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An efficient method for regioselective synthesis of C-7 Mannich bases of 6-hydroxyaurones was accomplished by the N,N-dialkylaminomethylation using aminals prepared from dimethylamine, dipropylamine, bis(2-methoxyethyl)amine, N-methylbutylamine, N-methylbenzylamine, morpholine, piperidine, and 1-methylpiperazine. Further transformation of 7-(N,N-dialkylamino)methyl group in these aurones led to formation of C-7 acetoxymethyl and methoxymethyl derivatives of 6-hydroxyaurones, some of which showed promising inhibition of PC-3 prostate cancer cell proliferation in the high nanomolar to low micromolar range that exceeded that of cisplatin. Compound 12c (R3 = Ac, Ar = 3,4-OMePh) displays 75% inhibition of PC-3 prostate cancer cells proliferation at 300 nM concentration.

The reactions of cytisine with glycidyl ethers of 3-arylcoumarins were studied. A series of cytisine–coumarin conjugates were synthesized via regiospecific opening of the oxirane ring by cytisine. Methods for conjugating anabasine and cytisine with 3-arylcoumarins through a but-2-ynyl linker via reactions of propargyl ethers of 7-hydroxy- and 6-hydroxy-3-arylcoumarins with the alkaloids were proposed.

The reactions of cytisine with isoflavone glycidyl ethers were investigated. A series of cytisine–isoflavone conjugates were regioselectively synthesized via opening the oxirane ring by cytisine.

The transformations of 7-dimethylaminomethyl-6-hydroxyaurone and 5-dimethylaminomethyl-6-hydroxy-7-methylurone in the inversed electron-demand hetero-Diels–Alder reaction were studied. As a result of in situ thermal formation of o-quinone methides containing the benzofuranone moiety and cycloaddition of cyclic vinyl esters, 2-benzylidene derivatives of difuro[2,3-b:2',3'-f]chromen-3(2H)-one, furo[2,3-f]pyrano[2,3-b]chromen-3(2H)-one, difuro[2,3-b:3',2'-g]chromen-3(2H)-one, and furo[3,2-g]pyrano[2,3-b]chromen-3(2H)-one heterocyclic systems were synthesized. A similar reaction with cyclic enamines, accompanied by subsequent transformation of hemi-aminals, led to the formation of partially hydrogenated derivatives of furo[2,3-a]xanthen-3(2H)-one and furo[3,2-b]xanthen-3(2H)-one.

New coumarin-4-ylmethylphosphonates and coumarin-4-ylmethylphosphonic acids were synthesized and tested for antiviral activity.

The possibility of using the alkaloid anabasine in Mannich aminomethylation of coumarins was studied. Anabasine-coumarin conjugates in which the benzopyrone core was conjugated to anabasine through a methylene linker were synthesized.

This article provides generalized and systematic overview of data on the synthesis, stereoisomerism, and reactivity of aurones (2-benzylidenebenzofuran-3(2Н)-ones) published between the years 1910 and 2018. Analysis of the literature data shows that the most common precursors for the synthesis of aurones are 2'-hydroxychalcones, benzofuran-3(2Н)-ones, and 1-(2-hydroxyphenyl)-3-phenylprop-2-yn-1-ones. Reactions involving electrophiles, nucleophiles, as well as reduction reactions have been reviewed.

Reaction features of polyhydroxydeoxybenzoins and their heteroatomic analogs with succinic and glutaric anhydrides were studied and shown to be useful for synthesizing 3-(3-pyrazolyl)butyric acids and 4,11-dioxo-8,10,11,12-tetrahydro-4H,9H-pyrano[2,3-a]xanthene derivatives with a butyric acid moiety.

