Recent Advances in the Chemistry of Saturated Annulated Nitrogen-Containing Polycyclic Compounds

This review is devoted to the analysis of works published over the past 20 years on the chemistry of saturated annulated nitrogen-containing polycyclic compounds, the molecules of which consist of four, five, six, and seven cycles, and contain from one to eight endocyclic nitrogen atoms.


Introduction
Nitrogen compounds hold a special position among natural and synthetic organic substances. Nitrogen is present in important natural molecules: amino acids, proteins, nucleic acids, hormones, alkaloids, etc. Nitrogen compounds are significant for technology, agriculture, and medicine. Nitrogen is present in the molecules of numerous medicinal agents, organic fertilizers, polymer materials, and other valuable products. The number of new molecules containing several nitrogenous heterocyclic rings and possessing useful pharmacological properties is continuously increasing. In the next decade, the proportion of new nitrogen-containing pharmaceutical agents is expected to increase [1].
The current periodical literature contains numerous scientific publications devoted to the synthesis of unsaturated polyazapolycycles with different positions of nitrogen atoms at the periphery of the polycyclic skeleton [2]. However, there are markedly fewer publications dealing with saturated polyheterocyclic systems. In this review, we discuss and systematize the data published over the last 20 years on saturated N-containing polycyclic systems; the interest in these compounds is caused by their broad applicability in medical practice. We consider approaches to the targeted synthesis of tetra-, penta-, and hexacyclic saturated compounds containing one to several endocyclic nitrogen atoms in the molecule. As a rule, these molecules are designed using reactions such as cycloaddition, multicomponent cyclocondensation, and intramolecular cyclization, and the reduction of aza-aromatic systems to their saturated analogues. The review pays attention to some representatives of alkaloids, that is, N-containing polycyclic compounds of natural origin. Data on the biological activity found in some saturated N-containing polycyclic compounds are given.

