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Sonochemical 2,3-dideoxygenation of ecdysteroids with the Δ 2(3)-bond generation and activation of the C–C bonds of the steroid core in the poststerone derivatives, that causes the skeletal rearrangement have been carried out for the first time. Thus, the ultrasonically assisted reaction of 2,3-dimesyloxy derivatives of ecdysteroids with the NaI-Zn-DMF system gives rise to their 2,3-dideoxy-Δ2(3)-analogues with yields 70–92%. In the case of 2,3-dimesyloxypoststerone as the initial ecdysteroid substrate the reaction is accompanied by the activation of the allyl moiety and semipinacol rearrangement, resulting in the C13–C14 bond migration with C/D rings contraction/expansion and providing novel short chain (8R)-13(14 → 8)-abeo-isomer.

We report the experimental evaluation of the impact of 10 modified 20-hydroxyecdysone derivatives on the duration and efficacy of domestic fly imaginal reproduction in the strains with an increased (Sh gen) and decreased (L gen) lifespan. A scoring method is proposed to comparatively analyze the impact of the compounds on imaginal reproduction.

The one-pot three-component CuCl-catalyzed aminomethylation of the abietane diterpenoid propargyl esters by formaldehyde and secondary amines was studied for the first time. The novel diethylamino, pyrrolidine, and morpholine-substituted butynyl derivatives of abietic, dehydroabietic, levopimaric, maleopimaric and dihydroquinopimaric acids were obtained. It was shown that synthesis of the abietic acid propargyl ester by the reaction of the abietane diterpenoid with oxalyl chloride and dimethylformamide is accompanied by the formylation of the ring B at the C-7 position and the dehydrogenation of the ring C to form the dehydroabietic acid ester. The cytotoxic, antibacterial and fungicidal activities of the synthesized compounds were studied in vitro. The experimental results showed that the most promising compound was 7-formyl abietic derivative Mannich base with a pyrrolidine substituent, with an MIC of 16 μg/ml against methicillin-resistant S. aureus ATCC 43300, and 8 μg/ml against C. albicans ATCC 90028 and 4 μg/ml against C. neoformans H99; ATCC 208821. The dihydroquinopimaric acid derivative with the diethylamine fragment showed the greatest antiproliferative activity towards twelve tumor cell lines.

Novel side chain ω-fluorinated ecdysteroid analogues were obtained starting from ω-functionalized ecdysteroids. Thus, the reaction of diacetonides of 25RS-hydroxy- and 24-hydroxy 27-nor- and 25,26,27-tris-nor-20-hydroxyecdysone derivatives with diethylaminosulfur trifluoride (DAST) involves replacement of the terminal hydroxyl group and dehydration at the 14-position to give 25RS-fluoro- and 24-fluoro-14-anhydro analogues of ecdysteroids.

C-2 mono- and bis-1,2,3-triazole-linked analogs of lupane, ursane, and oleane triterpenoid saponins were synthesized for the first time using regioselective Cu(I)-catalyzed 1,3-dipolar cycloaddition (CuAAC) of peracetylated sugar azides and C-2 propynyl derivatives of triterpene acids. Cytotoxic activity of the synthesized compounds was studied in vitro at the National Cancer Institute (USA). Several of the synthesized compounds exhibited weak cytotoxic activity.

Effective one-pot synthesis of 1,2,3-triazole derivatives of maleopimaric and dihydroquinopimaric acids consists in the reaction of diterpene propargyl esters with organic azides generated in situ in the presence of СuI catalyst.

A number of nitrogen-, bromine-, and sulfur-containing derivatives of diene adducts of levopimaric acid have been synthesized. The testing of the compounds on Staphylococcus aureus and Klebsiella pneumoniae bacteria has shown that the compounds possess a weak antimicrobial activity.

