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Biologically Active Agents from Polycyclic Compounds through Biocatalytic and Chemical Approaches

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 24558

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Prof. Dr. Irina Ivshina

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Guest Editor

Institute of Ecology and Genetics of Microorganisms UB RAS – Perm Federal Research Center UB RAS, Perm, Russia
Interests: microbial diversity; microbial chemistry; bioconversion of organic pollutants; immobilization of microorganisms; biocatalysts based on actinobacteria; applied biocatalysis; biotechnology
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Dr. Victoria Grishko

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Guest Editor

Institute of Technical Chemistry, Perm Federal Research Centre, Ural Branch of the Russian Academy of Sciences, 3 Acad. Korolev St., 614013 Perm, Russia
Interests: chemistry of natural compounds; medicinal chemistry; biotransformation; terpenoids; biological activity

Special Issue Information

Dear colleagues,

This Special Issue is dedicated to problems of catalyst and technology developments intended for production of novel biologically active compounds from natural polycyclic alkaloids, glycosides, sapogenins, steroids, terpenoids, etc. Considering the chemical and structural variety of such substrates, as well as their stereochemical complexity, special emphasis is put on methods of selective transformation of polycyclic compounds, including methods based on enzymes and microbial whole cells. Compared with traditional organic synthesis, the use of microorganisms allows obtaining enantiomerically pure compounds via one-stage synthesis. This is due to their exceptional chemo- and stereoselectivity, a wide range of metabolizable substrates, the absent problem of minimizing side reactions or using multiple protection/deprotection steps, and also their stable activity in extreme environmental conditions. Biocatalysis is growing in demand in the industry, and this is mainly associated with greater availability of high-quality bioresources in world microbial collections, advances in genomics, proteomics, and also with synthetic biology and bioinformatics tools. Original research articles and reviews of this Special Issue may cover any aspects of transformation mechanisms of polycyclic compounds to produce novel derivatives with marked biological activities and valuable intermediates for the pharmaceutical industry. Interdisciplinary studies relying on new ideas and approaches are welcome.

Prof. Dr. Irina Ivshina
Dr. Victoria Grishko
Guest Editors

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Keywords

polycyclic compounds
biologically active compounds
green chemistry
biocatalysis
microorganisms and enzymes
immobilized biocatalysts
organic synthesis
chemistry of natural compounds

Published Papers (7 papers)

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Research

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16 pages, 742 KiB

Open AccessArticle

Isobornylchalcones as Scaffold for the Synthesis of Diarylpyrazolines with Antioxidant Activity

by Svetlana A. Popova, Evgenia V. Pavlova, Oksana G. Shevchenko, Irina Yu. Chukicheva and Aleksandr V. Kutchin

Molecules 2021, 26(12), 3579; https://doi.org/10.3390/molecules26123579 - 11 Jun 2021

Cited by 8 | Viewed by 2032

Abstract

The pyrazoline ring is defined as a “privileged structure” in medicinal chemistry. A variety of pharmacological properties of pyrazolines is associated with the nature and position of various substituents, which is especially evident in diarylpyrazolines. Compounds with a chalcone fragment show a wide range of biological properties as well as high reactivity which is primarily due to the presence of an α, β-unsaturated carbonyl system. At the same time, bicyclic monoterpenoids deserve special attention as a source of a key structural block or as one of the pharmacophore components of biologically active molecules. A series of new diarylpyrazoline derivatives based on isobornylchalcones with different substitutes (MeO, Hal, NO₂, N(Me)₂) was synthesized. Antioxidant properties of the obtained compounds were comparatively evaluated using in vitro model Fe²⁺/ascorbate-initiated lipid peroxidation in the substrate containing brain lipids of laboratory mice. It was demonstrated that the combination of the electron-donating group in the para-position of ring B and OH-group in the ring A in the structure of chalcone fragment provides significant antioxidant activity of synthesized diarylpyrazoline derivatives. Full article

(This article belongs to the Special Issue Biologically Active Agents from Polycyclic Compounds through Biocatalytic and Chemical Approaches)

