Aromatic versus Aliphatic Carboxyl Group as a Hydrogen Bond Donor in Salts and Cocrystals of an Asymmetric Diacid and Pyridine Derivatives

Bedeković, Nikola; Stilinović, Vladimir; Piteša, Tomislav

doi:10.1021/acs.cgd.7b00746

Cited by 21 publications

(8 citation statements)

References 36 publications

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“…Desiraju and co-workers recently reported 15 N ss-NMR spectroscopy to distinguish between salts and cocrystals, with SC-XRD as an additional technique. Salt cocrystals have also been studied using FT-IR. − Ito and co-workers used X-ray photoelectron spectroscopy (XPS) to understand tautomerism in intramolecular hydrogen bonds of N -salicylideneaniline derivatives. Intermolecular hydrogen bonding of isonicotinic acid has been investigated by XPS, where a thick film of isonicotinic acid was evaporated onto rutile TiO 2 (110) .…”

Section: Introductionmentioning

confidence: 99%

Can We Identify the Salt–Cocrystal Continuum State Using XPS?

Tothadi

Shaikh

Gupta

et al. 2021

Crystal Growth & Design

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X-ray photoelectron spectroscopy (XPS) is used to understand the nature of acid–base crystalline solids, to know whether the product is a salt (proton transfer, O–···H–N+) or a cocrystal (neutral adduct, O–H···N). The present study was carried out to explore if intermediate states of proton transfer from COOH to nitrogen (the proton resides between hydrogen bonded to O and N, O···H···N, quasi state) can be differentiated from a salt (complete proton transfer, N+–H··· O–) and cocrystal (no proton transfer, O–H···N) using N 1s XPS spectroscopy. The intermediate states of proton transfer arise when the pK a difference between the acid and the conjugate base is between −1 and 4, −1 < ΔpK a < 4, a situation common with COOH and pyridine functional groups present in drug molecules and pharmaceutically acceptable coformers. Complexes of pyridine N bases with aromatic COOH molecules in nine salts/cocrystals were cocrystallized, and their N 1s core binding energies in XPS spectra were measured. The proton state was analyzed by single-crystal X-ray diffraction for confirmation. Three new complexes were crystallized and analyzed by XPS spectra (without knowledge of their X-ray structures), to assess the predictive ability of XPS spectra in differentiating salt–cocrystal intermediate states against the extremities. The XPS results were subsequently confirmed by single-crystal X-ray data. Complexes of 3,5-dinitrobenzoic acid and isonicotinamide in 1:1 and 1:2 ratios exist as a salt and a salt–cocrystal continuum, respectively, as shown by the N 1s core binding energies. The proton states of the crystalline solids by XPS are in good agreement with the corresponding crystal structures. Other complexes, such as those of 3,5-dinitrobenzoic acid with 1,2-bis(4-pyridyl)ethylene, exhibit a salt–cocrystal continuum, maleic acids with 1,2-bis(4-pyridyl)ethylene and acridine are salts, 2-hydroxybenzoic acid and acridine is a salt, and the complex of 3,5-dinitrobenzoic acid and 3-hydroxypyridine is a salt and salt–cocrystal continuum, while fumaric acids with 1,2-bis(4-pyridyl)ethylene and acridine are cocrystals. Furthermore, three new acid–base complexes of 3,5-dinitrobenzoic acid with phenazine, 4-hydroxypyridine, and 4-cyanopyridine were studied initially by XPS and then confirmed by X-ray diffraction. In summary, since the N 1s binding energies cluster in a narrow range as cocrystals (398.7–398.9 eV) and salts (400.1–401.1 eV), it is clearly possible to differentiate between cocrystals and salts, but the salt–cocrystal continuum values in XPS spectra are clustered in an intermediate range of cocrystals and salts but overlap with those of cocrystal or salt binding energies.

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Section: Introductionmentioning

confidence: 99%

Can We Identify the Salt–Cocrystal Continuum State Using XPS?

Tothadi

Shaikh

Gupta

et al. 2021

Crystal Growth & Design

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“…In this context, supramolecular synthons , have provided a foundation for the assembly of solid-state architectures with desired structural features, topologies, and chemical compositions. − The hydrogen bond − is, due to its strength and directionality, undoubtedly the most frequently used synthetic vector in supramolecular synthesis . Consequently, much work has been devoted to exploring how hydrogen-bond specificity is affected by geometric, steric, and electronic features within a particular molecular structure. , However, it is still very challenging to predict which set of intermolecular interactions a given molecule is most likely to form in the solid state; how, in competition with other intermolecular forces, can hydrogen bonding be used to reliably direct molecular self-assembly in three dimensions? Without this knowledge, it will be extremely difficult to successfully tackle more complex questions such as whether a molecule will crystallize or not, or if it is prone to polymorphism , or not, issues which are of considerable importance to the manufacturing, delivery, and performance of any high-value molecular solids …”

