New Crystal Forms for Biologically Active Compounds. Part 1: Noncovalent Interactions in Adducts of Nevirapine with XB Donors

Stabilization of specific crystal polymorphs of an active pharmaceutical ingredient is crucial for preventing uncontrollable interconversion of various crystalline forms, which affects physicochemical properties as well as physiological activity. Co-crystallization with various excipients is an emerging productive way of achieving such stabilization in the solid state. In this work, we identified an opportunity for co-crystallization of antiviral drug nevirapine (NVP) with a classical XB donor, 1,2,4,5-tetrafluoro-3,6-diiodobenzene (1,4-FIB), as well as 1,3-diiodobenzene (1,3-DIB), which has been seldom employed as an XB donor to date. In the X-ray structures of NVP·1,4-FIB and NVP·1,3-DIB co-crystals, different hydrogen and halogen bonding modes were detected and further investigated via DFT calculations as well as topological analysis of the electron density distribution within the framework of the QTAIM method at the M06/DZP-DKH level of theory. Estimated energies of these supramolecular contacts vary from 0.6 to 5.7 kcal/mol

New Crystal Forms for Biologically Active Compounds. Part 2: Anastrozole as N-Substituted 1,2,4-Triazole in Halogen Bonding and Lp-π Interactions with 1,4-Diiodotetrafluorobenzene

For an active pharmaceutical ingredient, it is important to stabilize its specific crystal polymorph. If the potential interconversion of various polymorphs is not carefully controlled, it may lead to deterioration of the drug’s physicochemical profile and, ultimately, its therapeutic efficacy. The desired polymorph stabilization can be achieved via co-crystallization with appropriate crystallophoric excipients. In this work, we identified an opportunity for co-crystallization of anastrozole (ASZ), a well-known aromatase inhibitor useful in second-line therapy of estrogen-dependent breast cancer, with a classical XB donor, 1,2,4,5-tetrafluoro-3,6-diiodobenzene (1,4-FIB). In the X-ray structures of ASZ·1.5 (1,4-FIB) co-crystal, different non-covalent interactions involving hydrogen and halogen atoms were detected and studied by quantum chemical calculations and QTAIM analysis at the ωB97XD/DZP-DKH level of theory

Engineering of Thermal Stability in a Cold-Active Oligo-1,6-Glucosidase from Exiguobacterium sibiricum with Unusual Amino Acid Content

A gene coding for a novel putative amylase, oligo-1,6-glucosidase from a psychrotrophic bacterium Exiguobacterium sibiricum from Siberian permafrost soil was cloned and expressed in Escherichia coli. The amino acid sequence of the predicted protein EsOgl and its 3D model displayed several features characteristic for the cold-active enzymes while possessing an unusually high number of proline residues in the loops—a typical feature of thermophilic enzymes. The activity of the purified recombinant protein was tested with p-nitrophenyl α-D-glucopyranoside as a substrate. The enzyme displayed a plateau-shaped temperature-activity profile with the optimum at 25 °C and a pronounced activity at low temperatures (50% of maximum activity at 5 °C). To improve the thermal stability at temperatures above 40 °C, we have introduced proline residues into four positions of EsOgl by site-directed mutagenesis according to “the proline rule”. Two of the mutants, S130P and A109P demonstrated a three- and two-fold increased half-life at 45 °C. Moreover, S130P mutation led to a 60% increase in the catalytic rate constant. Combining the mutations resulted in a further increase in stability transforming the temperature-activity profile to a typical mesophilic pattern. In the most thermostable variant A109P/S130P/E176P, the half-life at 45 °C was increased from 11 min (wild-type) to 129 min

Molecular complexes of non-chelating polydentate Lewis bases with group 13 Lewis acids: crystal structure and computed energy of stepwise donor–acceptor bond formation

The crystal structures of five donor-acceptor (DA) complexes of 1 : 1 and 2 : 1 composition between E(C6F5)3 (E = B, Al, Ga and In) and pyrazine (pyz) as a non-chelating bidentate nitrogen-containing donor, as well as the GaI3 center dot pyz center dot GaI3 complex have been established for the first time. A joint analysis of the experimental structural data and the results of computations at the M06-2X/def2-TZVP level of theory reveals that with an increase in the number of acceptor molecules in the DA complex, the DA bond distances increase, while the DA bond energies and Wiberg bond indexes decrease, indicating a weaker bonding. The previously reported 'inverse' relationship between the Lewis acidity and the capacity of a polydentate donor to complex with multiple Lewis acids is not confirmed