Structure-activity relationships (SAR) in the aurone pharmacophore identified heterocyclic variants of the (Z)-2-benzylidene-6-hydroxybenzofuran-3(2H)-one scaffold that possessed low nanomolar in vitro potency in cell proliferation assays using various cancer cell lines, in vivo potency in prostate cancer PC-3 xenograft and zebrafish models, selectivity for the colchicine-binding site on tubulin, and absence of appreciable toxicity. Among the leading, biologically active analogs were (Z)-2-((2-((1-ethyl-5-methoxy-1H-indol-3-yl)methylene)-3-oxo-2,3-dihydrobenzofuran-6-yl)oxy)acetonitrile (5a) and (Z)-6-((2,6-dichlorobenzyl)oxy)-2-(pyridin-4-ylmethylene)benzofuran-3(2H)-one (5b) that inhibited in vitro PC-3 prostate cancer cell proliferation with IC50 values below 100 nM. A xenograft study in nude mice using 10 mg/kg of 5a had no effect on mice weight, and aurone 5a did not inhibit, as desired, the human ether-à-go-go-related (hERG) potassium channel. Cell cycle arrest data, comparisons of the inhibition of cancer cell proliferation by aurones and known antineoplastic agents, and in vitro inhibition of tubulin polymerization indicated that aurone 5a disrupted tubulin dynamics. Based on molecular docking and confirmed by liquid chromatography-electrospray ionization-tandem mass spectrometry studies, aurone 5a targets the colchicine-binding site on tubulin. In addition to solid tumors, aurones 5a and 5b strongly inhibited in vitro a panel of human leukemia cancer cell lines and the in vivo myc-induced T cell acute lymphoblastic leukemia (T-ALL) in a zebrafish model.

Aminomethylation of aurones was studied by using anabasine. The reaction in the case of 6-hydroxyaurones was shown to selectively provide 7-aminomethyl-6-hydroxyaurones, while 5-aminomethyl-6-hydroxy-7-methylaurones could be obtained by transamination of 5-dimethylaminomethyl derivatives of 6-hydroxy-7-methylaurones in the presence of anabasine.

Structural data of chromone alkaloids and antibiotics related to them that were isolated from natural sources up to 2017 are systematized in this review. Information on their biological activity is given.

Possible Mannich aminomethylation of isoflavone chromone rings was studied using the alkaloid anabasine. Anabasine-isoflavone conjugates in which the benzopyrone core was connected to anabasine through a methylene linker were synthesized.

The regioisomeric 6-hydroxy-4-methyl- and 4-hydroxy-6-methylaurones were synthesized. Aminomethylation by the action of aminals of secondary amines was investigated. It was shown that the reaction proceeds selectively with the formation of 7-aminomethyl-6-hydroxy-4-methyl- and 5-aminomethyl-4-hydroxy-6-methylaurones, respectively. The use of an excess of the aminals allows to obtain 5,7-bis(aminomethyl) derivatives of 6-hydroxy-4-methylaurones.

Aminomethylation of 7-substituted 6-hydroxyaurones was studied using primary and secondary amines. In the case of 6-hydroxy-7-methylaurones, their 5-dialkylaminomethyl derivatives or 7-benzylidene-3,4-dihydro-2Н-furo[3,2-g][1,3]benzoxazin-6(7Н)-ones were formed. The aminomethylation reaction of 6,7-dihydroxyaurones produced only 5-aminomethyl derivatives.

Aminomethylation of the natural isoflavones afromosin and cladrastin and their 2-methyl derivatives was studied. Several new Mannich bases of 7-hydroxy-6-methoxyisoflavones were synthesized under Mannich reaction conditions using aminals of secondary amines.

Recyclization by hydrazine of furo[3,2-b]pyrano[2,3-f]chromen-4-ones, dipyrano[2,3-b:2,3-f]chromen4-ones, and pyrano[2,3-a]xanthen-4-ones derived from natural isoflavonoids and their analogs was studied. The reaction was shown to proceed selectively with opening of the chromone ring. Several substituted 4-arylpyrazoles containing furo[3,2-b]chromen-5-ol, pyrano[2,3-b]chromen-6-ol, and xanthen-8-ol fragments were synthesized.

