33226-54-9

Upstream product

• 114301-53-0 8-benzyliminopentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecane-11-one 
• 2958-72-7 Cookson's diketone 
• 100-46-9 benzylamine 

Downstream Products

• 1394230-00-2 C₁₈H₁₆N₂O₄ 
• 1394230-02-4 C₁₈H₁₇NO₂ 
• 70755-21-4 C₁₁H₁₃NO 
• 95464-07-6 anti-11-hydroxypentacyclo<5.4.0.0^2,6.0^3,10.0^5,9>undecane-8-one 
• 100-46-9 benzylamine 

Relevant academic research and scientific papers

Design, synthesis and evaluation of pentacycloundecane and hexacycloundecane propargylamine derivatives as multifunctional neuroprotective agents

The multifactorial pathophysiology of neurodegenerative disorders remains one of the main challenges in the design of a single molecule that may ultimately prevent the progression of these disorders in affected patients. In this article, we report on twelve novel polycyclic amine cage derivatives, synthesized with or without a propargylamine function, designed to possess inherent multifunctional neuroprotective activity. The MTT cytotoxicity assay results showed the SH-SY5Y human neuroblastoma cells to be viable with the twelve compounds, particularly at concentrations less than 10 μM. The compounds also showed significant neuroprotective activity, ranging from 31% to 61% at 1 μM, when assayed on SH-SY5Y human neuroblastoma cells in which neurodegeneration was induced by MPP+. Calcium regulation assays conducted on the same cell line showed the compounds to be significant VGCC blockers with activity ranging from 26.6% to 51.3% at 10 μM; as well as significant NMDAr antagonists with compound 5 showing the best activity of 88.3% at 10 μM. When assayed on human MAO isoenzymes, most of the compounds showed significant inhibitory activity, with compound 5 showing the best activity (MAO-B: IC50 = 1.70 μM). Generally, the compounds were about 3–52 times more selective to the MAO-B isoenzyme than the MAO-A isoenzyme. Based on the time-dependency studies conducted, the compounds can be defined as reversible MAO inhibitors. Several structure activity relationships were derived from the various assays conducted, and the compounds’ possible putative binding modes within the MAO-B enzyme cavity were assessed in silico.

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.

S-nitrosylation and attenuation of excessive calcium flux by pentacycloundecane derivatives

A novel series of polycyclic amines, containing nitrogen monoxide donating moieties, were synthesised and tested for calcium channel and N-methyl-D-aspartate receptor modulating activity. The synthesised compounds were classified into two groups, based on their nitrogen monoxide donating moieties: unsaturated nitro compounds (1, 2 and 3) and nitro esters, or nitrates (4, 5 and 6). The nitrates were obtained via the reaction of hydroxyl functionalities with thionylchloride nitrate. All of the compounds synthesised exhibited significant (p 0.01) S-nitrosylation capacity. The calcium channel activity of the polycyclic amines was evaluated using a KCl mediated fluorescent calcium flux assay. All the compounds exhibited better calcium channel antagonism than the lead structure, NGP1-01, with compound 1 exhibiting calcium channel blockade comparable to the commercially available nimodipine at concentrations of 10 μM and 1 μM. Compounds 3 and 4 inhibited calcium flux to these levels at 10 μM concentrations. NMDA/glycine mediated N-methyl-Daspartate receptor (NMDAR) calcium influx inhibition was evaluated at a 100 μM concentration using a fluorescent calcium flux assay. All the compounds exhibited NMDAR antagonism with compounds 1 (25.4 %), 2 (20.24 %), 3 (33.14 %) and 6 (24.55 %) showing the most significant NMDAR inhibitory activity (p 0.01). No clear correlation was observed between the S-nitrosylation capabilities of the compounds and their calcium channel activity or NMDAR channel antagonism, indicating that other factors probably play a more decisive role in the mechanism of pentacycloundecylamine channel modulation. This could include the geometric and steric bulk considerations that have been described to contribute to the channel activities of the pentacycloundecylamines. All the compounds synthesised exhibited promising calcium channel and NMDAR channel inhibitory activity and show promise as potential lead compounds for drug development against neurodegeneration.