Selective and Reversible 1,3-Dipolar Cycloaddition of 2-(2-Oxoindoline-3-ylidene)acetates with Nitrones in the Synthesis of Functionalized Spiroisoxazolidines

The 1,3-dipolar cycloaddition of 2-(2-oxoindoline-3-ylidene)acetates with functionalized aldo- and ketonitrones proceeds with good selectivity to provide new highly functionalized 5-spiroisoxazolidines. A characteristic feature of these reactions is reversibility that allows for the control of the diastereoselectivity of cycloaddition. The reduction of obtained adducts using zinc powder in acetic acid leads to 1,3-aminoalcohols or spirolactones. For a number of the spiro compounds obtained, anticancer activity was found

Structures, Bonding and Sensor Properties of Some Alkaline o-Phthalatocuprates

Comprehensive study of the structure and bonding of disodium, dipotassium and diammonium di-o-phthalatocuprates(II) dihydrates has been undertaken. The crystal structure of ammonium o-phthalatocuprate has been determined. The identity of structures of phthalatocuprate chains in potassium and ammonium salts has been revealed. Vibrational spectra of all three compounds have been recorded, and the assignment of vibrational bands has been made. Force field calculations have shown a minor effect of outer-sphere cations (Na+, K+, NH4+) on both intraligand (C-O) and metal–ligand bond strengths. Synthesized compounds have been tested as electrochemical sensors on D-glucose, dopamine and paracetamol. Their sensitivity to analytes varied in the order of Na+ > K+ > NH4+. This effect has been explained by the more pronounced steric hindrance of copper ions in potassium and ammonium salts

Structural and Biochemical Characterization of a Cold-Active PMGL3 Esterase with Unusual Oligomeric Structure

The gene coding for a novel cold-active esterase PMGL3 was previously obtained from a Siberian permafrost metagenomic DNA library and expressed in Escherichia coli. We elucidated the 3D structure of the enzyme which belongs to the hormone-sensitive lipase (HSL) family. Similar to other bacterial HSLs, PMGL3 shares a canonical α/β hydrolase fold and is presumably a dimer in solution but, in addition to the dimer, it forms a tetrameric structure in a crystal and upon prolonged incubation at 4 °C. Detailed analysis demonstrated that the crystal tetramer of PMGL3 has a unique architecture compared to other known tetramers of the bacterial HSLs. To study the role of the specific residues comprising the tetramerization interface of PMGL3, several mutant variants were constructed. Size exclusion chromatography (SEC) analysis of D7N, E47Q, and K67A mutants demonstrated that they still contained a portion of tetrameric form after heat treatment, although its amount was significantly lower in D7N and K67A compared to the wild type. Moreover, the D7N and K67A mutants demonstrated a 40 and 60% increase in the half-life at 40 °C in comparison with the wild type protein. Km values of these mutants were similar to that of the wt PMGL3. However, the catalytic constants of the E47Q and K67A mutants were reduced by ~40%

Chitosan Sponges for Efficient Accumulation and Controlled Release of C-Phycocyanin

The paper proposed a new porous material for wound healing based on chitosan and C-phycocyanin (C-PC). In this work, C-PC was extracted from the cyanobacteria Arthrospira platensis biomass and purified through ammonium sulfate precipitation. The obtained C-PC with a purity index (PI) of 3.36 ± 0.24 was loaded into a chitosan sponge from aqueous solutions of various concentrations (250, 500, and 1000 mg/L). According to the FTIR study, chitosan did not form new bonds with C-PC, but acted as a carrier. The encapsulation efficiency value exceeded 90%, and the maximum loading capacity was 172.67 ± 0.47 mg/g. The release of C-PC from the polymer matrix into the saline medium was estimated, and it was found 50% of C-PC was released in the first hour and the maximum concentration was reached in 5–7 h after the sponge immersion. The PI of the released C-PC was 3.79 and 4.43 depending on the concentration of the initial solution