Aminomethylation of 6-hydroxy- and 6-hydroxy-7-methylaurones by the alkaloid cytisine was studied. It was shown that the aminomethylation of the 6-hydroxyaurones occurred at the 7-position of the benzofuran ring and at the 5-position if the 7-position was occupied.

Cytisine-linked isoflavonoids (CLIFs) inhibited PC-3 prostate and LS174T colon cancer cell proliferation by inhibiting a peroxisomal bifunctional enzyme. A pull-down assay using a biologically active, biotin-modified CLIF identified the target of these agents as the bifunctional, peroxisomal enzyme, hydroxysteroid 17β-dehydrogenase-4 (HSD17B4). Additional studies with truncated versions of HSD17B4 established that CLIFs specifically bind the C-terminus of HSD17B4 and selectively inhibited the enoyl CoA hydratase but not the D-3-hydroxyacyl CoA dehydrogenase activity. HSD17B4 was overexpressed in prostate and colon cancer tissues, knocking down HSD17B4 inhibited cancer cell proliferation, suggesting that HSD17B4 is a potential biomarker and drug target and that CLIFs are potential probes or therapeutic agents for these cancers.

A reliable method for the synthesis of B-ring hydroxylated homoisoflavonoids and 3-hetarylmethyl chromones has been developed. The method involves an initial oxa-Diels-Alder reaction of ortho-quinone methides generated from aryl/hetaryl-substituted ortho-( N, N-dimethylaminomethyl)phenols with (2 E)-3-( N, N-dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-ones and the subsequent cascade of reactions. This synthetic strategy avoids conventional multistep protocols and does not require the protection of hydroxyl groups, thus allowing the facile synthesis of a library of various aromatic and heterocyclic analogues of naturally occurring homoisoflavonoids.

A simple method of the synthesis of α-(3(5)-trifluoromethylpyrazol-5(3)-yl)-2-hydroxydeoxybenzoins by a chemoselective reaction of 2-(1,1,1-trifluoroacetonyl)chromones with hydrazine dihydrochloride was developed. This approach involves the initial attack of hydrazine at the carbonyl atom of the CF3C(O)CH2 group followed by the chromone ring opening at C-2 atom and subsequent cyclization to pyrazoles. Such synthetic strategy provides easy access to the novel type of pharmaceutically attractive 3-(trifluomethyl)pyrazole-deoxybenzoin hybrids in high yields.

The behavior of flavonoid Mannich bases in inverse electron-demand hetero-Diels–Alder reactions was studied. Isoflavones and aurones were used as examples to show that their Mannich bases reacted with 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)morpholine through an elimination mechanism and subsequent cycloaddition to form derivatives of the new heterocyclic systems pyrano[2′,3′:5,6]chromeno[3,2-c]pyridin-4-one and furo[2′,3′:5,6]chromeno[3,2-c]pyridin-3(2H)-one.

The possibility of introducing a substituted aminomethyl group into ring B of an isoflavone via reductive amination was studied. Several novel 2′-aminomethyl derivatives of natural 7-hydroxy-3′,5′ -dimethoxyisoflavone and its 7-O-methoxy derivative were synthesized.

Aminomethylation of 6-hydroxyaurones with primary amines was used to synthesize 2-benzylidene-8,9-dihydro-7H-furo[2,3-f][1,3]-benzoxazin-3(2H)-one derivatives, while opening of 1,3-oxazine ring in the presence of acid gave secondary amines containing a 6-hydroxyaurone moiety. Acetylation of 2-benzylidene-8,9-dihydro-7H-furo[2,3-f][1,3]benzoxazin-3(2H)-ones was also accompanied by opening of 1,3-oxazine ring.

The reaction of aloperine with isoflavone glycidyl ethers was investigated. A series of alkaloid–isoflavonoid conjugates were synthesized via regioselective opening of the oxirane ring by aloperine.

Aminomethylation of chrysin through the action of aminals was studied. 6,8-Bis-substituted chrysin derivatives were synthesized.