Physicochemical prediction of a brain-blood distribution profile in polycyclic amines

Recent investigation into the pharmacological character of the pentacyclo[5.4.0.02,6.03,10.05,9]undecyl and related polycyclic amines has revealed interesting facts regarding their possible use as neuroprotective agents. At this stage however, a clear shortcoming in the quest for further development of this novel class of compounds is the lack of concrete data on their ability to cross the blood-brain barrier (BBB). Working towards the aim of predicting BBB permeability, a series of related N-substituted 8-amino-8,11-oxapentacyclo[5.4.0.02,6.03,10.0 5,9]undecanes were synthesised. Compounds were characterised by both experimental and calculative methods, followed by biological assessment and statistical manipulation of the results obtained. In doing so, a simple biological model was established for the comparative evaluation of brain-blood distribution properties within the class. A highly sensitive ESI-MS.MS analytical procedure was developed for the detection of these compounds in biological tissues, indicating significant drug concentrations in the brain after intraperitoneal administration to C57Bl/6 mice. Stepwise multiple linear regression analysis of all data yielded two meaningful models (R2=0.9996 and R2=0.7749) depicting lipophilicity (log Poct), solvent accessible molecular volume (SV), molar refractivity (MR) and system energy as the prime determinants of the brain-blood profile for these amines. The inherently high lipophilicity potential within the series is attributed to strong hydrophobic influences dominating hydrogen bonding effects. A possible conformational and energy dependent preference at the site of permeation is also suggested. The proposed estimations allow for the expedient and reliable prediction of brain partitioning behaviour for related polycyclic amines, facilitating the early rejection of unsuitable candidates and enabling research to focus on neuroprotective activity.

Structure-activity relationships of polycyclic aromatic amines with calcium channel blocking activity

8-Benzylamino-8,11- oxapentacyclo[5.4.0.02,6.033,10.05,9]undecane (1) inhibits the calcium current in L-type calcium channels. A series of nitrobenzylamines (2, 3, 4), methoxybenzylamines (5,6, 7), methylpyridines (8, 9m 10), and a phenylhydrazine derivative (11) of 8,11- oxapentacyclo[5.4.0.02,6.03,105,9]undecane was synthesized. By substituting the 8,11-oxapentacyclo- [5.4.0.02,6.03,10.05,9]undecane skeleton with 3-hydroxyhexacyclo- [6.5.0.03,7.04,12.05,10.09,10]tridecane (12), 8,13- dioxapentacyclo[6.5.0.02,6.05,10.03.11]tridecane-9-one (13), and pentacyclo[5.4.0.02,6.03,10.05,9]undecane (14), the effect of the polycyclic skeleton could also be investigated. Increased inhibition of calcium current was observed with aromatic substitution (especially ortho and meta substitution) in the pentacycloundecane series. The calcium channel activities of the methoxy compounds were slightly higher than those of the corresponding nitro compounds while a definite decrease in activity was observed for the phenylhydrazine and aminomethylpyridine derivatives. Increased inhibition of the calcium current was also observed for structures in which the polycyclic 'cages' were enlarged. Structure-activity relationships in this series of compounds therefore appear to be dominated by geometric or steric constraints.

Polycyclic compounds and pharmaceutical compositions thereof

This invention provides compounds of the general formula I:, , A-NHR (I), , wherein A is 8,11-oxopentacyclo [5.4.0.02,6.03,10.05,9]-undecane optionally substituted with one or more substituents, preferably comprising an alkyl, aryl, hydroxy, keto or amine group, and R is hydrogen or an unsubstituted or substituted aromatic or an unbranched or branched alkyl group, the alkyl group preferably or optionally having as a substituent an aryl or hydroxy group or halogen; and acid addition salts of such compounds. This invention also provides processes for preparing the above compounds; and calcium antagonists and/or antihypertensive agents containing one or more of the above compounds.