A novel promising strain of actinobacteria Rhodococcus sp. 77-32 was identified. Its acetonetreated biomass the could be used as a biocatalyst for production of S-(-)-2-[6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl] ethanol (S-BCE), a precursor of natural α-tocols. It was established that a reaction of enantioselective hydrolysis of racemic (±)-2-(2-acetoxyethyl)-6-benzyloxy-2,5,7,8-tetramethylchroman (BCEA) occurred in the phosphate buffer–acetone system, resulting in enrichment of the residual substrate by S-enantiomer (S-(+)-2-(2-acetoxyethyl)-6-benzyloxy-2,5,7,8-tetramethylchroman, S-BCEA). It was shown that the hydrolysis was accompanied by stereoinversion of the formed product, R-(+)-2-[6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl] ethanol (R-BCE), into the S-BCE. The transformation conditions (acetone content, acidity, temperature, reaction duration) were optimized, providing simultaneous production of optically pure S-BCE and S-BCEA with an almost quantitative yield.

Oximation of 20-hydroxyecdysone oxo derivatives proceeds regio- and stereoselectively and provides (E)-configured oximes in quantitative yields. The Ni–Ra-catalyzed hydrogenation of the oximes affords novel α-aminoecdysteroids with the unchanged 14α-hydroxy-7-en-6-on native chromophore of ecdysteroids. The structures of synthesized compounds were confirmed by the means of homo- and heteronuclear one-dimensional and two-dimensional 1H and 13C NMR spectroscopy and X-ray crystallography.

Conjugation of native triterpenoids, namely, betulinic and ursolic acids, with a lypophilic triphenylphosphonium cation led to the dramatic enhancement, as compared to betulinic acid, of their ability to trigger the mitochondrial apoptosis pathway in various types of cancer cells., A series of new betulinic and ursolic acid conjugates with a lipophilic triphenylphosphonium cation, meant to enhance the bioavailability and mitochondriotropic action of natural triterpenes, have been synthesized. The in vitro experiments on three human cancer cell lines (MCF-7, HCT-116 and TET21N) revealed that all the obtained triphenylphosphonium triterpene acid derivatives not only showed higher cytotoxicity as compared to betulinic acid but were also markedly superior in triggering mitochondria-dependent apoptosis, as assessed using a range of apoptosis markers such as cytochrome c release, stimulation of caspase-3 activity, and cleavage of poly(ADP-ribose) polymerase, which is one of the targets of caspase 3. The IC50 was much lower for all triphenylphosphonium derivatives when compared to betulinic acid. Out of the tested group of conjugates, the most potent toxicity was exhibited by the betulinic acid conjugate 9 (for 9, the IC50 values against MCF-7 and TET21N cells were 0.70 μM and 0.74 μM; for betulinic acid (BA), IC50 > 25 μM against MCF-7 cells).

Reactions of poststerone with methyl iodide, allyl bromide, and propargyl bromide in lithium–ammonia solution resulted in its completely stereoselective 7α-alkylation accompanied by reduction of the 20-oxo group with formation of equimolar amounts of 20R- and 20S-hydroxy derivatives. The reaction of poststerone with excess allyl bromide afforded 7,7-bis-allyl 20R- and 20S-alcohols at a ratio of 3: 1. The reduction of the 20-oxo group in the alkylation of poststerone with excess propargyl bromide led to the formation of an equimolar mixture of Δ8(14)- and Δ8(9)-isomers with exclusive S configuration of C20.

Triterpene acids, namely, 20,29-dihydrobetulinic acid (BA), ursolic acid (UA) and oleanolic acid (OA) were converted into C-28-amino-functionalized triterpenoids 4&ndash, 7, 8a, 15, 18 and 20. These compounds served as precursors for the synthesis of novel guanidine-functionalized triterpene acid derivatives 9b&ndash, 12b, 15c, 18c and 20c. The influence of the guanidine group on the antitumor properties of triterpenoids was investigated. The cytotoxicity was tested on five human tumor cell lines (Jurkat, K562, U937, HEK, and Hela), and compared with the tests on normal human fibroblasts. The antitumor activities of the most tested guanidine derivatives was lower, than that of corresponding amines, but triterpenoids with the guanidine group were less toxic towards human fibroblasts. The introduction of the tris(hydroxymethyl)aminomethane moiety into the molecules of triterpene acids markedly enhanced the cytotoxic activity of the resulting conjugates 15, 15c, 18b,c and 20b,c irrespective of the triterpene skeleton type. The dihydrobetulinic acid amine 15, its guanidinium derivative 15c and guanidinium derivatives of ursolic and oleanolic acids 18c and 20c were selected for extended biological investigations in Jurkat cells, which demonstrated that the antitumor activity of these compounds is mediated by induction of cell cycle arrest at the S-phase and apoptosis.

