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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.

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

The possibility of using the alkaloid cytisine to synthesize N12-cytisinylethoxy derivatives of isoflavonoids and their analogs was studied. A series of substituted 7-(N12-cytisinylethoxy)isoflavones containing chromone and cytisine fragments connected through a linker were synthesized.

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.

Substituted 4-[(3-cyanopyridin-2-yl)thiomethyl]coumarins have been synthesized by the alkylation of 2-mercapto-4,6-dimethylnicotinonitrile with 4-chloromethylcoumarins. Substituted 4-(3-amino-thieno[2,3-b]pyridin-2-yl)coumarins have been obtained by a subsequent intramolecular condensation of the methylene and cyano groups. 6H-Chromeno[4,3-d]thieno[3,2-b:5,4-b']dipyridin-6-ones were isolated as a result of the interaction of these compounds with aldehydes, and their aminomethyl derivatives were synthesized.

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.

Mycosin protease-1 (MycP1) cleaves ESX secretion-associated protein B (EspB) that is a virulence factor of Mycobacterium tuberculosis, and accommodates an octapeptide, AVKAASLG, as a short peptide substrate. Because peptidoboronic acids are known inhibitors of serine proteases, the synthesis and binding of a boronic acid analog of the pentapeptide cleavage product, AVKAA, was studied using MycP1 variants from Mycobacterium thermoresistible (MycP1mth), Mycobacterium smegmatis (MycP1msm) and M. tuberculosis (MycP1mtu). We synthesized the boropentapeptide, HAlaValLysAlaAlaB(OH)2 (1) and the analogous pinanediol PD-protected HAlaValLysAlaAlaBO2(PD) (2) using an Fmoc/Boc peptide strategy. The pinanediol boropentapeptide 2 displayed IC50 values 121.6±25.3 μM for MycP1mth, 93.2±37.3 μM for MycP1msm and 37.9±5.2 μM for MycP1mtu. Such relatively strong binding creates a chance for crystalizing the complex with 2 and finding the structure of the unknown MycP1 catalytic site that would potentially facilitate the development of new anti-tuberculosis drugs.

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.

In an effort to screen natural compounds and their derivatives as novel agents for cancer treatment, we developed two semisynthetic nature compounds, A14 and A52, which have potencies in an in vitro cell proliferation studies against LS174T and PC-3 cells in the mid-nanomolar range. A14 inhibited more than 90% of in vitro cancer cell proliferation around 300 nM and also inhibited in vivo PC-3 prostate cancer xenografts in nude mice. Cell morphology studies and comparisons with known antineoplastic agents suggested that A14 disrupted microtubule organization. In vitro tubulin polymerization assay suggested that A14 inhibited this process. Based on molecular docking, A14 fits very well in the colchicine-binding site at the interface between the alpha-tubulin and beta-tubulin. Further analyses suggest that A14 sensitivity may correlate with CDK/cyclin activity. A14 inhibited PC-3 prostate cancer xenografts in nude mice. In addition to solid tumors, A14 and its analog A52 strongly inhibited a panel of human leukemia cancer cell lines. Furthermore, these compounds inhibited Myc-induced T cell acute lymphoblastic leukemia (T-ALL) in a zebrafish model. Although many tubulin inhibitors were available, there is no compound that targeting the colchicine-binding site has been approved by FDA for cancer treatment. This new family of tubulin polymerization inhibitors could be further developed for the treatment of both solid and liquid tumors. Citation Format: Yanqi Xie, Liliia Kril, Wen Zhang, Mykhaylo Frasinyuk, Svitlana Bondarenko, Elizabeth Hausman, Zachary Martin, Przemyslaw Wyrebek, Tianxin Yu, Changguo Zhan, Vitaliy Sviripa, Jessica Blackburn, David Watt, Chunming Liu. Novel tubulin polymerization inhibitors repress tumor xenografts in nude mice and leukemia in zebrafish [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2674.

The behavior of 7-hydroxy-4′-fluoroisoflavones under the conditions of the Mannich reaction with primary amines was studied. New 9-alkyl-substituted 3-(4-fluorophenyl)-9,10-dihydro-4H,8H-chromeno-[8,7-e][1,3]oxazin-4-ones were synthesized. A method was developed for the synthesis of 8-amino- methyl derivatives of isoflavones.

The alkylation of o-cyanophenol by 4-chloromethylcoumarins and subsequent intramolecular condensation by the cyano and methylene groups gives substituted 4-(3-amino-2-benzo-furanyl)coumarins. We studied the reactions of these compounds with acylating agents as well as with aldehydes, which lead to the 6H-[1]benzofuro[3,2-b]chromeno[4,3-d]pyridin-6-one system as the result of consecutive transformations.

