mechanisms and interactions. However, these results signify the important aspects of the pentacylcoundecylamine neuroprotectants across different biological study realms.

Theoretical studies on the propulsive and explosive performance of strained polycyclic cage compounds

Carbon-based cage compounds could be better candidates as propellant ingredients than the currently used ones as per molecular modellingab initiocalculations.

Synthesis of gem-difluoromethylenated polycyclic cage compounds.

The synthesis of gem-difluoromethylenated polycyclic cage compounds, utilizing PhSCF2SiMe3 as a gem-difluoromethylene building block, is described. The fluoride-catalyzed nucleophilic addition of PhSCF2SiMe3 to both maleic anhydride-cyclopentadiene and maleic anhydride-cyclohexadiene adducts was accomplished with high stereoselectivity to provide the corresponding adducts that were treated with Grignard reagents, followed by acid-catalyzed lactonization to afford the corresponding γ-butyrolactones, each as a single isomer. These γ-butyrolactones underwent intramolecular radical cyclization to give the corresponding tetracyclic cage γ-butyrolactones, which were employed as precursors for the synthesis of gem-difluoromethylenated tetracyclic cage lactols or tetracyclic cage furans, upon treatment with Grignard reagents.

Rationally Designed Multi-Targeted Agents Against Neurodegenerative Diseases

Neurodegenerative diseases are complex disorders with several pathoetiological pathways leading to cell death. Rationally designed multi-targeted agents, or "multi-targeted designed drugs" (MTDD) show significant promise in preclinical studies as neuroprotective and disease-modifying agents. In this review, we highlight the use of chemical scaffolds that lend themselves exquisitely to the development of MTDDs in neurodegeneration. Notably, synthetic polycyclic cage compounds have served as scaffolds for novel voltage-gated calcium channel blockers, NMDA receptor antagonists, and sigma-receptor ligands - attractive targets in neurodegeneration. In an entirely different approach, compounds containing the thiazolidinedione moiety (referred to as glitazones) alter mitochondrial function through the mitochondrial protein mitoNEET, an attractive new drug target for the treatment of neurodegenerative diseases. The design strategy for yet another agent, ladostigil, employed the amalgamation of active chemical moieties of the AChE inhibitor rivastigmine, and the monoamine oxidase-B (MAO-B) inhibitor rasagiline, leading to a single compound that targets both enzymes simultaneously. Natural products have also served as design templates for several MTDD design studies. In particular, the stilbene scaffold has become popular in particular due to the neuroprotective effects of the non-flavonoid natural product resveratrol. Recently, stilbene scaffold-based compounds were developed to reduce - through chelation with metal ions that interact with beta-amyloid - both metal-induced beta-amyloid protein aggregation, and ROS generated from this aggregate. Other subtle modifications of the stilbene motif led to the creation of reversible, non-competitive MAO inhibitors. Finally, compounds derived from the xanthine scaffold afford neuroprotection in Parkinson's disease through mechanisms that include dual adenosine A2A receptor antagonism and MAO-B inhibition.

ChemInform Abstract: Polycyclic Cage Structures as Lipophilic Scaffolds for Neuroactive Drugs

AbstractReview: 107 refs.

Polycyclic Cage Structures as Lipophilic Scaffolds for Neuroactive Drugs

Polycyclic cage scaffolds have been successfully used in the development of numerous lead compounds demonstrating activity in the central nervous system (CNS). Several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, and stroke, as well as drug abuse, can be modulated with polycyclic cage derivatives. These cage moieties, including adamantane and pentacycloundecane derivatives, improve the pharmacokinetic and pharmacodynamic properties of conjugated parent drugs and serve as an important scaffold in the design of therapeutically active agents for the treatment of neurological disorders. In this Minireview, we focus on the recent developments in the field of polycyclic cage compounds, as well as the relationship between the lipophilic character of these cage-derived drugs and the ability of such compounds to target and reach the CNS and improve the pharmacodynamic properties of compounds conjugated to it.

GIAO chemical shifts calculations of some polycyclic cage compounds: Unambiguous assignment of NMR signals and stereoisomers

Abstract GIAO model at DFT/B3LYP level of theory using the cc-pVTZ basis set was employed for calculations of 1H and 13C NMR chemical shifts (δ) for various rigid polycyclic compounds. The data obtained were used as an auxiliary tool to an unequivocal assignment of all 1H and 13C NMR signals and the endo/exo stereochemistry of the strained compounds studied. For these compounds the theoretical model adopted was sufficient to obtain a good description of chemical shifts.

ChemInform Abstract: Polycyclic Cage Compounds as Intermediates in Organic Chemistry

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

4,10-Diformyl-2,6,8,12-tetra-nitro-2,4,6,8,10,12-hexa-azatetra-cyclo-[5.5.0.0.0]dodeca-ne.