20R-Hydroxy short-chain ecdysteroids were synthesized by chemo- and stereoselective reduction of poststerone acetonide with L-Selectride or LiAlH4. The same reaction with the excess of L- Selectride followed by the treatment of the reaction mixture with hydrochloric acid is accompanied by (8R)-13(14 → 8)abeo- rearrangements, which resulted in the contraction/expansion of C/D pregnane rings. The reaction of 20R-hydroxy poststerone analogs with (diethylamino)sulfur trifluoride (DAST) proceeds through intramolecular rearrangements and provides D-homo- or 13,14-seco- androstane structures.

Reactions of maleopimaric and dihydroquinopimaric acid chlorides with propargyl alcohol and propargylamine afforded new terminal diterpene alkynes, and Sonogashira cross-coupling of the latter with 4-iodonitrobenzene led to the formation of arylalkynyl derivatives of Diels–Alder adducts of levopimaric acid.

In this study, water soluble hyaluronic acid (HA) based hydroxamate and conjugates with biologically active amines and hydrazides such as p- and o-aminophenols, anthranilic, 4- and 5-aminosalicylic acids, nicotinic, N-benzylnicotinic and isonicotinic hydrazides, p-aminobenzenesulfonamide (Streptocide), p-aminobenzoic acid diethylaminoethyl ester (Procaine), and 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one (4-aminoantipyrene) were examined as matrix metalloproteinase-2 inhibitors (MMPIs). In a dose of 0.27-270μM, the most efficient MMPIs were HA conjugates with o-aminophenol=4-aminoantipyrine>4-aminosalicylic acid>5-aminosalicylic acid. Conjugates with Streptocide, Procaine and HA hydroxamate showed 40-50% inhibitory effect at all used concentrations. Conjugates with anthranilic acid and isonicotinic hydrazide (Isoniazid) in a dose of 0.27μM inhibited enzyme activity by ∼70%, but with the concentration increase their inhibitory effect was decreased.

7α-Alkylation and 7,7-bis-alkylation of 20-hydroxyecdysone with propargyl bromide in a lithium–ammonia solution resulted in the formation of 7α-(2-propyn-1-yl)- and 7,7-bis(2-propyn-1-yl)-14-deoxy-Δ 8(14) -20-hydroxyecdysone in 92% and 75% yield respectively. Upon catalytic hydrogenation (10% Pd–C) of 7,7-bis(2-propyn-1-yl) derivative spirocyclization occurs by geminal 2-propyn-1-yl groups.

A new synthetic approach to the incorporation of an alkynyl group into pentacyclic triterpenoids was developed and utilized to prepare C (2)-propargyl derivatives of lupane- and ursane-type triterpenoic acids. Novel triterpenoid derivatives with a propynyl group at the C(2) atom were successfully used for click chemistry bioconjugation with glucopyranoside azides.

Reactions of ecdysteroids with alkyl halides in lithium-ammonia solution stereospecifically led to the formation of 7α-alkylated 14-deoxy-Δ8(14)-ecdysteroids. In the presence in the initial compound of free secondary hydroxy groups in the positions 2, 3, or 22 in some cases a side process of О-alkylation as well occurred.

