Synthesis and Characterization of New V Antagonist Compounds: The Separation of Four Atropisomeric Stereoisomers.

A new class of selective vasopressin receptor 1A (V) antagonists was identified, where "methyl-scan" was performed around the benzene ring of the 5-hydroxy-triazolobenzazepine core. This led to the synthesis of two 10-methyl derivatives, each possessing a chiral axis and a stereogenic center. The four atropisomeric stereoisomers (involving two enantiomer pairs and atropisomeric diastereomers) could be successfully isolated and spectroscopically characterized.

On the utility of nonuniformly sampled two-dimensional NMR spectra in the pharmaceutical industry.

In this work, we discuss representative examples of the application of nonuniform sampling (NUS) in small-molecule structure determination in a pharmaceutical research and development and quality control setting. We demonstrate the advantages of NUS over traditional sampling in various industrial applications of nuclear magnetic resonance (NMR). We propose an optimal trade-off between the quality and the time efficiency of 'routine' measurements, as demonstrated via a test sample of vinpocetine analyzed on a 'work horse' NMR spectrometer.

Synthesis and Cytotoxic Activity of New Vindoline Derivatives Coupled to Natural and Synthetic Pharmacophores.

New alkaloid derivatives were synthesized to improve the biological activity of the natural alkaloid vindoline. To this end, experiments were performed to link vindoline with various structural units, such as amino acids, a 1,2,3-triazole derivative, morpholine, piperazine and N-methylpiperazine. The structure of the new compounds was characterized by NMR spectroscopy and mass spectrometry (MS).

Synthesis and In Vitro Anticancer Evaluation of Novel Chrysin and 7-Aminochrysin Derivatives.

Chrysin is a naturally occurring flavonoid with mild anticancer activity. In this paper we report the synthesis of new chrysin derivatives alkylated with -phenylchloroacetamides in position 7. A novel method was developed for the preparation of 7-aminochrysin derivatives via the Smiles rearrangement, resulting in diphenylamine-type compounds.

Attempted Synthesis of Alkaloids Condensed with Three-Membered Rings.

Our successful work for the synthesis of cyclopropanated vinblastine and its derivatives by the Simmons⁻Smith reaction was followed to build up further three-membered rings into the 14,15-position of the vindoline part of the dimer alkaloid. Halogenated 14,15-cyclopropanovindoline was prepared by reactions with iodoform and bromoform, respectively, in the presence of diethylzinc. Reactions of dichlorocarbene with vindoline resulted in the 10-formyl derivative.

Recent advancements, challenges, and practical considerations in the mass spectrometry-based analytics of protein biotherapeutics: A viewpoint from the biosimilar industry.

The extensive analytical characterization of protein biotherapeutics, especially of biosimilars, is a critical part of the product development and registration. High-resolution mass spectrometry became the primary analytical tool used for the structural characterization of biotherapeutics. Its high instrumental sensitivity and methodological versatility made it possible to use this technique to characterize both the primary and higher-order structure of these proteins.

The effect of conjugation on antitumor activity of vindoline derivatives with octaarginine, a cell-penetrating peptide.

Some Vinca alkaloids (eg, vinblastine, vincristine) have been widely used as antitumor drugs for a long time. Unfortunately, vindoline, a main alkaloid component of Catharanthus roseus (L.) G.

What NMR can do in the biopharmaceutical industry.

Nuclear magnetic resonance (NMR) spectroscopy has a unique capability to probe the primary and higher order molecular structure and the structural dynamics of biomolecules at an atomic resolution, and this capability has been greatly fortified over the last five decades by an astonishing NMR instrumental and methodological development. Because of these factors, NMR has become a primary tool for the structure investigation of biomolecules, spawning a whole scientific subfield dedicated to the subject. This role of NMR is by now well established and broadly appreciated, especially in the context of academic research dealing with proteins that are purified and isotope-labeled in order to facilitate the necessary sophisticated multidimensional NMR measurements.

Biomimetic synthesis and HPLC-ECD analysis of the isomers of dracocephins A and B.

Starting from racemic naringenin ((±)-), a mixture of dracocephin A stereoisomers 6-(2"-pyrrolidinone-5"-yl)naringenin (±)- and its regioisomer, dracocephin B 8-(2"-pyrrolidinone-5"-yl)naringenin (±)- originally isolated from , have been synthesized in a one-pot reaction. The separation of and was achieved by preparative HPLC. The four stereoisomers of each natural product were separated by analytical chiral HPLC and their absolute configuration was studied by the combination of HPLC-ECD measurements and TDDFT-ECD calculations.

