Pentacycloundecane Cage Research Articles

7-Meth-oxy-penta-cyclo-[5.4.0.02,6.03,10.05,9]undec-ane-8,11-dione.

The structure of 7-meth-oxy-penta-cyclo-[5.4.0.02,6.03,10.05,9]undecane-8,11-dione, C12H12O3, at 150 K has monoclinic (P21/c) symmetry. The penta-cyclo-undecane cage compound is composed of four five-membered rings, a planar four-membered ring and a six-membered ring in a boat conformation fused into a closed strained-cage framework. All of the five-membered rings adopt an envelope conformation.

Design and Synthesis of Pentacycloundecane Cage Compound Containing Oxazole Moiety

Design and Synthesis of Pentacycloundecane Cage Compound Containing Oxazole Moiety

Novel PCU cage diol peptides as potential targets against wild-type CSA HIV-1 protease: synthesis, biological screening and molecular modelling studies

We have synthesized a series of novel pentacycloundecane cage diol diacid (PCU diol diacid) incorporated C2-symmetric peptides. Their activity against the resistance-prone wild-type C-South African (C-SA) HIV protease (HIV PR) is reported. These compounds were obtained in moderate yields of 42–72 %. Amongst the nine compounds reported herein only compound 6, 7, 10 and 11 showed moderate IC50 values of 5–10 μM. Peptides 7 and 10 contain two phenylglycine and two tryptophan amino acids, respectively as side arms to the cage diol. Phenylglycine is a non-natural amino acid. Docking and molecular dynamics (MD) studies were carried out to understand the binding mode of the PCU moiety at the active site of the HIV PR enzyme. The computational results show that the cage diol peptide fits quite comfortably inside the active site of the enzyme. Not much movement is observed during the MD simulation and the hydrogen bonds that develop between the inhibitor and the enzyme pocket suggest that the inhibitor/HIV PR complex is stable at room temperature.

Synthesis and NMR elucidation of pentacycloundecane-derived hydroxy acid peptides as potential anti-HIV-1 agents

The synthesis and NMR elucidation of eight novel peptides incorporating the pentacycloundecane (PCU)-derived hydroxy acid are reported. The PCU cage amino acids were synthesized as racemates and the incorporation of the PCU-derived hydroxy acid with natural (S)-amino acids produced inseparable diastereomeric peptides. A series of overlapping signals from the cage and that of the peptide side chain was observed in the 1H- and 13C-NMR spectra, complicating the elucidation thereof. Two-dimensional NMR techniques proved to be a very useful tool in overcoming these difficulties. These compounds are potential HIV protease inhibitors.

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

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.

Molecular dynamics simulations of Ac-3Aib-Cage-3Aib-NHMe

Solvents play a stabilising role with the more stable conformations obtained in polar solvents than in vacuo. We investigate to what extent the structural propensities of the pentacyclo-undecane (PCU) cage polypeptide chain of the type Ac-3Aib-Cage-3Aib-NHMe are influenced in implicit water and in explicit solvents: methanol (MEOH), dimethyl sulphoxide (DMSO) and TIP3P water. The sampling of the α-helical conformations of the PCU cage polypeptide was investigated using the in-house modified PARM94 force-field parameters. Analysis of 50 ns molecular dynamics (MD) simulations revealed a tendency of the PCU cage polypeptide to assume bent structures, especially in polar solvents. The choice of solvents was designed to relate the simulations to physiological conditions. The individual amino-isobutyric acid residues predominantly sampled the right-handed and left-handed 310-helical conformations, indicating that the helical conformations are preferred in all four environments (in vacuo, MEOH, water and DMSO). Additionally, the 100 ns replica exchange MD (REMD) simulations of the PCU cage polypeptide in implicit water revealed more conformational variety present than in explicit solvents, and is more consistent with previous theoretical studies on the PCU cage residue. The present theoretical results may help in rationalising experimental results on these PCU cage polypeptides, and definitely show the importance of a dynamical approach for a correct interpretation and prediction of the conformational behaviour of the PCU cage molecules in different environments.

Synthesis and NMR elucidation of novel pentacycloundecane‐based peptides

The synthesis and NMR elucidation of two novel pentacycloundecane (PCU)-based peptides are reported. The PCU cage amino acids were synthesised as racemates and the incorporation of the cage amino acid with (S)-natural amino acids produced diastereomeric peptides. The diastereomeric 'cage' peptides were separated using preparative HPLC and the NMR elucidation of these PCU containing peptides are reported for the first time. The (1)H and (13)C NMR spectra showed series of overlapping signals of the cage skeleton and that of the peptide, making it extremely difficult to resolve the structure using one-dimensional NMR techniques only. The use of two-dimensional NMR techniques proved to be a highly effective tool in overcoming this problem.

Conformational Study of the PCU Cage Monopeptide: A Key Role of Some Force-Field Parameters

As had been previously reported standard AMBER parameters do not reproduce adequately ab initio calculations performed on the pentacycloundecane cage residue. The analysis of the geometries of the minimum energy structures compared with other residues allowed us to suspect the importance of bond stretching parameters in this case. Accordingly, we proceeded to compute new stretching and bending parameters from density functional theory calculations. Accordingly, the reliability of these parameters have been validated by predicting the correct conformational Ramachandran map. This is an example where the geometry of the side chain constrains the geometry of the residue backbone in such a way that you can get the right conformational profile by simple modification of some stretching and bending parameters.