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17 pages, 1414 KiB

Open AccessArticle

Enhancement of the Antioxidant and Skin Permeation Properties of Betulin and Its Derivatives

by Andrzej Günther, Edyta Makuch, Anna Nowak, Wiktoria Duchnik, Łukasz Kucharski, Robert Pełech and Adam Klimowicz

Molecules 2021, 26(11), 3435; https://doi.org/10.3390/molecules26113435 - 5 Jun 2021

Cited by 19 | Viewed by 3028

Abstract

This study investigated the antioxidant activity DPPH, ABTS, and Folin–Ciocalteu methods of betulin (compound 1) and its derivatives (compounds 2–11). Skin permeability and accumulation associated with compounds 1 and 8 were also examined. Identification of the obtained products (compound 2–11) and betulin isolated from plant material was based on the analysis of ¹H- NMR and ¹³C-NMR spectra. The partition coefficient was calculated to determine the lipophilicity of all compounds. In the next stage, the penetration through pig skin and its accumulation in the skin were evaluated of ethanol vehicles containing compound 8 (at a concentration of 0.226 mmol/dm³), which was characterized by the highest antioxidant activity. For comparison, penetration studies of betulin itself were also carried out. Poor solubility and the bioavailability of pure compounds are major constraints in combination therapy. However, we observed that the ethanol vehicle was an enhancer of skin permeation for both the initial betulin and compound 8. The betulin 8 derivative showed increased permeability through biological membranes compared to the parent betulin. The paper presents the transformation of polycyclic compounds to produce novel derivatives with marked antioxidant activities and as valuable intermediates for the pharmaceutical industry. Moreover, the compounds contained in the vehicles, due to their mechanism of action, can have a beneficial effect on the balance between oxidants and antioxidants in the body, minimizing the effects of oxidative stress. The results of this work may contribute to knowledge regarding vehicles with antioxidant potential. The use of vehicles for this type of research is therefore justified. Full article

(This article belongs to the Special Issue Biologically Active Agents from Polycyclic Compounds through Biocatalytic and Chemical Approaches)

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23 pages, 7338 KiB

Open AccessArticle

Discovery of Novel Sultone Fused Berberine Derivatives as Promising Tdp1 Inhibitors

by Elizaveta D. Gladkova, Arina A. Chepanova, Ekaterina S. Ilina, Alexandra L. Zakharenko, Jóhannes Reynisson, Olga A. Luzina, Konstantin P. Volcho, Olga I. Lavrik and Nariman F. Salakhutdinov

Molecules 2021, 26(7), 1945; https://doi.org/10.3390/molecules26071945 - 30 Mar 2021

Cited by 6 | Viewed by 2680

Abstract

A new type of berberine derivatives was obtained by the reaction of berberrubine with aliphatic sulfonyl chlorides. The new polycyclic compounds have a sultone ring condensed to C and D rings of a protoberberine core. The reaction conditions were developed to facilitate the formation of sultones with high yields without by-product formation. Thus, it was shown that the order of addition of reagents affects the composition of the reaction products: when sulfochlorides are added to berberrubine, their corresponding 9-O-sulfonates are predominantly formed; when berberrubine is added to pre-generated sulfenes, sultones are the only products. The reaction was shown to proceed stereo-selectively and the cycle configuration was confirmed by 2D NMR spectroscopy. The inhibitory activity of the synthesized sultones and their 12-brominated analogs against the DNA-repair enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1), an important target for a potential antitumor therapy, was studied. All derivatives were active in the micromolar and submicromolar range, in contrast to the acyclic analogs and 9-O-sulfonates, which were inactive. The significance of the sultone cycle and bromine substituent in binding with the enzyme was confirmed using molecular modeling. The active inhibitors are mostly non-toxic to the HeLa cancer cell line, and several ligands show synergy with topotecan, a topoisomerase 1 poison in clinical use. Thus, novel berberine derivatives can be considered as candidates for adjuvant therapy against cancer. Full article

(This article belongs to the Special Issue Biologically Active Agents from Polycyclic Compounds through Biocatalytic and Chemical Approaches)