The Chemistry of Galanthamine. Classical Synthetic Methods and Comprehensive Study on its Analogues.

Galanthamine as an Amaryllidaceae alkaloid has an important role in the treatment of Alzheimer's disease. Some efforts were made to elaborate the total synthesis, and hundreds of its derivatives were prepared to find a more effective molecule with advantageous properties. Moreover, almost every part of the tetracycle was changed; in members of the rings, in the nature and position of the heteroatoms, and ring-opened analogues were also synthesized.

The influence of 5-HT(2A) activity on a 5-HT(2C) specific in vivo assay used for early identification of multiple acting SERT and 5-HT(2C) receptor ligands.

As a result of our exploratory programme aimed at elaborating dually acting compounds towards the serotonin (5-HT) transporter (SERT) and the 5-HT2C receptor a novel series of 3-amino-1-phenylpropoxy substituted diphenylureas was identified. From that collection two promising compounds (2 and 3) exhibiting highest 5-HT2C receptor affinity strongly inhibited the 5-HT2C receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) induced hypomotility in mice. In further pursuance of that objective (2-aminoethyl)(benzyl)sulfamoyl diphenylureas and diphenylpiperazines have also been elaborated.

Detection by HPLC and structural characterization by NMR and MS of a natural deuterium isotopologue of ulipristal acetate.

Herein we discuss the structure elucidation of an unknown peak detected by HPLC in the active pharmaceutical ingredient ulipristal acetate during analytical method development. An extensive chromatographic, MS and NMR spectroscopic study gave the surprising result that the detected component is the natural-abundance mono-deuterium isotopologue of the API. To the best of our knowledge this is the first example where such a mono-deuterium isotopologue could be resolved from its mother component by HPLC and structurally fully characterized by NMR and MS.

New oxidative decomposition mechanism of estradiol through the structural characterization of a minute impurity and its degradants.

Herein we discuss the structure elucidation of a labile estradiol-related degradant, X1. X1 was detected at Gedeon Richter as an unknown trace impurity in a pharmaceutical formulation containing estradiol (1a) and norethisterone acetate (NA) as active ingredients. The structural identification of X1 proved to be an unusually complex task involving an initial structural hypothesis based on some limited analytical data (UV) obtained from the formulation, synthetic work targeting the proposed structure, chromatographic enrichment from the synthetic reaction mixture, (HPLC)-MS and MS-MS studies of the formulation and of samples from the synthesis using almost all available ionization modes, preparative LC enrichment, and the complementary use of off-line and on-line NMR techniques.

NMR and mass spectrometric characterization of vinblastine, vincristine and some new related impurities--part II.

In the course of developing a new, improved process at Gedeon Richter for the production of the "bisindole" alkaloids vinblastine (VLB) and vincristine (VCR), some novel VLB/VCR-related trace impurities were detected by analytical HPLC at the production site. Repeated attempts to isolate and purify these unknown impurities by preparative liquid chromatography yielded small amounts of materials whose main components were the unknown impurities, but were still contaminated with other VLB/VCR-related compounds. In spite of these difficulties, by using a combination of high-resolution (LC-)MS/MS and off-line 1D and 2D ultra high-field NMR techniques and leaning on the relevant spectroscopic data for VLB and VCR as discussed in Part 1 [1], we could unambiguously solve the structures of, and could give a complete spectral characterization for, the trace impurities.

NMR and mass spectrometric characterization of vinblastine, vincristine and some new related impurities - part I.

In the course of exploring the possibilities of developing a new, improved process at Gedeon Richter for the production of the "bisindole" alkaloids vinblastine (VLB) and vincristine (VCR), some novel VLB/VCR-related trace impurities were detected by analytical HPLC. Following isolation by preparative HPLC, a combination of 1D and 2D ultra high-field NMR and high-resolution (HR) (LC-)MS/MS studies allowed the structural identification and complete spectral characterization of several hitherto unpublished VLB/VCR-analogue impurities. Since the impurities could not be isolated in entirely pure forms and were available only in minute, mass-limited quantities, accessing the spectral information needed for their ab initio structure determination was met with various practical difficulties.

Modifications on the basic skeletons of vinblastine and vincristine.

