Search

The feasibility of heteronuclear solid-state magic-angle spinning (MAS) NMR experiments for probing [super 15]N-[super 17]O dipolar and J couplings in two isotopically labeled model compounds, glycine*[super 2]HCl and uracil is demonstrated. The results revealed that [super 15]N-[super 17]O solid-state NMR experiments could further be applied to identify specific structure-determining hydrogen-bonding interactions in proteins and nucleic acids.

Various computational and experimental studies are conducted to analyze the weak hydrogen bonding in uracil and 4-cyano-4'-ethynylbiphenyl. The methodology is shown to be extremely helpful for calculating the NMR chemical shifts in the solid state of such complexes.

Among the factors determining the quantum coherence of the spin in molecular magnets are the presence and the nature of nuclear spins in the molecule. We have explored modifying the nuclear-spin environment in CrNi-based molecular nanomagnets by replacing hydrogen atoms with deuterium or the halogen atoms, fluorine or chlorine. We find that the spin coherence, studied at low temperatures by pulsed electron-spin resonance, is modified by a range of factors, including nuclear spin and magnetic moment, changes in dynamics owing to nuclear mass, and molecular morphology changes. [ABSTRACT FROM AUTHOR]

By means of the 1H chemical shifts and the proton-proton proximities as identified in 1H double-quantum (DQ) combined rotation and multiple-pulse spectroscopy (CRAMPS) solid-state NMR correlation spectra, ribbon-like and quartet-like self-assembly can be identified for guanosine derivatives without isotopic labeling for which it was not possible to obtain single crystals suitable for diffraction. Specifically, characteristic spectral fingerprints are observed for dG(C10)2 and dG(C3)2 derivatives, for which quartet-like and ribbon-like self-assembly has been unambiguously identified by 15N refocused INADEQUATE spectra in a previous study of 15N-labeled derivatives (Pham, T. N.; et al. J. Am. Chem. Soc.2005, 127, 16018). The NH 1H chemical shift is observed to be higher (13-15 ppm) for ribbon-like self-assembly as compared to 10-11 ppm for a quartet-like arrangement, corresponding to a change from NH…N to NH…O intermolecular hydrogen bonding. The order of the two NH21H chemical shifts is also inverted, with the NH2 proton closest in space to the NH proton having a higher or lower 1H chemical shift than that of the other NH2 proton for ribbon-like as opposed to quartet-like self-assembly. For the dG(C3)2 derivative for which a single-crystal diffraction structure is available, the distinct resonances and DQ peaks are assigned by means of gauge-including projector-augmented wave (GIPAW) chemical shift calculations. In addition, 14N-1H correlation spectra obtained at 850 MHz under fast (60 kHz) magic-angle spinning (MAS) confirm the assignment of the NH and NH2 chemical shifts for the dG(C3)2 derivative and allow longer range through-space N…H proximities to be identified, notably to the N7 nitrogens on the opposite hydrogen-bonding face. [ABSTRACT FROM AUTHOR]

A disaccharide is a challenging case for high-resolution 1H solid-state NMR because of the 24 distinct protons (14 aliphatic and 10 OH) having 1H chemical shifts that all fall within a narrow range of approximately 3 to 7 ppm. High-resolution 1H (500 MHz) double-quantum (DQ) combined rotation and multiple pulse sequence (CRAMPS) solid-state NMR spectra of β-maltose monohydrate are presented. 1H–1H DQ-SQ CRAMPS spectra are presented together with 1H (DQ)–13C correlation spectra obtained with a new pulse sequence that correlates a high-resolution 1H DQ dimension with a 13C single quantum (SQ) dimension using the refocused INEPT pulse-sequence element to transfer magnetization viaone-bond 13C–1H Jcouplings. Compared to the observation of only a single broad peak in a 1H DQ spectrum recorded at 30 kHz magic-angle spinning (MAS), the use of DUMBO 1H homonuclear decoupling in the 1H DQ CRAMPS experiment allows the resolution of distinct DQ correlation peaks which, in combination with first-principles chemical shift calculations based on the GIPAW (Gauge Including Projector Augmented Waves) plane-wave pseudopotential approach, enables the assignment of the 1H resonances to the 24 distinct protons. We believe this to be the first experimental solid-state NMR determination of the hydroxyl OH 1H chemical shifts for a simple sugar. Variable-temperature 1H–1H DQ CRAMPS spectra reveal small increases in the 1H chemical shifts of the OH resonances upon decreasing the temperature from 348 K to 248 K. [ABSTRACT FROM AUTHOR]

