Synthesis of furanotriterpenoids from betulin and evaluation of Tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibitory properties of new semi-synthetic triterpenoids.

For the first time, a synthetic route for preparing lupane and oleanane derivatives with a hydrogenated furan ring as a cycle A of triterpene scaffold is described. Most of the synthesized compounds, furanoterpenoids and their synthetic intermediates, were non-toxic against the tested cancer and non-cancerous cell lines, and evinced significant inhibitory activity with IC 1.0-9.

Actinomycetes as Producers of Biologically Active Terpenoids: Current Trends and Patents.

Terpenes and their derivatives (terpenoids and meroterpenoids, in particular) constitute the largest class of natural compounds, which have valuable biological activities and are promising therapeutic agents. The present review assesses the biosynthetic capabilities of actinomycetes to produce various terpene derivatives; reports the main methodological approaches to searching for new terpenes and their derivatives; identifies the most active terpene producers among actinomycetes; and describes the chemical diversity and biological properties of the obtained compounds. Among terpene derivatives isolated from actinomycetes, compounds with pronounced antifungal, antiviral, antitumor, anti-inflammatory, and other effects were determined.

Synthesis and Anticancer Activity of A-Ring-Modified Derivatives of Dihydrobetulin.

Multidrug resistance (MDR) is a common phenomenon in clinical oncology, whereby cancer cells become resistant to chemotherapeutic drugs A common MDR mechanism is the overexpression of ATP-binding cassette efflux transporters in cancer cells, with P-glycoprotein (P-gp) being one of them. New 3,4-seco-lupane triterpenoids, and the products of their intramolecular cyclization with the removed 4,4-gem-dimethyl group, were synthesized by the selective transformations of the A-ring of dihydrobetulin. Among the semi-synthetic derivatives, the MT-assay-enabled methyl ketone (), exhibiting the highest cytotoxicity (0.

IEGM 1360, an Effective Biocatalyst of C3 Oxidative Transformation of Oleanane Triterpenoids.

Unlabelled: The optimal conditions for C3 oxidative biotransformation of 1.0 g/L pentacyclic triterpenoids oleanolic (OA) and glycyrrhetinic (GA) acids were determined using the resting cells of IEGM 1360 from the Regional Specialised Collection of Alkanotrophic Microorganisms. Resting cell suspensions (OD 2.

The Molecular Mechanisms of Oleanane Aldehyde-β-enone Cytotoxicity against Doxorubicin-Resistant Cancer Cells.

Oleanane aldehyde-β-enone (), being the semi-synthetic derivative of the triterpenoid betulin, effectively inhibits the proliferation of HBL-100 and K562 cancer cells (IC 0.47-0.53 µM), as well as the proliferation of their resistant subclones with high P-gp expression HBL-100/Dox, K562/i-S9 and K562/i-S9_Dox (IC 0.

Stereoselective Epoxidation of Triterpenic Allylic Alcohols and Cytotoxicity Evaluation of Synthesized Compounds.

The epoxidation process of semi-synthetic triterpenoids 2-methyl-3-oxo-19β,28-epoxy- 18α-olean-1-ene, and its allylic alcohol derivatives were examined. 1,2α-epoxide, as the main product, was found to be formed from the starting enone exposed to -chloroperbenzoic acid (mCPBA). In the case of hydroxy-directed mCPBA-oxidation of triterpenic allyl alcohols and their 3α-alkyl-substituted derivatives, inversion of C1 and C2 asymmetric centers with the formation of 1,2β-epoxyalcohols took place.

Triterpenoids with modified A-ring as modulators of P-gp-dependent drug-resistance in cancer cells.

Semi-synthetic A-cycle modified triterpenic derivatives with A-cycle condensed with a heterocyclic fragment (compound 1) and fragmented A-ring (compound 2) were tested for cytotoxicity against several tumor cell cultures and doxorubicin (Dox)-resistant cell lines. The equal cytotoxicity of the tested compounds to the parental tumor cell lines (HBL-100, K562) and their resistant subclones (HBL-100/Dox, K562/i-S9) was revealed. The overexpression of ABCB1 (MDR1) gene and P-glycoprotein (P-gp) was confirmed for both resistant subclones of tumor cells.

Label-Free Single Cell Viability Assay Using Laser Interference Microscopy.

Laser interference microscopy (LIM) is a promising label-free method for single-cell research applicable to cell viability assessment in the studies of mammalian cells. This paper describes the development of a sensitive and reproducible method for assessing cell viability using LIM. The method, based on associated signal processing techniques, has been developed as a result of real-time investigation in phase thickness fluctuations of viable and non-viable MCF-7 cells, reflecting the presence and absence of their metabolic activity.

