Photodegradation of Dacarbazine Catalyzed by Vitamin B and Flavin Adenine Dinucleotide Under Visible-Light Irradiation.

Purpose: Drug photodegradation is a matter of great concern because it can result in potency loss and adverse side effects. This study examines the light-induced degradation of dacarbazine catalyzed by vitamin B and flavin adenine dinucleotide (FAD) under light-emitting diode (LED) or fluorescent light irradiation.

Methods: Dacarbazine was irradiated with LED (405 nm) or fluorescent light in the presence of various equivalents of vitamin B or FAD.

Stereochemical properties of quazepam and its affinity for the GABA receptor.

C9-methylated quazepam 1 was prepared, and its physicochemical properties were investigated. The atropisomers of 1 were isolated as (aR, aS) and (aS, aR) isomers. Their absolute configurations were determined based on ECD spectra in comparison with those calculated using the time-dependent density functional theory.

Fentanyl-Type Antagonist of the μ-Opioid Receptor: Important Role of Axial Chirality in the Active Conformation.

In recent years, synthetic opioids have emerged as a predominant cause of drug-overdose-related fatalities, causing the "opioid crisis." To design safer therapeutic agents, we accidentally discovered μ-opioid receptor (MOR) antagonists based on fentanyl with a relatively uncomplicated chemical composition that potentiates structural modifications. Here, we showed the development of novel atropisomeric fentanyl analogues that exhibit more potent antagonistic activity against MOR than naloxone, a morphinan MOR antagonist.

Isomerization of -Cinnamamides into -Cinnamamides Using a Recycling Photoreactor.

The photocatalytic synthesis of thermodynamically less-stable -alkenes has received considerable research attention in recent years. In this study, a recycling photoreactor was applied to the photoisomerization of -alkenes (cinnamamide and Weinreb amide derivatives) to produce -alkenes. The closed-loop recycling system comprises an immobilized photosensitizer to achieve rapid photoisomerization and a high-performance liquid chromatography instrument for separation of the / diastereomers.

Enzyme from Padina arborescens Holmes Synthesizes Parinaric Acid, a Conjugated Tetraenoic Fatty Acid, from α-Linolenic Acid.

Conjugated fatty acids have anticancer effects. Therefore, the establishment of a synthetic method for conjugated fatty acids is important for overcoming cancer. Here, we attempted to synthesize conjugated fatty acids using enzymes extracted from seaweeds containing these fatty acids.

Stereochemistry of -Acyl-5-dibenzo[,]azepin-7(6)-ones.

The stereochemical properties of -acyl-5-dibenzo[,]azepin-7(6)-ones (-), which inhibit potassium channels in T cells, were examined by freezing their conformational change due to 4-methyl substitution. -Acyl-5-dibenzo[,]azepin-7(6)-ones exist as pairs of enantiomers [(a, a), (a, a)], and each atropisomer is separable at room temperature. An alternate procedure for preparing 5-dibenzo[,]azepin-7(6)-ones involves the intramolecular Friedel-Crafts cyclization of -benzyloxycarbonylated biaryl amino acids.

Stereochemical Analysis of Trifluoroacetamide Derivatives Based on Through- HF Spin-Spin Couplings.

In this study, the conformational properties of tertiary trifluoroacetamides in dibenzoazepine ( and ) and benzodiazepine ( and ) derivatives, which exist as equilibrated - and amide conformers in solution, were investigated by H and F NMR spectroscopy. In all cases, one of the methylene protons neighboring the nitrogen atom of the minor conformer showed a finely split pattern due to coupling with the trifluoromethyl fluorine atoms, as confirmed by F-decoupling experiments. One-dimensional (1D) and two-dimensional (2D) H-F heteronuclear Overhauser spectroscopy (HOESY) experiments were performed to confirm whether these couplings are attributable to through- spin-spin couplings (TBCs) or through- spin-spin couplings (TSCs).

Conversion of Racemic Alkyl Aryl Sulfoxides into Pure Enantiomers Using a Recycle Photoreactor: Tandem Use of Chromatography on Chiral Support and Photoracemization on Solid Support.

Chiral sulfoxides are valuable in the fields of medicinal chemistry and organic synthesis. A recycle photoreactor utilizing the concept of deracemization, where a racemate is converted into a pure enantiomer, is developed and successfully applied in the syntheses of chiral alkyl aryl sulfoxides. The recycling system consists of rapid photoracemization using an immobilized photosensitizer and separation of the enantiomers via chiral high-performance liquid chromatography, and the desired pure chiral sulfoxides are obtained after 4-6 cycles.

Atropodiastereoselective 5-Acylation of 1,5-Benzodiazepin-2-ones with ()-2-Phenylpropanoyl and ()-2-Phenylbutanoyl Chlorides.