Treatment of substituted 2-(2,4-dihydroxyphenacyl)thiazole and 2-(2,4-dihydroxyphenacyl)benzothiazole with propionic and isobutyric anhydrides gives the substituted 2-ethyl-and 2-isopropyl-7-acyloxychromones. The use of pivaloyl chloride gives 1-pivaloyloxy-2-hetarylstyrene derivatives.

2-Alkyl-3-(1-methyl-2-benzimidazolyl)-7-acyloxychromones were synthesized by the reaction of substituted or unsubstituted 2-(2,4-dihydroxyphenacyl)-1-methylbenzimidazoles with the acid chlorides and anhydrides of carboxylic acids. The products were converted into 2-alkyl-7-hydroxychromones as a result of acid hydrolysis.

The regioselective condensations of various 7-hydroxyisoflavonoids with bis(N,N-dimethylamino)methane in a Mannich reaction provided C-8 N,N-dimethylaminomethyl-substituted isoflavonoids in good yield. Similar condensations of 7-hydroxy-8-methylisoflavonoids led to the C-6-substituted analogs. Thermal eliminations of dimethylamine from these C-6 or C-8 N,N-dimethylaminomethyl-substituted isoflavonoids generated ortho-quinone methide intermediates within isoflavonoid frameworks for the first time. Despite other potential competing outcomes, these ortho-quinone methide intermediates trapped dienophiles including 2,3-dihydrofuran, 3,4-dihydro-2H-pyran, 3-(N,N-dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one, 1-morpholinocyclopentene, and 1-morpholinocyclohexene to give various inverse electron-demand Diels-Alder adducts. Several adducts derived from 8-N,N-dimethylaminomethyl-substituted isoflavonoids displayed good activity in the 1-10 μm concentration range in an in vitro proliferation assay using the PC-3 prostate cancer cell line.

4-Aminomethyl analogs of the natural coumarin daphnetin were synthesized. The reaction of 4-chloromethyl-coumarins with aliphatic and aromatic amines was studied.

New substituted 4-chloromethylcoumarins that were used as alkylating agents to modify cytisine were synthesized by Pechmann condensation. A series of 4-(12-cytisylmethyl)coumarins containing pharmacophores of the natural heterocycles coumarin and cytisine in a single molecule was prepared. The alkylation gave the best results if diisopropylethylamine was used as the base.

Recyclization of the chromone ring in several natural isoflavonoids and their analogs by reaction with hydroxylamine was studied. It has been found that the most suitable base for carrying out the reaction is N-methylmorpholine. Several derivatives of 4-aryl-5-(2-hydroxyphenyl)isoxazole were synthesized.

8-Aminomethyl derivatives of 7-hydroxychromones were prepared by reaction of methylene-bis-cytisine with substituted 7-hydroxychromones. The structures of the synthesized compounds were investigated using NMR spectroscopy.

8-Aminomethyl derivatives of 7-hydroxycoumarins were prepared by reaction of methylene-bis-cytisine and substituted 7-hydroxycoumarins.

The regiospecific Mannich aminomethylation of 7-hydroxyisoflavonoids using bis(N,N-dimethylamino)methane afforded C-8 substituted N,N-dimethylaminomethyl adducts, and the regioselective aminomethylation of 5-hydroxy-7-methoxyisoflavonoids afforded predominantly the C-6 substituted N,N-dimethylaminomethyl adducts. Acetylation of these C-6 or C-8 Mannich bases with potassium acetate in acetic anhydride provided access to the corresponding acetoxymethyl derivatives that were subsequently converted to hydroxymethyl- and methoxymethyl-substituted 5-hydroxy- or 7-hydroxyisoflavonoids related to naturally occurring flavonoids. The C-8 acetoxymethyl, hydroxymethyl or methoxymethyl-substituted isoflavonoids possessed promising inhibitory potency in the low micromolar range in a prostate cancer PC-3 cell proliferation assay.

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.

Oximes of 2,4-dihydroxybenzophenones, 1-(2,4-dihydroxyphenyl)-2-phenylethanones, and 1-(2,4-di-hydroxyphenyl)-2-phenoxyethanones were dehydrated with 1,1'-carbonyldiimidazole, yielding 3-substi-tuted 6-hydroxy-1,2-benzisoxazoles, aminomethylation reactions of which were studied with various reagents.

Isoflavones (I) undergo Mannich reaction with amino alcohols such as (III), (V), as well as (VII) and an excess formaldehyde (II) to afford in principle two tautomeric products that incorporate two molecules of HCHO for each equivalent amino alcohol.

Recyclization of the chromone ring in a series of analogs of natural isoflavonoids by reaction with amidines was studied.

2-(Un)substituted-2′-methoxy-7-hydroxyisoflavones were synthesized. They were derivatized at the phenol hydroxyl using alkylation and acylation reactions and Mannich base formation.

3-(2-Pyridyl)coumarins were prepared by reaction of substituted salicylaldehydes and 2-pyridylacetonitrile. Benzylation, acylation, and aminomethylation of 7-hydroxy-3-(2-pyridyl)coumarin was studied.