Tetracyclanes with One Endocyclic Nitrogen Atom
Among saturated tetracyclic compounds with one endocyclic nitrogen atom, a mention should be made of natural compounds corresponding to the class of alkaloids. An example is (−)-lycopodine, the molecule of which is a 6/6/6/6 annulated polycyclic system. R.G. Carter and co-workers were the first to carry out the total enantioselective synthesis of (−)-lycopodine [3,4]. The intramolecular Michael reaction (C-7 and C-8) of keto sulfone 1, and the subsequent Staudinger reduction of chiral azide 2 gave precursor 3. The organocatalyzed Mannich cyclization (C-4 and C-13) of precursor 3 afforded azatricyclane 4 in 54% Like (−)-lycopodine 5, (+)-clavolonine 10 is also a Lycopodium alkaloid. The difference between azatetracyclanes 5 and 10 is in that the latter has a hydroxyl group in position C-6. Despite the structural similarity of these two derivatives, their total syntheses proceed via different intermediates, but include similar chemical reactions [5], particularly, the Staudinger reduction of azide 6 to give imine 7 and intramolecular Mannich cyclization of imine 7 to tricyclane 8. The Mannich reaction is preceded by epimerization of imine 7 on treatment with HCl in methanol. The subsequent nucleophilic substitution results in replacement of the -OMe group in tricyclane 8 by halogen, while alkaline hydrolysis of product 9 enables the synthesis of (+)-clavolonine 10 in 10% yield (Scheme 2). Scheme 2. Synthesis of (+)-clavolonine.
A number of representatives of Lycopodium alkaloids such as fawcettimine, lycoflexine, and serratinine type alkaloids also deserve attention, due to their unique tetracyclic structures containing two contiguous quaternary stereocenters and interesting biogenetic interconnections within this intriguing family. The research group headed by Yu-Rong Yang proposed [6] a general strategy for the total synthesis of (+)-fawcettimine 18, (+)-lycoflexine 20, and serratinine 24. The key steps of this strategy include the highly efficient Helquist annulation to assemble the cis-fused carbocycle 13; facile construction of aza-C 9 -membered derivatives 15 and 16 by double N-alkylation strategy; and SmI 2 reduction of hydroxylated tricyclane 17 followed by Boc-deprotection and epimerization to (+)-fawcettimine 18. The (+)-fawcettimine 18 synthesized in this way was transformed into (+)-lycoflexine 20 in 95% yield by intramolecular Mannich cyclization. For successful synthesis of serratinine type alkaloid 24, the authors used asymmetric Shi epoxidation followed by post-treatment of Owing to the efforts of an international research group from France and Vietnam [19], total synthesis of tetracyclic (-)-schoberine 39, as a representative of Myrioneuron alkaloids, was accomplished. Their structural peculiarity is the presence of the decahydroquinoline (DHQ) core. The subsequent attachment of rings C and D to the DHQ core (rings A and B) consistently generated the schoberine skeleton with a series of chiral centers. Cyclic alcohol 34 was converted to (-)-myrionine 37 via a sequence of reactions. The intramolecular cyclization of 37 induced by POCl3 in refluxing toluene followed by treatment with NaOH in methanol gave iminium 38. The reduction of 38 by LiAlH4 in THF afforded 39 in a good yield (87%) (Scheme 6). Examples of the synthesis of other Myrioneuron alkaloids ( Figure 2) have been described [20,21]. Schoberine B was evaluated in vitro against hepatitis C virus (HCV). Owing to the efforts of an international research group from France and Vietnam [19], total synthesis of tetracyclic (-)-schoberine 39, as a representative of Myrioneuron alkaloids, was accomplished. Their structural peculiarity is the presence of the decahydroquinoline (DHQ) core. The subsequent attachment of rings C and D to the DHQ core (rings A and B) consistently generated the schoberine skeleton with a series of chiral centers. Cyclic alcohol 34 was converted to (-)-myrionine 37 via a sequence of reactions. The intramolecular cyclization of 37 induced by POCl 3 in refluxing toluene followed by treatment with NaOH in methanol gave iminium 38. The reduction of 38 by LiAlH 4 in THF afforded 39 in a good yield (87%) (Scheme 6). Matrine type alkaloids 32, the polycyclic skeleton of which is formed by two fused quinolizidine moieties A/B and C/D and contains four stereocenters at C-5, C-6, C-7, and C-11, were isolated from the Oxytropisochrocephala plant [13][14][15]. Cheng-jian Tan and coworkers studied the antiproliferative activity of these bis-quinolizidines against five human tumor cell lines (A549, KB, KB-VIN, MDA-MB-231, and MCF7) [16]. These compounds were also shown to suppress the expression of HSC70 protein, which plays a key role in the replication of hepatitis B virus [17]. In 2022, Chinese scientists were able to isolate ochrocephalamines E 33 [18]. This is the first example of quinolizidine alkaloid with a 6/6/6/5 polycyclic system ( Figure 1). Owing to the efforts of an international research group from France and Vietnam [19], total synthesis of tetracyclic (-)-schoberine 39, as a representative of Myrioneuron alkaloids, was accomplished. Their structural peculiarity is the presence of the decahydroquinoline (DHQ) core. The subsequent attachment of rings C and D to the DHQ core (rings A and B) consistently generated the schoberine skeleton with a series of chiral centers. Cyclic alcohol 34 was converted to (-)-myrionine 37 via a sequence of reactions. The intramolecular cyclization of 37 induced by POCl3 in refluxing toluene followed by treatment with NaOH in methanol gave iminium 38. The reduction of 38 by LiAlH4 in THF afforded 39 in a good yield (87%) (Scheme 6). Examples of the synthesis of other Myrioneuron alkaloids ( Figure 2) have been described [20,21]. Schoberine B was evaluated in vitro against hepatitis C virus (HCV). Examples of the synthesis of other Myrioneuron alkaloids ( Figure 2) have been described [20,21]. Schoberine B was evaluated in vitro against hepatitis C virus (HCV).  Przyby and co-worker [22] reported a method for isolation of (±)−lupanine, an alkaloid with a tetracyclic bis-quinolizine cage, and subsequent separation of the racemate into optically pure enantiomers. The LiAlH4 reduction of (−)−lupanine 40 enabled the synthesis of (+)−sparteine 41 (Scheme 7), which is of interest for its pharmacological activity and as a chiral ligand for asymmetric synthesis. Przyby and co-worker [22] reported a method for isolation of (±)−lupanine, an alkaloid with a tetracyclic bis-quinolizine cage, and subsequent separation of the racemate into optically pure enantiomers. The LiAlH 4 reduction of (−)−lupanine 40 enabled the synthesis of (+)−sparteine 41 (Scheme 7), which is of interest for its pharmacological activity and as a chiral ligand for asymmetric synthesis. Przyby and co-worker [22] reported a method for isolation of (±)−lupanine, an alkaloid with a tetracyclic bis-quinolizine cage, and subsequent separation of the racemate into optically pure enantiomers. The LiAlH4 reduction of (−)−lupanine 40 enabled the synthesis of (+)−sparteine 41 (Scheme 7), which is of interest for its pharmacological activity and as a chiral ligand for asymmetric synthesis. Scheme 7. The transformation of (-)-lupanine in (+)-sparteine.