5-Acylation of 1-methyl-1,5-benzodiazepin-2-ones with ()-2-phenylpropanoyl and ()-2-phenylbutanoyl chlorides afforded the (a,a,)-atropisomer () diastereoselectively over the (a,a,)-isomer () in the ratio of 1:0.06-0.15.

Proteomics-Based Transporter Identification by the PICK Method: Involvement of TM7SF3 and LHFPL6 in Proton-Coupled Organic Cation Antiport at the Blood-Brain Barrier.

A proton-coupled organic cation (H/OC) antiporter working at the blood-brain barrier (BBB) in humans and rodents is thought to be a promising candidate for the efficient delivery of cationic drugs to the brain. Therefore, it is important to identify the molecular entity that exhibits this activity. Here, for this purpose, we established the roteomics-based dentification of transporter by rosslinking substrate in eyhole (PICK) method, which combines photo-affinity labeling with comprehensive proteomics analysis using SWATH-MS.

Atropisomeric Properties of N-Alkyl/Aryl 5H-Dibenz[b,f]azepines.

The atropisomeric properties of N-alkyl and N-aryl 4-substituted 5H-dibenz[b,f]azepines were investigated. The N-alkylation and N-arylation of 4-Cl or 4-Me substituted compounds was performed; however, none of the atropisomers produced were separated by chiral HPLC. Notably, we observed that the rotation of the four axes (ax.

Axial chirality and affinity at the GABA receptor of triazolobenzodiazepines.

Triazolobenzodiazepines substituted with a methyl group at the C1- and C10-positions and chloro group at C2' of pendant-phenyl were prepared and their physicochemical properties were investigated. The atropisomers of 1,10-disubstituted triazolobenzodiazepines, 1d and 1f, were isolated as (aR, aS) and (aS, aR) isomers. Their absolute configurations were determined on the basis of CD spectra in comparison with those of stereochemically defined 9-methyl-1,4-benzodiazepin-2-ones.

Photoisomerization of Sulindac and Ozagrel Hydrochloride by Vitamin B Catalyst Under Visible Light Irradiation.

Purpose: Photoisomerization of the E/Z-alkene structures of drugs is a matter of concern as it could result in potency loss and adverse side effects. This study focused on light-induced isomerization of sulindac and ozagrel hydrochloride catalyzed by concomitant vitamin B under light-emitting diode (LED) or fluorescent light.

Methods: In the presence of 0.

Rapid Photoracemization of Chiral Alkyl Aryl Sulfoxides.

The photoracemization of chiral alkyl aryl sulfoxides with a photosensitizer has not been sufficiently investigated thus far. Therefore, in this study, a rapid photoracemization reaction of enantiopure alkyl aryl sulfoxides using 1 mol % 2,4,6-triphenylpyrylium tetrafluoroborate (TPT) was developed. Various substitution patterns were tolerated and every racemization reaction proceeded extremely fast ( = 1.

Atropisomeric Properties of -Acyl/-Sulfonyl 5-Dibenzo[,]azepin-7(6)-ones.

The stereochemistry of -acyl/-sulfonyl 5-dibenzo[,]azepin-7(6)-ones (, ) was examined in detail by freezing the conformation with a methyl group at the C-4 of dibenzoazepine. Because the two axes (axis 1, axis 2) move together concertedly, and exist only as a pair of enantiomers [(a, a) and (a, a)], which was confirmed by X-ray analysis of . It was elucidated that the amide derivatives exist in equilibrium with the /-amide (100:2-100:34), which means that the exocyclic bond (axis 3) is not in concert with the endocyclic axes (axis 1, axis 2).

Conformational Preference of 2'-Fluoro-Substituted Acetophenone Derivatives Revealed by Through-Space H-F and C-F Spin-Spin Couplings.

The conformational properties of 2'-fluoro-substituted acetophenone derivatives were elucidated based on H-F and C-F through-space spin-spin couplings (TS-couplings), which occur between two atoms constrained at a distance smaller than the sum of their van der Waals radii. This study revealed that 2'-fluoro-substituted acetophenone derivatives in solutions form exclusively - conformers by analyzing their NMR spectra focused on the TS-couplings. The magnitudes of the coupling constants (H, F) and (C, F) correlate linearly with the value of the dielectric constant of the solvents.

Differentiation of Positional Isomers of Halogenated Benzoylindole Synthetic Cannabinoid Derivatives in Serum by Hybrid Quadrupole/Orbitrap Mass Spectrometry.

Legally regulated synthetic cannabinoids (SCs) are continuously being created by making minor positional modifications to pre-existing analogs; thus, compounds with minor structural differences must be isolated and identified accurately. For iodo-benzoylindole derivatives of SCs, only specific isomers are currently the target of legal control, and it is necessary to establish an analytical method for accurately identifying positional isomers. In this study, we synthesized a series of 57 designer drugs and developed a screening method for identifying halogen positional isomers on the phenyl ring of benzoylindole derivative SCs in serum.