Derivatives of the natural isoflavone formononetin were synthesized. Acylation and alkylation of the phenolic hydroxyls and the chromone ring were investigated.

2-(Un)substituted-3′,4′-dimethoxy-7-hydroxyisoflavones were synthesized. Their derivatives substituted at the phenolic hydroxyl were prepared by alkylation and acylation. Aminomethyl derivatives were also prepared.

Analogs of the natural isoflavonoids biochanin A and orobol were synthesized. Alkylation involving phenolic hydroxyls and the chromone ring was studied.

Homologs of the natural isoflavonoid pseudobaptigenin containing benzodioxane and benzodioxepane fragments were synthesized. Methanesulfonyl, carbamoyl, aminomethyl, and coumarin-containing isoflavone derivatives were prepared.

Chromones of type (III) or (VII) are prepared by the reaction of acetophenone derivatives of type (I) with cyclic carboxylic anhydrides.

The reaction of substituted salicylaldehydes with 2-benzimidazolyl- and 2-benzothiazolylacetonitriles gives the corresponding 3-hetarylcoumarins. The alkylation, acylation, and aminomethylation reactions of these 7-hydroxy-substituted hetero isoflavonoid analogs has been studied.

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.

Methods for preparation of 3-hetarylchromones, which are isoflavone heteroanalogs, and the reactions of these compounds with either preservation or opening of the pyrone ring are reviewed.

The rise of drug-resistant Mycobacterium tuberculosis lends urgency to the need for new drugs for the treatment of tuberculosis (TB). The identification of a serine protease, mycosin protease-1 (MycP1), as the crucial agent in hydrolyzing the virulence factor, ESX-secretion-associated protein B (EspB), potentially opens the door to new tuberculosis treatment options. Using the crystal structure of mycobacterial MycP1 in the apo form, we performed an iterative ligand- and structure-based virtual screening (VS) strategy to identify novel, nonpeptide, small-molecule inhibitors against MycP1 protease. Screening of ∼485 000 ligands from databases at the Genomics Research Institute (GRI) at the University of Cincinnati and the National Cancer Institute (NCI) using our VS approach, which integrated a pharmacophore model and consensus molecular shape patterns of active ligands (4D fingerprints), identified 81 putative inhibitors, and in vitro testing subsequently confirmed two of them as active inhibitors. Thereafter, the lead structures of each VS round were used to generate a new 4D fingerprint that enabled virtual rescreening of the chemical libraries. Finally, the iterative process identified a number of diverse scaffolds as lead compounds that were tested and found to have micromolar IC50 values against the MycP1 target. This study validated the efficiency of the SABRE 4D fingerprints as a means of identifying novel lead compounds in each screening round of the databases. Together, these results underscored the value of using a combination of in silico iterative ligand- and structure-based virtual screening of chemical libraries with experimental validation for the identification of promising structural scaffolds, such as the MycP1 inhibitors.

Substituted 4-[(3-cyanopyridin-2-yl)thiomethyl]coumarins have been synthesized by the alkylation of 2-mercapto-4,6-dimethylnicotinonitrile with 4-chloromethylcoumarins. Substituted 4-(3-amino-thieno[2,3-b]pyridin-2-yl)coumarins have been obtained by a subsequent intramolecular condensation of the methylene and cyano groups. 6H-Chromeno[4,3-d]thieno[3,2-b:5,4-b']dipyridin-6-ones were isolated as a result of the interaction of these compounds with aldehydes, and their aminomethyl derivatives were synthesized.

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.

The reaction of a-(2-benzthiazolyl)-2, 4-dihydroxy-5-alkylacetophenones with anhydrides and chlorides of carboxylic acids yielded 3-(2-benzthiazolyl)chromones with electron-acceptor and electron-donor substituents, as well as chromones unsubstituted in the 2 -position. Their acylation, alkylation, and aminoacylation reactions and their interaction with electrophilic and nucleophilic reagents were studied.

The behavior of 7-hydroxy-4′-fluoroisoflavones under the conditions of the Mannich reaction with primary amines was studied. New 9-alkyl-substituted 3-(4-fluorophenyl)-9,10-dihydro-4H,8H-chromeno-[8,7-e][1,3]oxazin-4-ones were synthesized. A method was developed for the synthesis of 8-amino- methyl derivatives of isoflavones.

The alkylation of o-cyanophenol by 4-chloromethylcoumarins and subsequent intramolecular condensation by the cyano and methylene groups gives substituted 4-(3-amino-2-benzo-furanyl)coumarins. We studied the reactions of these compounds with acylating agents as well as with aldehydes, which lead to the 6H-[1]benzofuro[3,2-b]chromeno[4,3-d]pyridin-6-one system as the result of consecutive transformations.