Synthesis and Biological Evaluation of Pentacycloundecylamines and Triquinylamines as Voltage‐Gated Calcium Channel Blockers

Abstract

Preclinical studies for neurodegenerative diseases have shown a multi-targeted approach to be successful in the treatment of these complex disorders with several pathoetiological pathways. Polycyclic compounds, such as NGP1-01 (7a), have demonstrated the ability to target multiple mechanisms of the complex etiology and are referred to as multifunctional compounds. These compounds have served as scaffolds with the ability to attenuate Ca2+ overload and excitotoxicity through several pathways. In this study, our focus was on mitigating Ca2+ overload through the L-type calcium channels (LTCC). Here, we report the synthesis and biological evaluation of several novel polycyclic compounds. We determined the IC50 values for both the pentacycloundecylamines and the triquinylamines by means of a high-throughput fluorescence calcium flux assay utilizing Fura-2/AM. The potential of these compounds to offer protection against hydrogen peroxide-induced cell death was also evaluated. Overall, 8-benzylamino-8,11-oxapentacyclo[5.4.0.02,6.03,10.05,9]undecane (NGP1-01, 7a) had the most favorable pharmacological profile with an IC50 value of 86 μM for LTCC inhibition and significant reduction of hydrogen peroxide-induced cell death. In general, the triquinylamines were more active as LTCC blockers than the oxa-pentacycloundecylamines. The aza-pentacycloundecylamines were potent LTCC inhibitors, with 8-hydroxy-N-phenylethyl-8,11-azapentacyclo[5.4.0.02,6.03,10.05,9]undecane (8b) also able to offer significant protection in the cell viability assays.

Triple-Dearomative Photocycloaddition: A Strategy to Construct Caged Molecular Frameworks

“…Polycyclic caged compounds have been widely used in medicinal chemistry, 9−17 and their intriguing structures often present challenges from a synthetic chemistry standpoint 10,13,14,16,18,19 (Figure 3B). For example, cubane 8 is a monoamine oxidase B (MAO-B) inhibitor 20 and requires a 15step synthesis; 10 NGP1−01 9 14 is a pentacycloundecane derivative with broad bioactivity [9][10][11][12][13]15,16,18 and requires a five-step synthesis; tromantadine 10 21 is an adamantane derivative with antiviral activity and is synthesized in five steps.…”

“…Polycyclic caged compounds have been widely used in medicinal chemistry, − and their intriguing structures often present challenges from a synthetic chemistry standpoint ,,,,, (Figure B). For example, cubane 8 is a monoamine oxidase B (MAO-B) inhibitor and requires a 15-step synthesis; NGP1–01 9 is a pentacycloundecane derivative with broad bioactivity − ,,, and requires a five-step synthesis; tromantadine 10 is an adamantane derivative with antiviral activity and is synthesized in five steps. In comparison, caged compound 6 bearing the 2H -benzo-dioxo-pentacycloundecane (BDPC) moiety is synthesized in a one-step process from a chromone ester substrate and was found to be the only product in the reaction (Figure A).…”

Synthetic Entry to the 2-Azatricyclo[4.3.2.04,9]undecane Ring System via Tropone

“…The development of methods for synthesizing such ring systems has attracted attention due to their presence, perhaps most notably, in the tropane skeleton, as well as in a number of monoterpenoid indole alkaloids, Lycopodium alkaloids, and Daphniphyllum alkaloids . Representative examples of biologically active alkaloids from these classes are shown in Figure ( 1 – 3 ), all of which have garnered significant interest from the synthetic community. − Moreover, a number of non-natural azapolycycles such as 4 have been found to possess diverse biological activities …”

Antimicrobial action of arylsulfonamides bearing (aza)norbornane and related motifs: evaluation of new promising anti-MRSA agents

“…[23] The most common neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, and stroke, as well as drug abuse, have been modulated with the polycyclic cage derivatives. [5,[24][25][26] A signi cant progress in the use of сage compounds in the drug discovery was caused by the development of lead-oriented synthesis concept. [27,28] Thus, cage compounds were proposed as bioisosteres for arenes, to reduce the number of the aromatic rings in lead-like molecules.…”