Novel betulinic, ursolic, and oleanolic acid derivatives, containing a guanidine moiety have been designed and synthesized in an attempt to develop potent antitumor, antibacterial and antifungal agents. Triterpenoic acids were converted into C-28-aminotriterpenoids in which polyamine moieties were bound with C-28 carboxylic group through an amide or ester bonds. These compounds served as precursors for the synthesis of novel guanidine-functionalized triterpenoic acids derivatives. The cytotoxicity was tested on five human tumor cell lines (Jurkat, K562, U937, HEK, and Hela) and compared with the tests on normal human fibroblasts. The antitumor activities of the most tested guanidine derivatives was lower than that of corresponding amines, but triterpenoids with the guanidine group were less toxic to human fibroblasts. The identified lead molecules with the highest antitumor characteristics were selected for extensive biological testing according to flow cytometry data, which showed that the antitumor activity of these compounds is caused by apoptotic processes and induction of cell cycle arrest in the S-phase. Most of the tested guanidine derivatives showed a good antibacterial effect against Gram-positive bacteria Staphylococcus aureus (MICs values 0.5-4.0 mg/mL) and expressed significant antifungal activity against Candida albicans (4.0 mg/mL) and Cryptococcus neoformans (0.25-4.0 mg/mL), higher than the standard fluconazole (8.0 mg/mL).

A novel promising strain of actinobacteria Rhodococcus sp. 77-32 was identified. Its acetonetreated biomass the could be used as a biocatalyst for production of S-(-)-2-[6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl] ethanol (S-BCE), a precursor of natural α-tocols. It was established that a reaction of enantioselective hydrolysis of racemic (±)-2-(2-acetoxyethyl)-6-benzyloxy-2,5,7,8-tetramethylchroman (BCEA) occurred in the phosphate buffer–acetone system, resulting in enrichment of the residual substrate by S-enantiomer (S-(+)-2-(2-acetoxyethyl)-6-benzyloxy-2,5,7,8-tetramethylchroman, S-BCEA). It was shown that the hydrolysis was accompanied by stereoinversion of the formed product, R-(+)-2-[6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl] ethanol (R-BCE), into the S-BCE. The transformation conditions (acetone content, acidity, temperature, reaction duration) were optimized, providing simultaneous production of optically pure S-BCE and S-BCEA with an almost quantitative yield.

The long-term stress protective effects have been revealed among newly synthesized 9α-hydroxy-5α-ecdysteroids via a short-term heat stress tests (housefly Musca domestica). An increase as well as a reduce of protective effects for synthesized compounds have been demonstrated in comparison with the reference ecdysteroid 20-hydroxyecdysone, which obtained from the juice of Serratula coronata. The interdependence between stress- and geroprotective properties of the test models with their genotypic features and the structure of ecdvsteroids has been established.

This paper reports the selective oxidation of hyaluronic acid (HA) by stoichiometric quantity of 2,2,6,6-tetramethylpiperidine-1-oxoammonium chloride (TEMPO + ) in aqueous alkaline medium. High efficiency of the HA oxidation and quantitative yield of carboxy-HA per starting TEMPO + , as well as unusual behavior of the oxidation system generating an oxygen upon alkali-induced oxoammonium chloride decomposition are demonstrated. The scheme for HA oxidation involving both TEMPO + and oxygen produced upon the TEMPO + Cl − decomposition and/or air oxygen is proposed. For comparison, the data on stoichiometric oxidation of such substrates as dermatan sulfate, water-soluble potato starch, methyl 2-acetamido-2-deoxy- β - d -glucopyranoside and ethanol are presented.

N-Alkyl- and N-arylaminoecdysteroids were synthesized for the first time by reductive amination of ω-oxoecdysteroids. By using aliphatic or aromatic diamines, dimeric ecdysteroids with an ethylenediamine or p-phenylenediamine bridge at the C(24), C(24′)-position of the monomeric moieties were obtained.

New cyclopentene-fused octahydropyridoquinolines and octahydrophenanthrolines were prepared by a stereoselective three-component cyclocondensation of benzene-1,4-diamine, cyclopenta-1,3-diene, and an aromatic aldehyde. Single-crystal X-ray diffraction data provided evidence for the formation of cyclopentene-fused octahydropyridoquinolines and octahydrophenanthrolines with a syn -planar arrangement of the cyclopentene rings. The cyclocondensation of benzene-1,4-diamine, cyclopenta-1,3-diene, and formaldehyde gave new type of polycyclic compound containing four cyclopentene moieties oriented in a mutually antiplanar manner.