Structural Requirements for Uptake of Diphenhydramine Analogs into hCMEC/D3 Cells Via the Proton-Coupled Organic Cation Antiporter.

There is increasing evidence that a proton-coupled organic cation (H/OC) antiporter facilitates uptake of various central nervous system-active drugs, such as the histamine H1 receptor antagonist diphenhydramine, into the brain. The purpose of this study was to clarify the structural requirements for H/OC antiporter-mediated uptake into hCMEC/D3 cells, an established in vitro model of the human blood-brain barrier, by using a series of diphenhydramine analogs. For this purpose, we synthesized seven tertiary amine analogs and three amide analogs.

Elucidation of the Active Conformation of Antiproliferative Sulfonamides, 5-Arylsulfonyl-1,5-benzodiazepin-2-ones.

The 5-arylsulfonyl-1,5-benzodiazepin-2-ones with antiproliferative activity were prepared and successfully separated into the (a,a)- and (a,a)-atropisomers with extraordinary stability (Δ = ∼130 kJ/mol) by freezing the conformation around the sp-sp axis in an Ar-N(SO) moiety with a C6-methyl group. Also, by introducing a C3-methyl group (central chirality) into the 1,5-benzodiazepine nucleus, the stereochemistry at the axis was biased to take solely one diastereomer with a relative stereochemistry of (a*,a*,3*). The (a) stereochemistry was crucial for exerting the antiproliferative activity.

4-Substituted carbamazepine derivatives: Conformational analysis and sodium channel-blocking properties.

The physicochemical properties of 4-substituted carbamazepine derivatives were investigated. It was elucidated that the 4-substitution is not effective in reducing the rotations (E/Z) about the N-C1' axes around the outer carbamoyl moiety. However, the atropisomers were isolated with high stereochemical stability, meaning that the 4-substitution reduced the butterfly motion of the tricyclic ring system efficiently.

Elucidation of the E-Amide Preference of N-Acyl Azoles.

The conformational properties of N-acyl azoles (imidazole, pyrazole, and triazole) were examined. The N-2',4',6'-trichlorobenzoyl azoles were stable in methanol at room temperature, and no hydrolyzed products were observed over 7 days in the presence of 5% trifluoroacetic acid or 5% triethylamine in CDCl. The high stability may be explained by the double-bond amide character caused by the steric hindrance due to the ortho-substituents in the benzoyl group.

Comprehensive Quantitation Using Two Stable Isotopically Labeled Species and Direct Detection of N-Acyl Moiety of Sphingomyelin.

Sphingomyelin (ceramide-phosphocholine, CerPCho) is a common sphingolipid in mammalian cells and is composed of phosphorylcholine and ceramide as polar and hydrophobic components, respectively. In this study, a qualitative liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS/MS) analysis is proposed in which CerPCho structures were assigned based on product ion spectra corresponding to sphingosylphosphorylcholine and N-acyl moieties. From MS/MS/MS analysis of CerPCho, we observed product ion spectra of the N-acyl fatty acids as [RCO] ions as well as sphingosylphosphorylcholine.

Tolvaptan-Type Vasopressin Receptor Ligands: Important Role of Axial Chirality in the Active Form.

The anti and syn isomers of tolvaptan-type compounds, N-benzoyl-5-hydroxy-1-benzazepines (5a-c), were prepared in a stereocontrolled manner by biasing the conformation with a methyl group at C9 and C6, respectively, and the enantiomeric forms were separated. Examination of the affinity at the human vasopressin receptors revealed that the axial chirality (aS) plays a more important role than the central chirality at C5 in receptor recognition, and the most preferable form was shown to be (E,aS,5S).

Stereochemistry of N-Benzoyl-5-substituted-1-benzazepines Revisited: Synthesis of the Conformationally Biased Derivatives and Revision of the Reported Structure.

The syn (aR*,5R*) and anti (aS*,5R*) diastereomers of N-benzoyl-C5-substituted-1-benzazepines originating in the chiralities at C5 and the Ar-N(C═O) axis were first stereoselectively synthesized by biasing the conformation with a substituent at C6 and C9, respectively. Detailed examination of the stereochemistry (i.e.

N-benzoyl-1,5-benzothiazepine and its S-oxide as vasopressin receptor ligands: insight into the active stereochemistry around the seven-membered ring.

The stereochemistry of N-benzoyl-1,5-benzothiazepine and its S-oxide derivatives as vasopressin receptor ligands was examined in detail by freezing the conformation with a methyl group at the C6 or C9 of 1,5-benzothiazepine. It was revealed that the active forms recognized by the receptors are (cis,aS) for 1,5-benzothiazepine (5-7)-II and (cis,1S,aS) (syn) for its S-oxide (8-10)-II. The C9-methyl derivative of 1,5-benzothiazepine S-oxide (10-II) was designed and synthesized, achieving the putative active syn-isomer.