Compares sexual behavior data from weekly, daily questionnaires and a coital diary. Challenges in sexual behavior research; Data collection instruments; Advantages of the methods.

Heteronuclear solid-state magic-angle spinning (MAS) NMR experiments for probing 15N-17O dipolar and Jcouplings are presented for [²H(NH3),1-13C,15N,17O2]glycine··HCI and [15N2,17O2]uracil. Two-dimensional 15N-17O correlation spectra are obtained using the R³-HMQC experiment; for glycine-²HCl, the intensity of the resolved peaks for the C=O and C-O²H 17O resonances corresponds to the relative magnitude of the respective 15N-17O dipolar couplings. 17O-15N REDOR curves are presented for glycine·²HCI; fits of the initial buildup (ΔS/S < 0.2) yield effective dipolar couplings in agreement with (±20%) the root-sum-squared dipolar couplings determined from the crystal structure. Experimental 15N-17O REAPDOR curves for the 15N resonances in glycine·²HCI and uracil fit well to the universal curve presented by Goldbourt et al. (J. Am. Chem. Soc. 2003, 125, 11194). Heteronuclear 13C-17O and 15N-17O J couplings were experimentally determined from fits of the quotient of the integrated intensity obtained in a heteronuclear and a homonuclear spin-echo experiment, SQ(r) = SHET(v)/SHOM(τ). For glycine·²HCI, ¹JCO was determined as 24.7 ± 0.2 and 25.3 ± 0.3 Hz for the C=O and C-O²H resonances, respectively, while for uracil, the average of the two NHïO hydrogen-bond-mediated J couplings was determined as 5.1 ± 0.6 Hz. In addition, two-bond intramolecular J couplings, 2JOO = 8.8 ± 0.9 Hz and ²JN1,N3 = 2.7 ± 0.1 Hz, were determined for glycine·2HCI and uracil, respectively. Excellent agreement was found with J couplings calculated using the CASTEP code using geometrically optimized crystal structures for glycine·HCI [¹Jco(C=O) = 24.9 Hz, ¹Jco(C-OH) = 27.5 Hz, ²JOO = 7.9Hz] and uracil [2hJN1,O4 = 6.1 Hz, 2hJN3,O4 = 4.6 Hz, ²JN1,N3 = 2.7 Hz]. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors alone, or in combination with chemotherapy failed to provide meaningful clinical activity for patients with microsatellite stable (MSS) colorectal cancer (CRC). ONC201 is a small molecule that inactivates AKT and ERK signaling and actives the TRAIL pathway. Preclinical studies indicated potential benefits of combining ONC201 with checkpoint inhibitors. This is a phase Ib/II trial of ONC201 plus nivolumab for patient with MSS CRC who progressed on standard treatment., Methods: Enrolled patients received ONC201 plus nivolumab in a dose de-escalation fashion to determine the maximum tolerated dose (MTD). Additional patients were enrolled in the dose-expansion cohort. ONC201 at a dose of 625 mg was given orally at day -7 of cycle 1, followed by weekly dosing. Nivolumab was given every 2 weeks at 240 mg IV starting on day 1 of every cycle (cycle =28 days). The primary end point was dose-limiting toxicity (DLT) during the observation window (run-in dose day -7, cycle 1 to assessment pre-dosing cycle 2). The plan was to enroll 28 additional patients at the MTD so that a total of 34 patients would be treated at the MTD. Pharmacokinetics (PKs) and tumor biopsies were collected at several time points per study protocol., Results: A total of 13 patients (8 patients in the dose escalation *6 evaluable*) were enrolled between December 4, 2019 and March 2021. All patients had received ≥2 previous lines of chemotherapy and had confirmed microsatellite stability or mismatch repair-proficient tumors. No DLTs were observed with 625 mg ONC201 in the first three patients. Three additional patients were enrolled at the same dose to confirm safety. Two patients progressed during the DLT period and had to be replaced. During the dose-expansion part, five patients were enrolled and none required dose reduction or modification. No objective tumor response was observed in the 13 treated patients. Disease progression was confirmed at the time of the first imaging evaluation at 8 weeks following cycle 2. Post discussion at the Data and Safety Monitoring Board (DSMB) on May 25, 2021, the principal investigator (PI) and Committee voted to close the study to new patient enrollment prior to reaching accrual of 34 patients, secondary to lack of efficacy., Conclusions: In this study of patients with advanced MSS CRC, combination ONC201/nivolumab was well-tolerated; objective responses to ONC201/nivolumab were not observed., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-23-69/coif). K.A. reports grants from BMS and Chimerix to conduct the trial. W.E.D. is a co-founder of Oncoceutics, Inc., a subsidiary of Chimerix. W.E.D. has disclosed his relationship with Oncoceutics/Chimerix and potential conflict of interest to his academic institution/employer and is fully compliant with NIH and institutional policy that is managing this potential conflict of interest. The other authors have no conflicts of interest to declare., (2024 Translational Gastroenterology and Hepatology. All rights reserved.)