Nitric Oxide Synthase Inhibition by Pentacycloundecane Conjugates of Aminoguanidine and Tryptamine

This paper describes the synthesis and in-vitro activity of pentacycloundecane-conjugated aminoguanidine and tryptamine analogues on nitric oxide synthase (NOS) using rat brain homogenate. Both aminoguanidine and tryptamine-derived NOS inhibitors show selectivity towards the inducible and neuronal isoforms of the NOS enzyme, but are weak inhibitors and complete inhibition of the enzyme occurs only at high millimolar concentrations. In view of the increased NOS inactivation observed with alkyl substitution of these structures, the present study aimed to evaluate the effect of the pentacycloundecane cage moiety as an alkyl substituent on the in vitro NOS inhibition of aminoguanidine and tryptamine compounds. Comparison of the IC(50) values of aminoguanidine (IC(50) = 2.306x10(-3) M) and 8-imino-N-guanidino-pentacyclo-undecane 2 (IC(50) = 8.803x10(-5) M) revealed a more than 26-fold increase in potency. The ability of tryptamine to inhibit NOS activity was also markedly improved by the various pentacycloundecane substituents. The compounds, 3-hydroxy-4-[3-(2-aminoethyl)indole]-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecane 4 and 8-[3-(2-aminoethyl) indole]-pentacyclo[5.4.0(2,6).0(3,10).0(5,9)]undecane 7 showed the best activity of the tryptamine analogues with a more than 3-fold increase in nitric oxide synthase inhibition. The results confirmed that the pentacycloundecane structure substantially enhanced the NOS inhibitory potency as observed for the six new NOS inhibitors.

Synthesis and NMR elucidation of pentacyclo-undecane diamine derivatives as potential anti-tuberculosis drugs

The complete structural elucidation of six novel pentacycloundecane (PCU) derivatives is reported. The target molecules are potential anti-tuberculosis agents. The addition of side arms to the PCU cage skeleton at position C-8/C-11 results in major overlapping of the methine resonances of the 1H NMR spectrum. The use of 2D NMR techniques proved to be a very useful tool in overcoming the difficulties encountered in the elucidation of cage compounds using 1H and 13C spectra only. All compounds reported are meso compounds thereby simplifying the complexity of the NMR spectra.

A molecular dynamics study of the pentacyclo-undecane cage amino acid tripeptide

In this paper, we report on the conformational profile of the pentacyclo-undecane (PCU) cage tripeptide carried out by molecular dynamics (MD) simulation using water as an explicit solvent. The MD solution phase studies carried on the model peptide analogues (A)=Ac–Ala–Ala–Ala–NHMe; (B)=Ac–Cage–Cage–Cage–NHMe; (C)=Ac–Ala–Cage–Ala–NHMe and (D)=Ac–Ala–Pro–Ala–NHMe, are used as a complimentary technique to the corresponding gas phase simulated annealing (SA) study previously carried out in our laboratory. No significant structural changes were observed over the MD trajectories. However, the results reported here provide further evidence that the (PCU) cage amino acid exhibits C 7eq, C 7aq, α R and α L conformations, and the theoretical results suggest that the PCU cage amino acid is a strong β-turn inducer. These results support the prediction that when the PCU cage residues are in the ( i) and ( i+2) positions, the β-turn can be extended in either direction to form anti-parallel β-pleated sheets, thereby forming the basis of the mechanism for the folding back of the chain in a cross-β-turn structure.

Experimental and computational studies of the regioselective protection of hydantoins using anhydride

The regioselective protection of alcohols, amines and a cage lactam with acetic anhydride was previously investigated. A six-membered cyclic transition state of acetic anhydride with the reagent was found. The same computational model was applied to three lactam systems, namely 5-methylhydantoin, 5,5-dimethyl-hydantoin and a pentacyclo-undecane cage hydantoin. The density functional hybrid method B3LYP was employed along with the 6-31+G(d) basis set to obtain the optimised geometries and corresponding energies of the different reagents, transition states and products. The computational model described herein correctly predicts the experimentally observed products. The synthesis and the NMR elucidation of three novel mono-Boc protected hydantoins are reported.

Synthesis of chiral pentacyclo-undecane ligands and their use in the enantioselective alkylation of benzaldehyde with diethylzinc

The synthesis of a new class of chiral pentacycloundecane cage annulated bidentate ligands is reported. This class of ligands can be used in many reactions that are catalysed by amino alcohol ligands. The ability of the chiral ligands to asymmetrically catalyse the reaction between diethylzinc and benzaldehyde was investigated. The cage annulated bidentate ligands have C 1 symmetry and showed poor to good enantioselectivity with high yields compared to previous systems reported using other amino alcohol ligands. An important conclusion from the results is that both ligands should be involved in the mechanism as the bidentate ligands gives much improved enantioselectivity when compared with a single chiral source molecule. This system could be utilised as a versatile probe for examining the reaction mechanism.

Synthesis and transport studies of a new class of cage-annulated chiral macrocycles

The synthesis of a new class of chiral pentacycloundecane cage annulated macrocycles is reported. The ability of the chiral hosts to transport racemic phenylglycine methyl ester enantioselectively through a chloroform membrane in a U-tube was compared to that of related pyridine macrocycles. The cage annulated macrocycles showed weak to moderate enantioselectivity and very high rates of transport compared to previous systems reported using the same counter ion (PF 6 −). The rate of transport was slowed by changing to a relatively harder counter ion (Cl −).