Molecular Dynamics and Static Solvation Studies of Amiloride

Buono, Ronald A.; Venanzi, Thomas J.; Zauhar, Randy J.; Luzhkov, V. B.; Venanzi, Carol A.

doi:10.1021/ja00083a039

Cited by 14 publications

(14 citation statements)

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“…This also suggests that the planar conformation of the protonated amiloride molecule is preferred not only in gas phase and in solution [17,18,20], but also in different crystalline structures [21,22].…”

Section: żEs Lawska Oleksyn and Stadnickamentioning

confidence: 92%

“…For these molecules this angle is 5.66(9) • and 11.63(7) • , respectively. Also the planar conformation of the protonated form of amiloride is preferred in gas phase and solvent, with the torsion angle O1 C5 C4 N1 value 180 • [17,18,20]. This conformation is stabilized by intramolecular hydrogen bonds between O1 and N6, as well as O1 and N4, which are observed also in the crystalline structures.…”

Section: Structure Of Amiloride Picratementioning

confidence: 98%

“…NMR structural investigations of amiloride as well as molecular theoretical calculations of molecular structure have been carried out [17][18][19][20]. The crystal structure of amiloride hydrochloride has been reported only recently [21].…”

Section: Introductionmentioning

confidence: 99%

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Amiloride Conformation: The Effect of Different Crystalline Environments

2004

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The crystal structure of (3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidine picrate has been determined with the use of X-ray diffraction method. The crystals are triclinic, space group Pī with a = 10.2980(4)Å, b = 12.4322(4)Å, c = 14.4310 (5)The asymmetric unit consists of one amiloride cation, picrate anion, and three DMSO molecules from the solvent, two of which are disordered. The molecules of amiloride and picrate are almost planar. The guanidine group of amiloride is protonated and makes a kind of a salt bridge with phenolate and forms hydrogen bonds with ortho-nitro oxygen atoms of picrate. The pairs of amiloride cation-picrate anion, transformed by the inversion center and translated by 2a and c, are mutually parallel and are connected by molecules of DMSO. The conformation of amiloride picrate is compared with those in other crystal structures.

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Section: żEs Lawska Oleksyn and Stadnickamentioning

confidence: 92%

Section: Structure Of Amiloride Picratementioning

confidence: 98%

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Amiloride Conformation: The Effect of Different Crystalline Environments

2004

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“…The same behavior was noted for amiloride. 28 Similarly, Figure 5c shows that in the presence of solvent the energy cost of the protonated E form of tambjamine attaining a nonplanar conformer is minimal in the ranges ∠NCCN ) 0-30°or 150-180°. This indicates that the molecule has a great deal of flexibility in adjusting its conformation to the DNA binding site.…”

Section: Discussionmentioning

confidence: 88%

A Molecular Orbital Study of Tambjamine E and Analogues

Skawinski

Venanzi

2004

J. Phys. Chem. A

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Hartree-Fock (HF/6-31G*), electron correlation (MP2/6-31G*, B3LYP/6-31G*, B3LYP/6-31G*(d,p)), and semiempirical (AM1, AM1/SM5.4) calculations were carried out on the DNA AT-specific intercalator tambjamine E in order to investigate the effect of protonation, side chains, electron correlation, and solvent on the inter-ring NCCN rotational barrier and relative planarity of the A and B rings. These properties relate to the flexibility of tambjamine and the ease by which it could adjust its inter-ring twist angle to adopt the propeller twist of DNA in order to form a nonclassical intercalation complex. The E configuration of protonated tambjamine was found to be more stable than the Z due to solvent stabilization and intramolecular hydrogen bonding. Inclusion of electron correlation increased the NCCN rotational barrier by about 2 kcal/mol. Solvent and the presence of the enamine side chain were shown to have a significant effect in lowering the NCCN rotational barrier. For the E configuration of protonated tambjamine, both the Hartree-Fock (HF) and density functional theory (DFT) methods predicted nonplanar minima around 20°, whereas DFT calculated the global energy minimum (GEM) to be planar (180°) in contrast to the HF nonplanar GEM (166°). However, both the HF and DFT results showed that there are broad regions (∠NCCN ) 0-30°and 150-180°) in which there is a minimal energetic cost for the E configuration of protonated tambjamine to adopt a nonplanar conformation. Such flexibility of tambjamine around the inter-ring bond could allow the molecule to adjust its NCCN angle to fit the propeller twist of the DNA base pair in order to form a nonclassical intercalation complex.

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“…1(b)), the presence of a carbonyl group as intramolecular H‐bond acceptor often enables the assignment of the two amino groups without the need for any additional receptor in order to reduce exchange. This has been shown, e.g., in the conformational investigation of amiloride,15 one of the most prominent acylguanidines in the literature 16–20. The application of cryo‐solvents allowed freezing the rotation around the bond between the central guanidine carbon (C G ) and the acylated nitrogen.…”

Section: Introductionmentioning

confidence: 96%

Chemical shift assignment and conformational analysis of monoalkylated acylguanidines

Kleinmaier

Gschwind

2010

Magnetic Reson in Chemistry

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Monoalkylated acylguanidines are important functional groups in many biologically active compounds and additionally applied in coordination chemistry. Yet a straightforward assignment of the individual NH chemical shifts and the acylguanidine conformations is still missing. Therefore, in this study, NMR spectroscopic approaches for the chemical and especially the conformational assignment of protonated monoalkylated acylguanidines are presented. While NOESY and (3)J(H, H) scalar couplings cannot be applied successfully for the assignment of acylguanidines, (4)J(H, H) scalar couplings in (1)H,(1)H COSY spectra allow for an unambiguous chemical shift and conformational assignment. It is shown that these (4)J(H, H) long-range couplings between individual acylguanidinium NH resonances are observed solely across all-trans (w) pathways. Already one cis orientation in the magnetisation transfer pathway leads to signal intensities below the actual detection limit and significantly lower than cross-peaks from (2)J(NH, NH) couplings or chemical exchange. However, it should be noted that also in the case of conformational exchange being fast on the NMR time scale, averaged cross-peaks from all-trans (4)J(H, H) scalar couplings are detected, which may lead at first glance to an incomplete or even wrong conformational analysis.

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Molecular Dynamics and Static Solvation Studies of Amiloride

Cited by 14 publications

References 1 publication

Amiloride Conformation: The Effect of Different Crystalline Environments

Amiloride Conformation: The Effect of Different Crystalline Environments

A Molecular Orbital Study of Tambjamine E and Analogues

Chemical shift assignment and conformational analysis of monoalkylated acylguanidines

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