Triquinane scaffolds: Shape and geometry as a function of saturation and bridgehead groups

Young, Lois-May; Zeller, Mat­thias; Geldenhuys, Werner J.; Malan, Sarel F.; Schyf, Cornelis J. Van der

doi:10.1016/j.molstruc.2013.04.030

Cited by 1 publication

(5 citation statements)

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“…Reagents and conditions: (a) benzene, 5°C; (b) acetone, UV, 6 h; (c) THF, 5°C, NH 2 R; (d) benzene, Δ, H 2 O, 1 h; (e) MeOH, THF, NaBH 4 ; (f) HOAc, MeOH, NaBH 3 CN, 12 h. The synthesis of 19 was achieved by selective decarboxylation of ( 4 ) by means of Huang–Minlon reaction followed by reductive amination with NaBH 4 . Compound ( 19 ) was previously synthesized by Geldenhuys et al, and the synthesis is described in the original paper .…”

Section: Resultsmentioning

confidence: 99%

“…The cis , syn , cis triquinane scaffold ( 10 ), which is a thermal‐fragmented derivative of the pentacycloundecane ( 4 ), retains the bulkiness (±10%) of 4 as expressed in molecular volume ( 4 : 498 Å 3 and 10 : 552 Å 3 ) and solvent accessible surface area ( 4 : 325 Å 2 and 10 : 351 Å 2 ) . The triquinane scaffold, in addition to contributing a larger surface area to the geometric conformation, was also found to be a less‐strained asymmetric compound with greater flexibility . The cis , syn , cis triquinane system can only be derived through thermal fragmentation and we aimed to optimize and simplify the method for the synthesis of the triquinylamines by redesigning the apparatus (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies demonstrated that altering the geometric conformation of the polycyclic scaffold by increasing the size and volume leads to an increase in activity . This could explain why the triquinane compounds were more active, as the triquinane scaffold has a larger size and solvent accessible surface area (SASA) . The triquinane scaffold shows promise in the design of novel LTCC blockers.…”

Section: Resultsmentioning

confidence: 99%

“…for C 11 H 14 O 2 : 178.2277, found: 178.1072. As discussed by Young et al , this compound was also characterized by means of single crystal X‐ray analysis.…”

Section: Methodsmentioning

confidence: 99%

“…In addition to the spectroscopic analysis, this compound was characterized by means of single crystal X‐ray analysis. We reported the synthesis and characterization for this compound in Young et al .…”

Section: Methodsmentioning

confidence: 99%

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

Young

Geldenhuys

Domingo

et al. 2016

Archiv der Pharmazie

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…for C 11 H 14 O 2 : 178.2277, found: 178.1072. As discussed by Young et al , this compound was also characterized by means of single crystal X‐ray analysis.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations