Structure elucidation of 11‐amino‐8‐hydroxypentacyclo[5.4.0.02, 6.03, 10.05, 9]undecane‐8,11‐lactam through selective acetylation and complete 1H and 13C NMR spectral assignment of the mono‐, di‐ and triacetates

Martins, Charles Ferreira; Viljoen, A. M.; Kruger, Hendrik G.; Wessels, Philippus L.

doi:10.1002/mrc.1355

Cited by 8 publications

(4 citation statements)

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“…In this section, we considered the PCU-lactam, lactim and lactone models shown in Figure 5 . The two reported sets of 1 H NMR signals in various solvents suggested the lactim–lactam tautomeric equilibrium exists [ 19 , 20 ]. In (CD 3 ) 2 SO the major tautomer is the lactam form, while for dioxane the lactim is dominant.…”

Section: Resultsmentioning

confidence: 99%

“…We calculated the asymmetry parameters (η) and quadrupole coupling constants (χ) of nitrogen and oxygen atoms involved in the cage region of PCU-lactam, its tautomer lactim [ 19 , 20 ] and PCU-lactone models in vacuum and in solvent media (water, DMSO and dioxane). The solvation effect (aqueous solution) on the Gibbs free energy of solvation (ΔG sol ) were also evaluated utilizing the self-consistent reaction field (SCRF) keyword [ 90 ] with the solvation model on density (SMD) [ 91 ].…”

Section: Methodsmentioning

confidence: 99%

“…One cage peptoid [ 15 ] also showed promising anti HIV PR activity. The synthesis of the PCU-lactam ( 1 ) [ 17 - 19 ] and lactone ( 2 ) 12, [ 18 , 20 ] is well established.

Figure 1 Structures of different types of cages [ 12 - 14 , 16 ] .…”

Section: Introductionmentioning

confidence: 99%

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Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study

et al. 2015

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BackgroundNovel pentacycloundecane (PCU)-lactone-CO-EAIS peptide inhibitors were designed, synthesized, and evaluated against wild-type C-South African (C-SA) HIV-1 protease. Three compounds are reported herein, two of which displayed IC50 values of less than 1.00 μM. A comparative MM-PB(GB)SA binding free energy of solvation values of PCU-lactam and lactone models and their enantiomers as well as the PCU-lactam-NH-EAIS and lactone-CO-EAIS peptide inhibitors and their corresponding diastereomers complexed with South African HIV protease (C-SA) was performed. This will enable us to rationalize the considerable difference between inhibitory concentration (IC50) of PCU-lactam-NH-EAIS and PCU-lactone-CO-EAIS peptides.ResultsThe PCU-lactam model exhibited more negative calculated binding free energies of solvation than the PCU-lactone model. The same trend was observed for the PCU-peptide inhibitors, which correspond to the experimental activities for the PCU-lactam-NH-EAIS peptide (IC50 = 0.076 μM) and the PCU-lactone-CO-EAIS peptide inhibitors (IC50 = 0.850 μM). Furthermore, a density functional theory (DFT) study on the natural atomic charges of the nitrogen and oxygen atoms of the three PCU-lactam, PCU-lactim and PCU-lactone models were performed using natural bond orbital (NBO) analysis. Electrostatic potential maps were also used to visualize the electron density around electron-rich regions. The asymmetry parameter (η) and quadrupole coupling constant (χ) values of the nitrogen and oxygen nuclei of the model compounds were calculated at the same level of theory. Electronic molecular properties including polarizability and electric dipole moments were also calculated and compared. The Gibbs theoretical free solvation energies of solvation (∆Gsolv) were also considered.ConclusionsA general trend is observed that the lactam species appears to have a larger negative charge distribution around the heteroatoms, larger quadrupole constant, dipole moment and better solvation energy, in comparison to the PCU-lactone model. It can be argued that these characteristics will ensure better eletronic interaction between the lactam and the receptor, corresponding to the observed HIV protease activities in terms of experimental IC50 data.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-015-0115-5) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study

et al. 2015

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“…[1,[5][6][7][8][9][10][11] Geminal/vicinal proton-proton coupling and long-range proton-proton interactions result in broad unresolved resonances. However, the emergence of a range of standard 2D NMR techniques has helped a great deal in overcoming these problems.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and NMR elucidation of novel pentacyclo-undecane diamine ligands

et al. 2009

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The synthesis and NMR elucidation of eight novel pentacyclo-undecane (PCU) diamine compounds are reported. These ligands are potential anti-inflammatory agents to be used against rheumatoid arthritis (RA). Onedimensional NMR techniques ( 1 H and 13 C spectra) show major overlapping of methine resonances of the ''cage'' (PCU) thereby making it extremely difficult to assign all NMR signals. This overlapping occurs as a result of the substitutions made at the quaternary carbons (C-8/C-11) of the cage. Two-dimensional NMR techniques proved to be a useful tool in overcoming this problem.

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Pentacycloundecane‐diol‐Based HIV‐1 Protease Inhibitors: Biological Screening, 2D NMR, and Molecular Simulation Studies

et al. 2012

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Novel compounds incorporating a pentacycloundecane (PCU) diol moiety were designed, synthesized, and evaluated as inhibitors of the wild-type C-South African (C-SA) HIV-1 protease. Seven compounds are reported herein, three of which displayed IC(50) values in the 0.5-0.6 μM range. The cytotoxicity of PCU cage peptides toward human MT-4 cells appears to be several orders of magnitude less toxic than the current antiviral medications ritonavir and lopinavir. NMR studies based on the observed through-space (1)H,(1)H distances/contacts in the EASY-ROESY spectra of three of the considered PCU peptide inhibitors enabled us to describe their secondary solution structure. Conserved hydrogen bonding interactions were observed between the hydroxy group of the PCU diol inhibitors and the catalytic triad (Asp25, Ile26, Gly27) of HIV protease in docking and molecular dynamics simulations. The biological significance and possible mode of inhibition by PCU-based HIV protease inhibitors discussed herein facilitates a deeper understanding of this family of inhibitors and their potential application to a vast number of alternative diseases related to proteases.

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Structure elucidation of 11‐amino‐8‐hydroxypentacyclo[5.4.0.0^{2, 6}.0^{3, 10}.0^{5, 9}]undecane‐8,11‐lactam through selective acetylation and complete ¹H and ¹³C NMR spectral assignment of the mono‐, di‐ and triacetates

Cited by 8 publications

References 9 publications

Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study

Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study

Synthesis and NMR elucidation of novel pentacyclo-undecane diamine ligands

Pentacycloundecane‐diol‐Based HIV‐1 Protease Inhibitors: Biological Screening, 2D NMR, and Molecular Simulation Studies

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