Recyclization of 7-O-β-(N,N-dialkylamino)ethyl derivatives of formononetin, 2-methylformononetin, and 2-methylcladrin through the action of hydroxylamine was studied. A series of 4-aryl-5-[2-hydroxy-4-β-(N,N-dialkylamino)ethoxyphenyl]isoxazoles were prepared.

The possibility of using the alkaloid aloperine for aminomethylation of a chromone ring was studied. A series of 8-(aloperin-12-yl)methyl-substituted isoflavone derivatives were synthesized.

A synthetic method for 7-hydroxy-5-methoxyisoflavones starting from 5,7-dihydroxyisoflavones was developed. Dimethylcarbamoylchloride was proposed for protection of the 7-hydroxy group. Aminomethylation of the synthesized 7-hydroxy-5-methoxyisoflavones by formaldehyde aminals was studied.

Aminomethylation of natural isoflavones by amino acids was studied. Conditions for selective production of N-(4H-4-oxochromen-8-yl)methyl-substituted amino acids were found.

An improved procedure for the synthesis of 7′-hydroxy-3,4′-bicoumarins has been developed. Their 8′-aminomethyl derivatives were obtained by interaction with aminals.

An oxazine ring was annelated to benzopyran-4-one and benzopyran-2-one cores by reacting 7-hydroxyisoflavones and 7-hydroxycoumarins with lupinylamine and formalin. The new derivatives 9,10-dihydro- 4H,8H-chromeno(8,7-e)(1,3)oxazin-4-one and 9,10-dihydro-2H,8H-chromeno(8,7-e)(1,3)oxazin-2-one containing a lupinine moiety in the 9-position were prepared. The presence of a hydroxyl in lupinine enabled several esters of carboxylic and dicarboxylic acids (3-5) with antiviral, antitumor, hepatoprotective, antituberculosis, anticholinesterase, and anesthetic properties (6, 7) to be prepared from it. A series of new derivatives of 4-aminoquinoline that included a lupinylamine moiety (2) exhibited antimalarial activity (8). Salts of lupinine with 3- or 4-azomethinebenzoic acids were also synthesized (9). Several azomethines of lupinylamine (10) and its phosphorylated derivatives (11) were prepared. The goal of the present work was to introduce the lupinine moiety into natural flavonoids and their analogs because the combination in one molecule of two natural heterocyclic groups could facilitate the manifestation of properties important for practical use. The appropriate ratio of substrate, amine, and formaldehyde in the presence of a basic catalyst under Mannich reaction conditions is known to form derivatives of 3,4-dihydro-1,3-benzoxazines as a result of electrophilic substitution (12-14). We considered it interesting to study the reaction features of flavonoids with lupinylamine and formalin. Heating formononetin (3a) (15), 7-hydroxy-2-methoxyisoflavone (3b) (16) and its 2-methyl derivative 3d (17), and 7-hydroxy-2-methylisoflavone (3c), which was isolated from Glycyrrhiza glabra (18), with an equivalent amount of 2 and a two-fold excess of formalin in propan-2-ol in the presence of a catalytic amount of 4-(dimethylamino)pyridine (DMAP) produced derivatives of 9,10-dihydro-4H,8H-chromeno(8,7-e)(1,3)oxazin-4-one (4a-d) in satisfactory yields without preliminary preparation of N,N-bis-(hydroxymethyl)amine. Thus, we synthesized several new derivatives 4a-d containing a lupinine moiety in the 9-position as a result of simultaneous C- and O-aminomethylation of the benzopyran-4-one core. 3-Arylcoumarins, certain representatives of which were isolated from plant material, are flavonoids according to their biogenetic origin. We studied the reaction features of 3-aryl-7-hydroxycoumarins (5a-c) with 2 and formalin. Like for the 7-hydroxyisoflavones, the Mannich reaction occurred with satisfactory yield without preliminary preparation of N,N-bis

Aminomethylation of the natural isoflavonoid sophoricoside (genistein-4-O-β-D-glucoside) was studied. It was shown that the most convenient method for performing the aminomethylation was the use of aminals. 6,8-bis-Substituted derivatives of sophoricoside were synthesized.