Ozonation of quinopimaric acid methyl ester and its 2,3-dihydro derivatives involves 1,2-addition of ozone to the sterically hindered double bonds with formation of peroxy epoxides and intramolecular interaction products.

We studied the antischistosomal activity of betulin, betulinic acid and its 9 triphenylphosphonium derivatives characterized by a covalently linkage of the hydrophobic fragment of triterpenoid at C(2)- or C(30)-position with the triphenylphosphonium moiety via a hydrocarbon bridge. The triphenylphosphonium salts showed in vitro antischistosomal activity against newly transformed schistosomula (NTS) and adult worms of Schistosoma mansoni at low micromolar concentrations. In contrast betulin and betulinic acid were inactive against NTS and adult S. mansoni. Of the 9 triphenylphosphonium derivatives tested, the allyl salts 10 (IC50 of 0.76 μg/mL) and 11 (IC50 of 0.64 μg/mL) demonstrated the highest antischistosomal activity against adult S. mansoni. Low worm burden reductions of 22% were observed in vivo for these two compounds. In conclusion, triphenylphosphonium derivatives were obtained from available natural betulin by simple transformations, rendering it practical and useful for large scale application. However, further structural modifications are necessary to translate the promising antischistosomal in vitro activities into in vivo.

4-Aryl-8-fluoro-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolines are synthesized by acid-catalyzed (CF3CO2H) three-component cyclocondensation of 4-fluoroaniline with aromatic aldehydes and cyclopentadiene. Stable ozonides with (1R*,4S*,5aR*,6S*,11bS*)-configurations are obtained by ozonolysis of corresponding trifluoroacetyl derivatives.

A three-component acid-catalyzed cyclocondensation of 5-aminoquinoline and 5-aminoisoquinoline with aromatic aldehydes and cyclopentadiene leads to (6S*,6aR*,9aS*)-6-aryl-6,6a,7,9a-tetrahydro-5H-cyclopenta[c]-1,7-and (6S*,6aR*,9aS*)-6-aryl-6,6a,7,9a-tetrahydro-5H-cyclopenta[c]-1,8-phenanthrolines.

Conjugates of poly-α-(1→4)-L-guluronic and poly-β-(1→4)-D-mannuronic acids with 1-phenyl-2,3-dimethyl-4-aminopyrazol-5-one (4-aminoantipyrine) were synthesized and characterized using 1H–13C HSQC spectra by the contents of intact A units, modified B units, and triad sequences of units with an A center (AAA, AAB + BAA, and BAB) and with a B center (BBB, BBA + ABB, and ABA).

Three-component cyclocondensation of methyl 12-aminodehydroabietate with cyclopentadiene and formaldehyde or acetaldehyde under acid catalysis afforded polysubstituted naphthoquinoline derivatives with fused oxetanocyclopentane and cyclopentene fragments. Ozonation of the double bond in the N-trifluoroacetyl cyclopentene derivatives gave the corresponding ozonide.

Acid-catalyzed acetalization of 24-oxo-25,26,27-trinor analogs of ecdysteroids in the reaction with 2,3-di-O-benzylascorbic acid diastereospecifically gives the corresponding S-diastereoisomer with respect to the acetal chiral center.

Three-component condensation of lower aliphatic aldehydes (C1-C3) with arylamines and cyclopentadiene (the Povarov reaction) gave 3a,4,5,9b-tetrahydro-3H-cyclopenta[c]-quinolines. Ozonization of their N-trifluoroacetyl derivatives afforded the corresponding ozonides. Cyclocondensation of 4-fluoroaniline with formaldehyde and cyclopentadiene gave earlier unknown 2-fluoro-3b,6,6a,7,9,9a,10,12a-octahydrobenzo[i,j]dicyclopenta[b,g]quinolizine.