Weak hydrogen bonds are increasingly hypothesized to play key roles in a wide range of chemistry from catalysis to gelation to polymer structure. Here, 15 N/ 13 C spin-echo magic-angle spinning (MAS) solid-state nuclear magnetic resonance (NMR) experiments are applied to "view" intermolecular CH···N hydrogen bonding in two selectively labeled organic compounds, 4-[ 15 N] cyano-4'-[ 13 C 2 ] ethynylbiphenyl ( 1 ) and [ 15 N 3 , 13 C 6 ]-2,4,6-triethynyl-1,3,5-triazine ( 2 ). The synthesis of 2- 15 N 3 , 13 C 6 is reported here for the first time via a multistep procedure, where the key element is the reaction of [ 15 N 3 ]-2,4,6-trichloro-1,3,5-triazine ( 5 ) with [ 13 C 2 ]-[(trimethylsilyl)ethynyl]zinc chloride ( 8 ) to afford its immediate precursor [ 15 N 3 , 13 C 6 ]-2,4,6-tris[(trimethylsilyl)ethynyl]-1,3,5-triazine ( 9 ). Experimentally determined hydrogen-bond-mediated 2h J CN couplings (4.7 ± 0.4 Hz ( 1 ) and 4.1 ± 0.3 Hz ( 2 )) are compared with density functional theory (DFT) gauge-including projector augmented wave (GIPAW) calculations, whereby species-independent coupling values 2h K CN (29.0 × 10 19 kg m -2 s -2 A -2 ( 1 ) and 27.9 × 10 19 kg m -2 s -2 A -2 ( 2 )) quantitatively demonstrate the J couplings for these "weak" CH···N hydrogen bonds to be of a similar magnitude to those for conventionally observed NH···O hydrogen-bonding interactions in uracil ( 2h K NO : 28.1 and 36.8 × 10 19 kg m -2 s -2 A -2 ). Moreover, the GIPAW calculations show a clear correlation between increasing 2h J CN (and 3h J CN ) coupling and reducing C(H)···N and H···N hydrogen-bonding distances, with the Fermi contact term accounting for at least 98% of the isotropic 2h J CN coupling.

