Synthesis of Novel Vindoline‐Chrysin Hybrids Mayer, Szabolcs; Nagy, Nóra; Keglevich, Péter ...
Chemistry & biodiversity,
January 2022, 2022-Jan, 2022-01-00, 20220101, Volume:
19, Issue:
1
Journal Article
Peer reviewed
Vinca alkaloids are well‐known microtubule targeting agents, which are used against some types of cancer. Vindoline is one of the monomeric Vinca alkaloids which does not have anti‐tumor effect, ...although its derivatives have serious impact on the field of these indole alkaloids. Chrysin is a secondary plant metabolite, which has broad‐spectrum biological activity, among others anticancer activity. Chrysin had shown synergic effect with several antiproliferative compounds (e. g., doxorubicin, cisplatin and ciglitazone), therefore, we attempted the synthesis of a novel vindoline‐chrysin hybrid molecule. However, in the first case a diphenylamine structure was isolated. The mechanism of the unexpected reaction was studied, and then the originally targeted hybrid was synthesized by a reverse route coupling. A further hybrid was produced using a different site of the molecule. The antitumor activities were determined against 60 human tumor cell lines (NCI60), where the aimed hybrid showed low micromolar GI50 values on most of the cell lines.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A new class of selective vasopressin receptor 1A (V1A) 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. According to the in vitro pharmacological profiles of the compounds, the human V1A receptor has a strong preference toward the isomers having an aR axial chirality, the most active isomer being the aR,5S isomer. Furthermore, the structure–activity relationships obtained for the isomers and for the newly synthesized analogues could be tentatively explained by an in silico study.
•Advances of the past ten years in the MS-based characterization of protein biotherapeutics.•How to cope with industrial and regulatory requirements.•How to obtain accurate and reliable analytical ...data in a time- and cost-efficient way.•New sample preparation approaches, measurement techniques and data evaluation strategies.•Increasing role of mass spectrometry
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. However, even by using high-end instrumentation, analysts face several challenges with regard to how to cope with industrial and regulatory requirements, that is, how to obtain accurate and reliable analytical data in a time- and cost-efficient way. New sample preparation approaches, measurement techniques and data evaluation strategies are available to meet those requirements. The practical considerations of these methods are discussed in the present review article focusing on hot topics, such as reliable and efficient sequencing strategies, minimization of artefact formation during sample preparation, quantitative peptide mapping, the potential of multi-attribute methodology, the increasing role of mass spectrometry in higher-order structure characterization and the challenges of MS-based identification of host cell proteins. On the basis of the opportunities in new instrumental techniques, methodological advancements and software-driven data evaluation approaches, for the future one can envision an even wider application area for mass spectrometry in the biopharmaceutical industry.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•Biosimilars development.•The multiple role of modern NMR spectroscopy.•Characterizing therapeutic proteins.
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. However, the more recent industrial development, manufacturing, and quality control of biopharmaceuticals provide a different framework for NMR. For example, protein drug substances are not isotope-labeled and are present in a medium of excipients, which make structural NMR measurements much more difficult. On the other hand, biotechnology involves many other analytical requirements that can be efficiently addressed by NMR. In this respect the scope and limitations of NMR are less well understood. Having the non-expert reader in mind, herein we wish to highlight the ways in which modern NMR can effectively support biotechnological developments. Our focus will be on biosimilar proteins, pointing out certain cases where its use is probably essential. Based partly on literature data, and partly on our own hands-on experience, this paper is intended to be a guide for choosing the proper NMR approach for analytical questions concerning the structural comparability of therapeutic proteins, monitoring technology-related impurities, protein quantification, analysis of spent media, identification of extractable and leachable components, etc. Also, we focus on critical considerations, particularly those coming from drug authority guidelines, which limit the use of the well-established NMR tools in everyday practice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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. In silico studies of the Smiles rearrangement were performed. We also present the in vitro antiproliferative activity of the synthesized compounds against 60 human tumor cell lines (NCI60). The most potent derivative exhibited nanomolar antitumor activity on the MCF7 cell line of breast cancer (GI
= 30 nM) and on the HCT-15 cell line of colon cancer (GI
= 60 nM).
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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. In addition, we present case studies where the application of NUS contributed significantly to the successful completion of some challenging structure determination task at hand. To that end, in some cases, we combined NUS with a method of decoupling in the indirect dimension that gives ‘constant time’ nuclear Overhauser effect spectroscopy (NOESY) and ‘constant time’ heteronuclear multiple bond correlation (HMBC) spectra. NUS proved to be superior over traditional sampling even for the analysis of trace impurities, where the need to cope with a thousand‐fold or even larger dynamic range and low signal‐to‐noise ratio for the impurity signals is quite a challenge.
We demonstrate the advantages of nonuniform sampling (NUS) over traditional sampling in several pharmaceutical industrial applications of nuclear magnetic resonance. We propose an optimal trade‐off between the quality and time efficiency of routine measurements. Furthermore, we present four case studies where the application of NUS contributed significantly to the successful completion of challenging structure‐elucidation tasks. NUS proved to be superior over traditional sampling even for the analysis of trace impurities.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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). Several compounds exhibited in vitro antiproliferative activity against human gynecological cancer cell lines with IC
values in the low micromolar concentration range.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Contrary to common belief, high-resolution liquid-state NMR spectroscopy can distinguish between enantiomers in a nonracemic mixture even in the absence of any chiral additive if the structure of the ...analyte as well as the applied experimental conditions allow for weak intermolecular associations to be formed between the analyte molecules. Although the phenomenon, herein called self-induced recognition of enantiomers (SIRE), has been known for almost 50 years, it is still hardly used for analytical purposes. In this review we provide an overview of the history of SIRE with some practical guidance on how to elicit and make best use of it with modern NMR instrumentation. A compact description of the underlying basic theory is also given. In both the theoretical and experimental parts we rely heavily on our own insights and experiences gained on the subject, and many of those aspects are published here for the first time.
•NMR spectroscopy can distinguish between enantiomers in the absence of any chiral additive.•Weak intermolecular self-associations are behind this effect.•The method offers a very elegant way to measure enantiomeric excess.•Thus underlying theory is presented in a compact manner.•Practical guidance is given on eliciting this effect.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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