3-epi-2-Dehydro-20-hydroxyecdysone and its 20,22-acetonide were reduced with lithium tris(secbutyl) hydridoborate selectively at the 2-oxo group with formation of 2β,3β-dihydroxy derivatives and the corresponding 2α,3α epimers which were separated by chromatography.

Ozonolysis of ω-anhydro-20-hydroxyecdysone diacetonide gave a mixture of 24- and 25-oxo derivatives, and only the first of these (23-carbaldehyde) reacted with malonic acid according to Knoevenagel to give 14α-hydroxy-2β,3β: 20,22-bis(isopropylidenedioxy)-6-oxo-27-nor-5β-cholesta-7,24-dien-26-oic acid. The oxidation of 23-carbaldehyde with ozone, followed by treatment with diazomethane, afforded 20-hydroxy-25,26,27-trinorecdysone-23-carboxylic acid methyl ester diacetonide.

Acid-catalyzed three-component condensation of methyl 12-aminodehydroabietate, aromatic aldehydes, and cyclopentadiene gave methyl (4R)-4-aryl-6-isopropyl-10,13a-dimethyl-3a,4,5,8,9,9a,10,11,12,13,13a,13d-dodecahydro-3H-cyclopenta[c]naphtho[1,2-f]quinoline-10-carboxylates and their (4S)-diastereomers. Ozonolysis of the double bond in their N-trifluoroacetyl derivatives synthesized from the (4R)-diastereomers afforded the corresponding ozonides with the (1S,4R,5aS,6R,11aR,12R,15aS,15dR)-configuration.

New derivatives of lupane triterpenoids, viz., 20,29-dihydrobetulinic and 3-epi-20,29-dihydrobetulinic acid derivatives containing triphenylphosphonium fragments as substituents were synthesized. These compound considerably exceed betulinic acid in antitumor activity.

Catalytic hydrogenation is extensively used in steroid chemistry. The interest in transformations to the steroid skeleton of ecdysteroids has been increasing in the past years. Essential interest in the chemistry of ecdysteroids is caused by the selective reduction of Δ7 bond with the formation of 7,8-dihydro analogues, because this process allows one to obtain modified structures with new biological activity. Catalytic hydrogenation of isolated and conjugated double bonds and functional groups in ecdysteroids derivatives has been considered in review.

The long-term stress protective effects have been revealed among newly synthesized 9α-hydroxy-5α-ecdysteroids via a short-term heat stress tests (housefly Musca domestica). An increase as well as a reduce of protective effects for synthesized compounds have been demonstrated in comparison with the reference ecdysteroid 20-hydroxyecdysone, which obtained from the juice of Serratula coronata. The interdependence between stress- and geroprotective properties of the test models with their genotypic features and the structure of ecdvsteroids has been established.

The review considers transformations of ecdysteroids (mostly of 20-hydroxyecdysone and its derivatives) involving the A, B, C, and D rings of the steroid skeleton and the side chain, which are used in the synthesis of minor phyto- and zooecdysteroids and structural analogs of ecdysteroids.

Selective transformations of available phytoecdysteroids to access minor ecdysteroids and some new their structural analogs are reviewed. Among them are the one-step transformation of ecdysteroids into 2-dehydro-3-epi-ecdysteroids by oxidation with ozone in pyridine, and the catalytic hydrogenation of ecdysteroids, including conjugated diene ones under basic conditions. 7,8α-Dihydro- and 7,8α-dihydro-14α-deoxyecdysteroids were synthesized by these methods. 9α,14α-Epoxyecdysteroids with the oxetane cycle in the C ring were obtained for the first time. The acid-catalyzed rearrangement of 9α,14α-epoxyecdysteroids gave 9α,13α-epoxy derivatives with the 18-methyl group migrated to the 14β-position.

Nitroxyl radical TEMPO is found to catalyze the decomposition of sodium hypochlorite in an aqueous-alkali medium. The mechanism of NaOCl decomposition to form ClO· radical is proposed which involves protonated TEMPO, oxoammonium salt TEMPO+, and hydroxyl radical.