The title compound TNDFIW, C8H8N10O10, is a caged heterocycle substituted with four nitro and two formyl groups. It is related to the hexa­azaisowurtzitane family of high-density high-energy polycyclic cage compounds. Four nitro groups are appended to the four N atoms of the two five-membered rings, while the other two formyl groups are attached to the two N atoms of the six-membered ring, which adopts a boat conformation. The compound has a cage structure which is constructed from one six-membered and two five-membered rings which are closed by a C—C bond, thus creating two seven-membered rings. There are a number of close intermolecular contacts [O⋯O = 2.827 (5), 2.853 (4) and 2.891 (5) Å; O⋯N = 2.746 (2) and 2.895 (2) Å] The calculated density of TNDFIW is 1.891 Mg m−3.

10-Formyl-2,4,6,8,12-pentanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.03,11.05,9]dodecane

The title compound, C7H7N11O11 (PNMFIW), is a caged heterocycle substituted with five nitro and one formyl groups. It is related to the hexa­azaisowurtzitane family of high-density high-energy polycyclic cage compounds. Four nitro groups are appended to the four N atoms of the two five-membered rings, while a nitro group and a formyl are attached to the two N atoms of the six-membered ring.

Medicinal chemistry of polycyclic cage compounds in drug discovery research

Saturated polycyclic hydrocarbon structures such as the monocyclic octane, bicylic norbornane and tricyclic adamantane have attracted the attention of several research groups since the 1930s. In the 1950s the synthesis of the so called bird-cage pentacyclo[5.4.0.02,6.03,10.05,9]undecane-8,11-dione, also known as Cookson’s diketone was reported. This pentacyclic cage diketone is the product of the intramolecular photocyclized Diels Alder adduct of p-bensoquinone and cyclopentadiene. The conversion of this diketone to its monoketone analog formed the basis of a variety of monosubstituted derivatives. Furthermore, acid-based rearrangement reactions of hydroxyl-substituted compounds led to, amongst others, the unique D3-trishomocubane symmetrical compounds, which consists of only five-membered carbon rings. The D3 stereoisomerism of the trishomobubane affords unique chemical challenges with potential medicinal implications. The medicinal chemistry of these cage compounds gained momentum in the 1980s with the discovery of the calcium-channel-modulating effects and antiviral activity thereof. The 1990s and 2000s saw several reports on a variety of pharmacological areas, i.e., dopaminergic, catecholaminergic, and focusing on disorders, in particular that of the central nervous system, such as neurodegeneration (Parkinson’s disease). These polycyclic structures have proved to be very useful in drug discovery research, in particular during the past 25 years.

Formation of novel polycyclic cage compounds through ‘uncaging’ of readily accessible higher cage compounds

The synthesis of the novel cage compounds 7-halomethyl-8-(carbomethoxy)tetracyclo[4.2.1.1 4,7.0 2,5]deca-3-(11)-ene-10-ones, methyl-4-methylene-6-oxopentacyclo[5.4.0.0. 2,5.0 3,10.0 7,9]undecane-9-carboxylate, 3-chloromethyl-4-(carbomethoxy)tetracyclo[4.2.1.1. 3,8.0 2,5]deca-7(11)ene-10-one, 2-bromo-5-methyl-8-methylene-6-oxotricyclo[5.3.0.0 3,9]decane-4-carboxylic acid and 2-bromo-5-methyl-8-methylene-6-oxotricyclo[5.3.0.0 3,9]decane-4-methyl carboxylate, achieved through base catalyzed rearrangement, is described.

Pharmacology and Structure—Activity Relationships of Bioactive Polycyclic Cage Compounds: A Focus on Pentacycloundecane Derivatives

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Pharmacology and structure-activity relationships of bioactive polycyclic cage compounds: a focus on pentacycloundecane derivatives.

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.

2,4,6,8,10,12-Hexabenzyl-5-(nitromethylene)-2,4,6,8,10,12-hexaazatricyclo[7.3.0.03,7]dodecane

The title compound, C49H49N7O2, is a crowded tricyclic heterocycle substituted with six benzyl groups. It is related to the hexa­aza­isowurtzitane family of high-density, high-energy polycyclic cage compounds. The central six-membered ring adopts a boat conformation which minimizes the steric repulsion of the six benzyl substituents. The nitro­methyl­ene substituent on the methyl­ene C atom of one of the five-membered rings has a considerable influence on the metric parameters of that ring. From the bond distances in the nitro group and the five-membered ring it appears that the mol­ecule is zwitterionic, rather than neutral, in the vicinity of the nitro group.

Synthesis of a Substituted Bi[cyclohepta-3,5(3′,5′)-dienyl]: A Possible Building Block for Domino Diels−Alder Reactions

A versatile 13-step synthesis of 1,1′-dimethoxy-4,4′,5,5′-tetrakis(trimethylsilyloxy)bicyclohepta-3,3′,5,5′-dienyl (11) is described. 11 represents a potential building block for the construction of polycyclic cage compounds through domino Diels−Alder and pincer reactions.

Formation of novel cage compounds via photoreaction of [3.3.3](1,3,5)cyclophane

Photoirradiation of [3 3](1,3,5)cyclophane 11 with a low pressure Hg lamp in CH 2Cl 2 in the presence or absence of water afforded new polycyclic cage compounds of chlorinated tribridged hexacyclododecane 12 or its hydroxy analogue 14 and tribridged tetracyclic olefin 13.