Biotransformation of Oleanane and Ursane Triterpenic Acids.

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.

Microbial Conversion of Toxic Resin Acids.

Organic wood extractives-resin acids-significantly contribute to an increase in the toxicity level of pulp and paper industry effluents. Entering open ecosystems, resin acids accumulate and have toxic effects on living organisms, which can lead to the ecological imbalance. Among the most effective methods applied to neutralize these ecotoxicants is enzymatic detoxification using microorganisms.

Synthesis, modification, and cytotoxic evaluation of 2,3-secotriterpenic β-ketoesters.

A set of β-ketoesters was synthesized from 2,3-seco-18αH-oleanane and 2,3-secolupane bromomethyl ketones. Additionally, hydroxy derivatives with the A-seco- or five-membered A ring were obtained as a result of the reduction or of alkaline hydrolysis of acetic acid β-ketoesters 4, 9. Cytotoxic screening revealed the compound 4 with marked activity (IC 3.

Synthesis, cytotoxic evaluation, and molecular docking studies of the semi-synthetic "triterpenoid-steroid" hybrids.

Synthetic transformations of steroids for drug discovery and improvement of drug effectiveness have been an important part of modern medicinal chemistry and pharmaceutical sciences. Pentacyclic triterpenoids, being represented in the nature by various structures and biogenetically related to steroids, can largely expand the spectrum of biologically active steroidal agents via synthesis of the so-called "triterpenoid-steroid" hybrids. In the presented work, the nitrile anion cyclizations of 3,4-secolupane and 3,4-seco-oleanane nitriles and follow-up synthetic transformations of the cyclized products with formation of the gemm-dimethyl-free A ring "triterpenoid-steroid" hybrids were studied.

Bioconversion of ecotoxic dehydroabietic acid using Rhodococcus actinobacteria.

Actinobactrial strains Rhodococcus erythropolis IEGM 267 and R. rhodochrous IEGM 107 were used to study biodegradation of dehydroabietic acid (DHA), a toxic tricyclic diterpenoid. The experiments were carried out in batch cultures of pre-grown rhodococci in the presence of 0.

Synthesis of cytotoxically active derivatives based on alkylated 2,3-seco-triterpenoids.

Extremely low content of biologically active triterpenoids with the fragmented or contracted ring A extractable from plants is the main disadvantage of their use in drug discovery and practical pharmacology. Development of new methods for synthesis of these compounds and their structural analogs from bioavailable triterpene precursors gives an opportunity to obtain promising agents for pharmacology with excellent yields. A new approach to synthesis of alkylated A-seco-triterpenoids, including the Beckmann fragmentation of 3-methyl-substituted allobetulin or betulinic acid methyl ester with 2-hydroxyimino group in the ring A was proposed.

Combined experimental and theoretical studies of regio- and stereoselectivity in reactions of β-isoxazolyl- and β-imidazolyl enamines with nitrile oxides.

Reactions of β-azolyl enamines and nitrile oxides were studied by both experimental and theoretical methods. ()-β-(4-Nitroimidazol-5-yl), (5-nitroimidazol-4-yl) and isoxazol-5-yl enamines smoothly react regioselectively at room temperature in dioxane solution with aryl, pyridyl, and cyclohexylhydroxamoyl chlorides without a catalyst or a base to form 4-azolylisoxazoles as the only products in good yields. The intermediate 4,5-dihydroisoxazolines were isolated as isomers during the reaction of ()-β-imidazol-4-yl enamines with aryl and cyclohexylhydroxamoyl chlorides.

Preparation of novel ring-A fused azole derivatives of betulin and evaluation of their cytotoxicity.

An efficient scheme to synthesize novel ring-A fused heterocyclic derivatives of betulin was developed. The starting reaction of this synthesis was one-pot selective bacterial oxidation of betulin to betulone used as the key compound to synthesize the substituted azoles such as C(2)-C(3)-fused 1,2,3-triazoles, oxazoles and 1,2,4-triazine, as well as C(1)-C(2)-fused isoxazoles. The semi-synthetic compounds were screened for their cytotoxic activity against human cancer cell lines A549, HCT 116, HEp-2, MS and RD TE32 with use of the photometric MTT assays.

The role of mitochondrial reactive oxygen species in cartilage matrix destruction.

Upregulation of matrix metalloproteinases (MMPs) is a hallmark of osteoarthritis progression; along with the role reactive oxygen species (ROS) may play in this process. Moreover, mitochondrial DNA damage and dysfunction are also present in osteoarthritic chondrocytes. However, there are no studies published investigating the direct relationship between mitochondrial ROS, mitochondrial DNA damage, and MMP expression.

Functionalization, cyclization and antiviral activity of A-secotriterpenoids.