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Review

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14 pages, 2764 KiB

Open AccessFeature PaperReview

Biosynthetic Strategies for Macrocyclic Peptides

by Wei Wang, S. Cyrus Khojasteh and Dian Su

Molecules 2021, 26(11), 3338; https://doi.org/10.3390/molecules26113338 - 1 Jun 2021

Cited by 7 | Viewed by 4734

Abstract

Macrocyclic peptides are predominantly peptide structures bearing one or more rings and spanning multiple amino acid residues. Macrocyclization has become a common approach for improving the pharmacological properties and bioactivity of peptides. A variety of ribosomal-derived and non-ribosomal synthesized cyclization approaches have been established. The biosynthesis of backbone macrocyclic peptides using seven new emerging methodologies will be discussed with regard to the features and strengths of each platform rather than medicinal chemistry tools. The mRNA display variant, known as the random nonstandard peptide integrated discovery (RaPID) platform, utilizes flexible in vitro translation (FIT) to access macrocyclic peptides containing nonproteinogenic amino acids (NAAs). As a new discovery approach, the ribosomally synthesized and post-translationally modified peptides (RiPPs) method involves the combination of ribosomal synthesis and the phage screening platform together with macrocyclization chemistries to generate libraries of macrocyclic peptides. Meanwhile, the split-intein circular ligation of peptides and proteins (SICLOPPS) approach relies on the in vivo production of macrocyclic peptides. In vitro and in vivo peptide library screening is discussed as an advanced strategy for cyclic peptide selection. Specifically, biosynthetic bicyclic peptides are highlighted as versatile and attractive modalities. Bicyclic peptides represent another type of promising therapeutics that allow for building blocks with a heterotrimeric conjugate to address intractable challenges and enable multimer complexes via linkers. Additionally, we discuss the cell-free chemoenzymatic synthesis of macrocyclic peptides with a non-ribosomal catalase known as the non-ribosomal synthetase (NRPS) and chemo-enzymatic approach, with recombinant thioesterase (TE) domains. Novel insights into the use of peptide library tools, activity-based two-hybrid screening, structure diversification, inclusion of NAAs, combinatorial libraries, expanding the toolbox for macrocyclic peptides, bicyclic peptides, chemoenzymatic strategies, and future perspectives are presented. This review highlights the broad spectrum of strategy classes, novel platforms, structure diversity, chemical space, and functionalities of macrocyclic peptides enabled by emerging biosynthetic platforms to achieve bioactivity and for therapeutic purposes. Full article

(This article belongs to the Special Issue Biologically Active Agents from Polycyclic Compounds through Biocatalytic and Chemical Approaches)

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26 pages, 3164 KiB

Open AccessReview

Biocatalysis in the Chemistry of Lupane Triterpenoids

by Jan Bachořík and Milan Urban

Molecules 2021, 26(8), 2271; https://doi.org/10.3390/molecules26082271 - 14 Apr 2021

Cited by 17 | Viewed by 4091

Abstract

Pentacyclic triterpenes are important representatives of natural products that exhibit a wide variety of biological activities. These activities suggest that these compounds may represent potential medicines for the treatment of cancer and viral, bacterial, or protozoal infections. Naturally occurring triterpenes usually have several drawbacks, such as limited activity and insufficient solubility and bioavailability; therefore, they need to be modified to obtain compounds suitable for drug development. Modifications can be achieved either by methods of standard organic synthesis or with the use of biocatalysts, such as enzymes or enzyme systems within living organisms. In most cases, these modifications result in the preparation of esters, amides, saponins, or sugar conjugates. Notably, while standard organic synthesis has been heavily used and developed, the use of the latter methodology has been rather limited, but it appears that biocatalysis has recently sparked considerably wider interest within the scientific community. Among triterpenes, derivatives of lupane play important roles. This review therefore summarizes the natural occurrence and sources of lupane triterpenoids, their biosynthesis, and semisynthetic methods that may be used for the production of betulinic acid from abundant and inexpensive betulin. Most importantly, this article compares chemical transformations of lupane triterpenoids with analogous reactions performed by biocatalysts and highlights a large space for the future development of biocatalysis in this field. The results of this study may serve as a summary of the current state of research and demonstrate the potential of the method in future applications. Full article