A disaccharide is a challenging case for high-resolution (1)H solid-state NMR because of the 24 distinct protons (14 aliphatic and 10 OH) having (1)H chemical shifts that all fall within a narrow range of approximately 3 to 7 ppm. High-resolution (1)H (500 MHz) double-quantum (DQ) combined rotation and multiple pulse sequence (CRAMPS) solid-state NMR spectra of beta-maltose monohydrate are presented. (1)H-(1)H DQ-SQ CRAMPS spectra are presented together with (1)H (DQ)-(13)C correlation spectra obtained with a new pulse sequence that correlates a high-resolution (1)H DQ dimension with a (13)C single quantum (SQ) dimension using the refocused INEPT pulse-sequence element to transfer magnetization via one-bond (13)C-(1)H J couplings. Compared to the observation of only a single broad peak in a (1)H DQ spectrum recorded at 30 kHz magic-angle spinning (MAS), the use of DUMBO (1)H homonuclear decoupling in the (1)H DQ CRAMPS experiment allows the resolution of distinct DQ correlation peaks which, in combination with first-principles chemical shift calculations based on the GIPAW (Gauge Including Projector Augmented Waves) plane-wave pseudopotential approach, enables the assignment of the (1)H resonances to the 24 distinct protons. We believe this to be the first experimental solid-state NMR determination of the hydroxyl OH (1)H chemical shifts for a simple sugar. Variable-temperature (1)H-(1)H DQ CRAMPS spectra reveal small increases in the (1)H chemical shifts of the OH resonances upon decreasing the temperature from 348 K to 248 K.

Heteronuclear solid-state magic-angle spinning (MAS) NMR experiments for probing (15)N-(17)O dipolar and J couplings are presented for [(2)H(NH(3)),1-(13)C,(15)N,(17)O(2)]glycine.(2)HCl and [(15)N(2),(17)O(2)]uracil. Two-dimensional (15)N-(17)O correlation spectra are obtained using the R(3)-HMQC experiment; for glycine.(2)HCl, the intensity of the resolved peaks for the CO and C-O(2)H (17)O resonances corresponds to the relative magnitude of the respective (15)N-(17)O dipolar couplings. (17)O-(15)N REDOR curves are presented for glycine.(2)HCl; fits of the initial buildup (DeltaS/S < 0.2) yield effective dipolar couplings in agreement with (+/-20%) the root-sum-squared dipolar couplings determined from the crystal structure. Experimental (15)N-(17)O REAPDOR curves for the (15)N resonances in glycine.(2)HCl and uracil fit well to the universal curve presented by Goldbourt et al. (J. Am. Chem. Soc. 2003, 125, 11194). Heteronuclear (13)C-(17)O and (15)N-(17)O J couplings were experimentally determined from fits of the quotient of the integrated intensity obtained in a heteronuclear and a homonuclear spin-echo experiment, S(Q)(tau) = S(HET)(tau)/S(HOM)(tau). For glycine.(2)HCl, (1)J(CO) was determined as 24.7 +/- 0.2 and 25.3 +/- 0.3 Hz for the CO and C-O(2)H resonances, respectively, while for uracil, the average of the two NH...O hydrogen-bond-mediated J couplings was determined as 5.1 +/- 0.6 Hz. In addition, two-bond intramolecular J couplings, (2)J(OO) = 8.8 +/- 0.9 Hz and (2)J(N1,N3) = 2.7 +/- 0.1 Hz, were determined for glycine.(2)HCl and uracil, respectively. Excellent agreement was found with J couplings calculated using the CASTEP code using geometrically optimized crystal structures for glycine.HCl [(1)J(CO)(CO) = 24.9 Hz, (1)J(CO)(COH) = 27.5 Hz, (2)J(OO) = 7.9 Hz] and uracil [(2h)J(N1,O4) = 6.1 Hz, (2h)J(N3,O4) = 4.6 Hz, (2)J(N1,N3) = 2.7 Hz].