The formylation of esters of 5-hydroxy-1-benzofuran-3-carboxylic acid has been studied. The interaction of the synthesized aldehydes with esters of β-keto acids and hetarylacetonitriles gave furo[3,2-f]coumarin-1-carboxylic acids derivatives.

Aminomethylation of natural 7-hydroxyisoflavones and their analogs by the alkaloid (−)cytisine was studied. Substituted 8-(cytisin-12-yl)methyl-7-hydroxyisoflavones were synthesized.

Recyclization of N 12-cytisinylethoxy derivatives of natural isoflavonoids and their analogs through the action of hydroxylamine was studied. Substituted 4-aryl-5-(2-hydroxyphenyl)isoxazoles containing cytisine and isoxazole fragments were synthesized. The structures of the synthesized compounds were established using 2D NMR spectroscopy.

The reaction of the analogs of natural 3-arylbenzopyran-2-ones with electrophilic reagents of aminal structure was studied. Substituted 8-aminomethyl-3-aryl-7-hydroxycoumarins were synthesized. The optimum conditions were determined for the production of 9-alkyl- and 9-(het)arylmethyl derivatives of 3-aryl-9,10-dihydro-2H,8H-chromeno[8,7-e][1,3]oxazin-2-one in the series of analogs of natural 3-arylbenzopyran-2-ones.

Nitrosation and cyclization of 4-(3-aminothieno[2,3-b]pyridine-2-yl)-2H-chromen-2-ones 1 afforded substituted 6H-chromeno[3,4-c]pyrido[3',2':4,5]thieno[2,3-e]pyridazin-6-ones 2 that inhibited the intermediary filament protein, vimentin, at low micromolar concentrations. This inhibition promoted the secretion of Prostate Apoptosis Response-4 protein (Par-4), which selectively triggered apoptosis in prostate cancer cells such as CWR22Rv1, LNCaP-derivative C4-2B, PC-3 and its aggressive analog, PC-3 MM2.

Aminomethylation involving the natural alkaloid (–)-cytisine of analogs of natural 3-arylbenzopyran-2ones was studied. Substituted 8-(cytisin-12-yl)methyl-3-aryl-7-hydroxycoumarins were synthesized.

Substituted pyridine and 2-quinoline analogs of chalcone have been synthesized. The homonuclear Overhauser effect has been used to assign the PMR signals of the olefinic protons of the indicated pyridine derivatives and to elucidate their steric orientation.

A study was carried out on the reaction of chiral benzodioxane, benzofuran, and thiazole derivatives of isoflavone with various lanthanide shift reagents (LSR). The PMR shifts depend on the LSR used, while detection of chirality for these compounds using chiral LSR was difficult. Lowering the temperature and adding Yb(FOD)3 may enhance the splitting of the PMR signals of chiral molecules in the presence of LSR.

Syntheses are reported far sterically hindered 2-substituted benzodioxane analogs of isoflavone. An optically active lanthanide shift reagent (LSR) was used to show that these products exist as mixtures of atropoisomers. The difference in the chemical shifts of the enantiomeric protons in the presence of the LSR may reach 2–3 ppm with decreasing temperature. Conclusions were drawn concerning the structure of the LSR-substrate adducts and their conformations.

2-{[(5-Hydroxy-2-oxo-2H-chromen-4-yl)methyl]sulfanyl}pyridine-3-carbonitrile derivatives were synthesized in a reaction of 4-chloromethyl-5-hydroxycoumarin with substituted 2-thioxopyridine-3-carbonitriles. The presence in the molecule of spatially adjacent active methylene, nitrile, and hydroxyl groups under the action of a base leads to consecutive intramolecular cyclization reactions with the formation of a novel heterocyclic system pyrano[4″,3″,2″:4′,5′]chromeno[2′,3′:4,5]thieno[2,3-b]pyridine.