(This article belongs to the Special Issue Biologically Active Agents from Polycyclic Compounds through Biocatalytic and Chemical Approaches)

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39 pages, 4958 KiB

Open AccessReview

Antiprotozoal and Antitumor Activity of Natural Polycyclic Endoperoxides: Origin, Structures and Biological Activity

by Valery M. Dembitsky, Ekaterina Ermolenko, Nick Savidov, Tatyana A. Gloriozova and Vladimir V. Poroikov

Molecules 2021, 26(3), 686; https://doi.org/10.3390/molecules26030686 - 28 Jan 2021

Cited by 17 | Viewed by 3194

Abstract

Polycyclic endoperoxides are rare natural metabolites found and isolated in plants, fungi, and marine invertebrates. The purpose of this review is a comparative analysis of the pharmacological potential of these natural products. According to PASS (Prediction of Activity Spectra for Substances) estimates, they are more likely to exhibit antiprotozoal and antitumor properties. Some of them are now widely used in clinical medicine. All polycyclic endoperoxides presented in this article demonstrate antiprotozoal activity and can be divided into three groups. The third group includes endoperoxides, which show weak antiprotozoal activity with a reliability of up to 70%, and this group includes only 1.1% of metabolites. The second group includes the largest number of endoperoxides, which are 65% and show average antiprotozoal activity with a confidence level of 70 to 90%. Lastly, the third group includes endoperoxides, which are 33.9% and show strong antiprotozoal activity with a confidence level of 90 to 99.6%. Interestingly, artemisinin and its analogs show strong antiprotozoal activity with 79 to 99.6% confidence against obligate intracellular parasites which belong to the genera Plasmodium, Toxoplasma, Leishmania, and Coccidia. In addition to antiprotozoal activities, polycyclic endoperoxides show antitumor activity in the proportion: 4.6% show weak activity with a reliability of up to 70%, 65.6% show an average activity with a reliability of 70 to 90%, and 29.8% show strong activity with a reliability of 90 to 98.3%. It should also be noted that some polycyclic endoperoxides, in addition to antiprotozoal and antitumor properties, show other strong activities with a confidence level of 90 to 97%. These include antifungal activity against the genera Aspergillus, Candida, and Cryptococcus, as well as anti-inflammatory activity. This review provides insights on further utilization of polycyclic endoperoxides by medicinal chemists, pharmacologists, and the pharmaceutical industry. Full article

(This article belongs to the Special Issue Biologically Active Agents from Polycyclic Compounds through Biocatalytic and Chemical Approaches)

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31 pages, 4540 KiB

Open AccessFeature PaperReview

Biotransformation of Oleanane and Ursane Triterpenic Acids

by Natalia A. Luchnikova, Victoria V. Grishko and Irina B. Ivshina

Molecules 2020, 25(23), 5526; https://doi.org/10.3390/molecules25235526 - 25 Nov 2020

Cited by 19 | Viewed by 3924

Abstract

Oleanane and ursane pentacyclic triterpenoids are secondary metabolites of plants found in various climatic zones and regions. This group of compounds is highly attractive due to their diverse biological properties and possible use as intermediates in the synthesis of new pharmacologically promising substances. By now, their antiviral, anti-inflammatory, antimicrobial, antitumor, and other activities have been confirmed. In the last decade, methods of microbial synthesis of these compounds and their further biotransformation using microorganisms are gaining much popularity. The present review provides clear evidence that industrial microbiology can be a promising way to obtain valuable pharmacologically active compounds in environmentally friendly conditions without processing huge amounts of plant biomass and using hazardous and expensive chemicals. This review summarizes data on distribution, microbial synthesis, and biological activities of native oleanane and ursane triterpenoids. Much emphasis is put on the processes of microbial transformation of selected oleanane and ursane pentacyclic triterpenoids and on the bioactivity assessment of the obtained derivatives. Full article

(This article belongs to the Special Issue Biologically Active Agents from Polycyclic Compounds through Biocatalytic and Chemical Approaches)

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