Triterpene derivatives with an α,β-alkenenitrile moiety in the five-membered ring A have been synthesized by nitrile anion cyclizations of 1-cyano-2,3-secotriterpenoids. Oxime-containing precursors, 2,3-secointermediates and five-membered ring A products of cyclizations were screened for in vitro antiviral activity against enveloped viruses - influenza A virus and human immunodeficiency virus type I (HIV-1). Lupane ketoxime and the 2,3-secolupane C-3 aldoxime which possess antiviral activities against both influenza A virus (EC50 12.

Synthesis, transformation and biological evaluation of 2,3-secotriterpene acetylhydrazones and their derivatives.

It has been previously shown that semi-synthetic A-secotriterpene acetylhydrazones of 1-cyano-28-methoxy-28-oxo-2,3-seco-2-norlup-20(29)-en-3-al and 1-cyano-2,3-seco-2-nor-19β,28-epoxy-18αH-olean-3-al (1, 2) inhibit the vesicular stomatitis virus (VSV) replication. To improve the antiviral activity against VSV, structural modifications of compounds 1 and 2 were performed, and new A-secoderivatives containing the acetylhydrazone fragment were obtained from betulonic acid and its methyl ester, allobetulone, and 3-oxo-18βH-glycyrrhetinic acid methyl ester. The inhibitory effects of these compounds on VSV replication in porcine embryo kidney (PEK) cells were determined after infection.

[Synthesis and biological activity of 2,3-secotriterpene acid mono- and diamides].

Four types of amide (C3; C28; C3-C28) conjugates based on 2,3-seco-18alphaH-oleanane and 2,3-secolupane mono- and dicarboxylic acids were synthesized. The range of diamide derivatives was supplemented with C3-C3' and C28-C28' dicondensed amides with two A-secotriterpene backbones educed by reacting monocarboxylic A-secoacids with biogenic amino acid lysine. Compounds with inhibitory action against herpes virus reproduction (EC50 8.

[Ionic conjugates of sulfate carboxymethyl cellulose with dialkylaminomethyl derivatives of 2-isobornyl-4-methylphenol: synthesis and study of anti-inflammatory and analgesic activity].

Water-soluble sulfate polysalts of carboxymethyl cellulose and tertiary aminomethyl derivatives of 2-isobornyl-4-methylphenol was obtained. For the synthesized conjugates investigated in vivo anti-inflammatory activity in the test of acute formalin inflammation and analgesic activity in tests the "hot plate" and "vinegar cramps".

[Biocatalytic synthesis of pharmacology perspective stigmast-4-en-3-one using Rhodococci cells].

The conditions for a directed biocatalytic oxidation of beta-sitosterol to a pharmacologically promising stigmast-4-en-3-one using Rhodococcus actinobacteria were selected. It was shown that palmitic acid induced the cholesterol oxidase reaction and allowed for the decrease in the bioconversion process duration from 7 to 5 days. The maximum level ofstigmast-4-ene-3-one formation was achieved using n-hexadecane as an additional growth substrate.

[Oxidative biotransformation of thioanisole by Rhodococcus rhodochrous IEGM 66 cells].

Comparative study of sulfoxidation activity of free and immobilized Rhodococcus rhodochrous IEGM 66 cells was performed. Free Rhodococcus cells (in the presence of 0.1 vol % n-hexadecane) displayed maximal oxidative activity towards thioanisole (0.

[Antiviral activity of 2,3-secotriterpenic hydrazones of lupane and 19beta,28-epoxy-18alpha-oleanane type].

Novel hydrazones of lupane and 19beta,28-epoxy-18alpha-oleanane type have been synthesized via interaction of 2,3-secotriterpenic aldehydonitriles with substituted hydrazines. As a result of investigation of 2,3-secotriterpenic hydrazones antiviral activity to the strain "Indiana" of vesicular stomatitis virus on two models of mammal's line cell infection, acetylhydrazone 1-cyano-2,3-seco-19beta,28-epoxy-18alpha-olean-3-al has been found to have a high prophylactic activity 0.00016 microg/ml to vesicular stomatitis virus and to inhibit a virus reproduction in primarily infected cells in 0.

[The synthesis of triterpenic amides based on 2,3-seco-1-cyano-19beta,28-epoxy-18alpha-olean-3-oic acid].

Novel 2,3-seco-triterpenic amides were prepared by the interaction of the chloride of 2,3-seco-l-cyano-19beta,28-epoxy-18alpha-oleane-3-oic acid with primary amines and synthetic and biogenic amino acids. A cytotoxic triterpenic conjugate with a residue of the ethyl ester of beta-alanine was found among the synthesized nitrogen-containing derivatives. Treatment with this conjugate in a concentration of 100 muM resulted in the 45.