Observation of OH…N scalar coupling across a hydrogen bond in nocathiacin I

Abstract

We report here the observation of O-H...N hydrogen-bond (1h)J(N,OH) scalar coupling in a biologically active natural product. The intramolecular hydrogen bond between the threonine hydroxyl (Thr-OH) group and the thiazolyl nitrogen at the second thiazole ring (Thz-2) in nocathiacin I was directly detected by a 1H-15N HMBC NMR experiment. The magnitude of the scalar coupling constant (1h)J(N,OH) was accurately measured to be 1.8 +/- 0.1 Hz by a J-resolved 1H-15N HMBC experiment. By adding the O-H...N distance restraint, the 3D solution structure of nocathiacin I was refined. The structure refinement indicated that the distance between the Thr-3 hydroxyl hydrogen and the Thz-2 nitrogen is <or=2.50 A in all the refined structures, and there are no NOE restraint violations >or= 0.23 A. The presence of an intramolecular hydrogen bond in nocathiacin I is further supported by a number of NMR parameters and additional NMR experiments. This observation provides valuable information for characterizing molecular conformations, and for studying structure-activity relationships.

Comparative analysis of hydrogen bonding with participation of the nitrogen, oxygen and sulfur atoms in the 2(2′‐heteroaryl)pyrroles and their trifluoroacetyl derivatives based on the 1H, 13C, 15N spectroscopy and DFT calculations

“…The value of 1h J(F α ,H-1) coupling constant as well as the intramolecular distance F α · · ·H-1 in 4-6 are typical of the series of molecules with a weak intramolecular hydrogen bond. [16] It is important to state that 1h J(F α ,H-1) and 2h J(F α ,N) coupling constants depend on the rotation of the heteroaryl moiety. In the anti orientation of the pyridine, furan or thiophene ring, the 1h J (F α ,H-1) and 2h J(F α ,N) couplings are always stronger in comparison with those of the conformations with the syn position of these rings (Table 4).…”

A review with comprehensive data on experimental indirect scalar NMR spin–spin coupling constants across hydrogen bonds

“…[53] Nocathiacin (small natural product) Nocathiacin (Scheme 11) is a tricyclic thiazolyl peptide in which a 1h J NH intramolecular coupling constant of 1.8 ± 0.1 Hz has been measured. [54] Although the coupling is an intramolecular one, because of the peptidic nature of the compound we have decided to include it here as a transition between inter-and intramolecular situations.…”

NMR-Based Investigation of Hydrogen Bonding in a Dihydroanthracen-1(4H)one from Rubia philippinensis and Its Soluble Epoxide Hydrolase Inhibitory Potential

“…However, based on the resultant NMR spectra (Figure and Figures S10–S12, Supporting Information), such an interconversion apparently does not occur. Alternatively, a temperature coefficient [Δδ/Δ T (K)] of the hydroxy proton was calculated to evaluate its hydrogen-bonding strength since heteronuclear couplings from an exchangeable hydrogen atom to heteroatoms (i.e., 13 C, 15 N, or 121 Sb and 123 Sb) were feasible via localized hydrogen bonding. − , The temperature coefficient of the hydroxy proton in acetone- d 6 was −1.8 ppb/K (200 to 300 K, acetone- d 6, 10 mM; Figure ), much stronger than those measured for the hydrogen bonds between HO-5 and the ketocarbonyl moieties in the flavonols kaempferol (−3.1 ppb/K) and quercetin (−2.9 ppb/K) and the flavone luteolin (−2.3 ppb/K) under similar VT NMR experimental conditions . This evidenced the presence of a robust intramolecular hydrogen bonding from HO-9 (δ H 16.07) to the C-1 carbonyl oxygen, transferring magnetization from the hydroxy proton to C-1 and C-2 in the HMBC experiment even with routine heteronuclear transfer delay and coupling constant settings ( n J CH = 8 Hz; Figure and Figure S7, Supporting Information).…”

“…Potential hydrogen bond formation, therefore, should be considered in screening and identification of drug prototypes . Among many approaches for detecting the presence of hydrogen bonding, the NMR method has been recognized as an important tool given its sensitivity for configurational and conformational changes . For instance, temperature coefficients of chemical shifts of hydroxy protons, prone to forming such nonbonding interactions, were obtained via variable-temperature (VT) 1 H NMR experiments, and the coefficients were used to evaluate hydrogen-bonding strength .…”

“…4 Among many approaches for detecting the presence of hydrogen bonding, the NMR method has been recognized as an important tool given its sensitivity for configurational and conformational changes. 5 For instance, temperature coefficients of chemical shifts of hydroxy protons, prone to forming such nonbonding interactions, were obtained via variable-temperature (VT) 1 H NMR experiments, and the coefficients were used to evaluate hydrogen-bonding strength. 6 In addition, scalar coupling constants between donors and acceptors involved in intra-molecular hydrogen bond formation were directly measurable utilizing several NMR experiments.…”