Section: Introductionmentioning

confidence: 99%

Evaluating Competing Intermolecular Interactions through Molecular Electrostatic Potentials and Hydrogen-Bond Propensities

Sandhu

McLean

Sinha

et al. 2017

Crystal Growth & Design

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The structural chemistry of six thiazole amides has been explored using experimental crystallographic data, and a combination of calculated hydrogen-bond propensities (HBPs) and hydrogen-bond energies. Both methods correctly identify the main hydrogen-bonded synthon, a pairwise N–H···N dimer, which appears in all the available structures. The strength and stability of the homosynthon in these compounds were tested by attempting to co-crystallize all six compounds with 20 different carboxylic acids. A total of 120 attempted reactions were carried out via liquid-assisted grinding experiments; sixty of these reactions produced a co-crystal, as indicated by IR spectroscopy. HBP calculations were employed in order to try to predict which of the 120 reactions would be successful. A multi-component score (MC score) was obtained from the hydrogen-bond propensity calculations, and this score coupled with a cut-off value >0.0 resulted in a 77% agreement between prediction and experiment (88% success for aliphatic acids and 67% for aromatic acids). By adjusting the MCcut‑off ≥ −0.1, the overall success rate for co-crystal prediction increased to 91% while significantly reducing the number of false negatives. The crystal structures of eight co-crystals were obtained, and all of them contain the synthon that was predicted by both hydrogen-bond energy and HBP calculations. The results demonstrate the importance of using complementary energy-based and structural chemistry methods for identifying which supramolecular pathways are accessible (and which are most likely) as small molecules transition from solution to the crystalline solid state.

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“…Several previous papers have identified the formation of LBHBs between carboxyl and nitrogen of pyridyl in compounds complexes through chemical calculations, ultralow temperature NMR and cocrystal structure studies [22,24,26,38], which was almost the same pattern with PAC-βGlu198 model. We calculated that the pKa value (using Propka 3.1) of βGlu198 to be 9.6, indicating that it is neutral (protonated) under normal conditions.…”

Section: An Lbhb Between Pac and βGlu198 Triggers Tubulin Degradationmentioning

confidence: 68%

“…and also form hydrogen bonds with βGlu198 (Fig. 4e) [38], they could not cause tubulin degradation effect and block PAC-induced degradation (Fig. 4f), suggesting that the hydrogen bond between OGlu198 and pyridine nitrogen of PAC may be special.…”

Section: The Pyridine Nitrogen Of Pac and Glu198 Of β-Tubulin Mediate The Tubulin Degradationmentioning

confidence: 99%

A new role of low barrier hydrogen bond in mediating protein stability by small molecules

Yang

Qiu

et al. 2021

Preprint

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Low barrier hydrogen bond (LBHB) is a special type of hydrogen bond which occurs where two heteroatoms with similar pKa values share a single proton resulting in an unusually strong and short hydrogen bond. LBHBs in protein play important roles in enzyme catalysis and maintaining protein structural integrity but its other biochemical roles are unknown. Here we report a novel function of LBHB in selectively inducing tubulin protein degradation. A tubulin inhibitor, 3-(3-Phenoxybenzyl) amino-β-carboline (PAC), promotes selective degradation of αβ-tubulin heterodimers by binding to the colchicine site of β-tubulin. Biochemical studies have revealed that PAC specifically destabilizes tubulin, making it prone to aggregation that then predisposes it to ubiquitinylation and then degradation. Structural activity analyses have indicated that the destabilization is mediated by a single hydrogen bond formed between the pyridine nitrogen of PAC and βGlu198, which is identified as a LBHB. In contrast, another two tubulin inhibitors only forming normal hydrogen bonds with βGlu198 exhibit no degradation effect. Thus, the LBHB accounts for the degradation. Most importantly, we screened for compounds capable of forming LBHB with βGlu198 and demonstrated that BML284, a Wnt signaling activator, also promotes tubulin heterodimers degradation in a PAC-like manner as expected. Our study has identified a novel approach for designing tubulin degraders, providing a unique example of LBHB function and suggests that designing small molecules to form LBHBs with protein residues resulting in the highly specific degradation of a target protein could be a new strategy for drug development.

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Aromatic versus Aliphatic Carboxyl Group as a Hydrogen Bond Donor in Salts and Cocrystals of an Asymmetric Diacid and Pyridine Derivatives

Cited by 21 publications

References 36 publications

Can We Identify the Salt–Cocrystal Continuum State Using XPS?

Can We Identify the Salt–Cocrystal Continuum State Using XPS?

Evaluating Competing Intermolecular Interactions through Molecular Electrostatic Potentials and Hydrogen-Bond Propensities

A new role of low barrier hydrogen bond in mediating protein stability by small molecules

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