The synthetic investigation of biologically active natural compounds serves two main purposes: (i) the total synthesis of alkaloids and their analogues; (ii) modification of the structures for producing more selective, more effective, or less toxic derivatives. In the chemistry of dimeric Vinca alkaloids enormous efforts have been directed towards synthesizing new derivatives of the antitumor agents vinblastine and vincristine so as to obtain novel compounds with improved therapeutic properties.

Structure elucidation of indole-indoline type alkaloids: a retrospective account from the point of view of current NMR and MS technology.

In this review our aim is to look back on how the structure elucidation of bisindoles, especially with focus placed on vinblastine and vincristine analogues, has evolved alongside with the development of MS and NMR over the last 60 years from the perspective of our present-day use of state-of-the-art MS and NMR instrumentation and on the basis of our own accumulated views and experience in the field.

Antioxidant activity-guided phytochemical investigation of Artemisia gmelinii Webb. ex Stechm.: isolation and spectroscopic challenges of 3,5-O-dicaffeoyl (epi?) quinic acid and its ethyl ester.

Although Artemisia gmelinii Webb. ex Stechm. has long been used in south and south-east Asia to treat many kinds of inflammatory diseases, up until now its bioactivity-coupled phytochemical characterization has not been reported.

Structure of the major degradant of ezetimibe.

In a recent contribution to this Journal Gajjar and Shah described the isolation and structure elucidation of the major alkaline degradant of ezetimibe, a lipid lowering agent [A.K. Gajjar, V.

Synthesis and in vitro antitumor effect of vinblastine derivative-oligoarginine conjugates.

Vinblastine is a widely used anticancer drug with undesired side effects. Its conjugation with carrier molecules could be an efficient strategy to reduce these side effects. Besides this, the conjugate could exhibit increased efficiency against resistant cells, e.

Synthesis and evaluation of 2'-hydroxyethyl trans-apovincaminate derivatives as antioxidant and cognitive enhancer agents.

A series of trans-2'-hydroxyethyl and 2'-acyloxyethyl apovincaminates 4b- f and 7b- f has been synthesized and evaluated for their antioxidant and antiamnesic effects. The new esters were prepared from 4a and 7a ethyl esters or from the corresponding carboxylic acid sodium salt. For starting materials 11a, b, a new stereoselective trans-reduction was elaborated.

Syntheses of vinca alkaloids and related compounds. 104. A concise synthesis of (-)-vincapusine.

beta-Iodo-enamines with an eburnane skeleton (5a and 5c) were obtained with the aid of iodine from compounds 2a and 2c and were then transformed into hydroxyl lactams (6a and 6c) with CuSO4.5H2O in a mixture of DMF and water. Lactams (6a and 6c) were reduced selectively with BH3.

[Synthesis and NMR structure elucidation of bromocryptine stereoisomers].

We describe for the first time the synthesis and NMR structural characterization of two important but so far ignored diasteroisomers of bromokryptine. During this work we have made some interesting insights regarding the conformational and epimerizational behaviour of these molecules.

Novel secoergoline derivatives inhibit both GABA and glutamate uptake in rat brain homogenates: synthesis, in vitro pharmacology, and modeling.

Three of twelve secoergoline derivatives (Z ethyl 4-[(ethoxycarbonylmethyl)methylamino]-2-methyl-3-phenylpent-2-enoate, 8; ethyl 1,6-dimethyl-3-oxo-5-phenyl-1,2,3,6-tetrahydropyridine-2-carboxylate, 9; Z methyl 4-[(methoxycarbonylmethyl)methylamino)-2-methyl-3-phenylpent-2-enoate, 11), containing bioisosteric sequences of GABA and Glu, inhibited both GABA and Glu transport through cerebrocortical membranes specifically. Compounds 8, 9, and 11 appeared to be equipotent inhibitors of GABA and Glu transport with IC50 values between 270 and 1100 microM, whereas derivatives 1-7, 10, and 12 were without effects. In the presence of GABA and Glu transport-specific nontransportable inhibitors, inhibition of GABA and Glu transport by 8, 9, and 11 proceeded in two phases.

Enantioefficient synthesis of alpha-ergocryptine: first direct synthesis of (+)-lysergic acid.

The first direct synthesis of (+)-lysergic acid (2a) suitable for scale-up has been achieved by the following reaction sequence. Bromoketones 4d or 4g were allowed to react with amine 5 followed by deprotection, and the resulting diketone 6c was transformed into the unsaturated ketone (+/-)-7 by the LiBr/Et(3)N system. Resolution afforded (+)-7, which was further transformed by Schöllkopf's method into the mixture of esters 2e and 2f.