Tetracyclanes with Four Endocyclic Nitrogen Atoms
The authors [23,24] demonstrated the possibility of preparing annulated tetraazatricyclanes, cis/trans-octahydrotetraazanaphthalenes 43, 44, and cis/trans-decahydrodiimidazopyrazines 45, 46, by condensation of triethylenetetramine 42 with glyoxal in water at 5 °C in the presence of Ca(OH)2 (Scheme 8). The ratio and the yield of the resulting tricyclanesare affected by both replacement of the solvent and increase in the reaction temperature [25].
Unlike the Italian researchers cited above, P. Desogere and co-worker [28] used N,N -bis-(aminoethyl)propane-1,3-diamine 53 as a linear tetramine. The condensation of tetramine 53 with glyoxal in ethanol at 0 • C resulted in the formation of tetraazatricyclane 54. The reaction of the obtained bis-aminal with chloroacetaldehyde in the presence of sodium cyanide afforded isomeric polycyclic compounds 55 and 56 in a total yield of 42% (Scheme 9). Unlike the Italian researchers cited above, P. Desogere and co-worker [28] used N,N′bis-(aminoethyl)propane-1,3-diamine 53 as a linear tetramine. The condensation of tetramine 53 with glyoxal in ethanol at 0 °C resulted in the formation of tetraazatricyclane 54. The reaction of the obtained bis-aminal with chloroacetaldehyde in the presence of sodium cyanide afforded isomeric polycyclic compounds 55 and 56 in a total yield of 42% (Scheme 9). Scheme 9. The synthesis of tetraazatetracyclane.
A Japanese research group headed by T. Okawara proposed [32] a method for the synthesis of tetraazaperhydropyrenes, which was based on the reaction of tetramine 69 with two equivalents of glyoxal and benzotriazole. The reduction of dibenzotriazoyltetraazaperhydropyrene 70 afforded a mixture of cis-and trans-tetraazaperhydropyrenes 71 a,b in 3% and 50% yields, respectively (Scheme 13).

Tetracyclanes with Five Endocyclic Nitrogen Atoms
Tetracyclane 75 can be readily prepared in 85% yield by cyclization of 1,4,7,10,13pentaazacyclopentadecane 74 with glyoxal in methanol at 20 °C (Scheme 15). The subsequent transformation of 75 enabled the synthesis of ethylene cross-bridged tetraazamacrocycle used as an efficient ligand for transition metals [34]. A Japanese research group headed by T. Okawara proposed [32] a method for the synthesis of tetraazaperhydropyrenes, which was based on the reaction of tetramine 69 with two equivalents of glyoxal and benzotriazole. The reduction of dibenzotriazoyltetraazaperhydropyrene 70 afforded a mixture of cis-and trans-tetraazaperhydropyrenes 71 a,b in 3% and 50% yields, respectively (Scheme 13).

Tetracyclanes with Five Endocyclic Nitrogen Atoms
Tetracyclane 75 can be readily prepared in 85% yield by cyclization of 1,4,7,10,13pentaazacyclopentadecane 74 with glyoxal in methanol at 20 °C (Scheme 15). The subsequent transformation of 75 enabled the synthesis of ethylene cross-bridged tetraazamacrocycle used as an efficient ligand for transition metals [34].

Tetracyclanes with Five Endocyclic Nitrogen Atoms
Tetracyclane 75 can be readily prepared in 85% yield by cyclization of 1,4,7,10,13pentaazacyclopentadecane 74 with glyoxal in methanol at 20 • C (Scheme 15). The subsequent transformation of 75 enabled the synthesis of ethylene cross-bridged tetraazamacrocycle used as an efficient ligand for transition metals [34].
A Japanese research group headed by T. Okawara proposed [32] a method for the synthesis of tetraazaperhydropyrenes, which was based on the reaction of tetramine 69 with two equivalents of glyoxal and benzotriazole. The reduction of dibenzotriazoyltetraazaperhydropyrene 70 afforded a mixture of cis-and trans-tetraazaperhydropyrenes 71 a,b in 3% and 50% yields, respectively (Scheme 13).

Tetracyclanes with Five Endocyclic Nitrogen Atoms
Tetracyclane 75 can be readily prepared in 85% yield by cyclization of 1,4,7,10,13pentaazacyclopentadecane 74 with glyoxal in methanol at 20 °C (Scheme 15). The subsequent transformation of 75 enabled the synthesis of ethylene cross-bridged tetraazamacrocycle used as an efficient ligand for transition metals [34].
An alternative method for the synthesis of hexaazatetracyclanes 79 [38] is based on the catalytic heterocyclization of glycoluril 76 a with N,N-bis-(methoxymethyl)-N-alkylamines (Scheme 17). Scheme 17. An alternative method for the synthesis of tetracyclicglycoluril derivatives.
Tetrakis(hydroxymethyl)-substituted glycoluril 80 was used as an efficient synthon [39,40] for the synthesis of 2,6-disubstituted hexaazahexahydrocyclopentafluorene-4,8-diones 81 (Scheme 18). The principle of three-component cyclocondensation of monothioglycoluril 82 with paraformaldehyde and structurally diverse primary amines was implemented [41] for the synthesis of tetraazatetracyclanes 83 (Scheme 19). Primary screening of the obtained compounds for antimicrobial activity revealed activity of the product with an ethyl substituent against the fungus Cryptococcus neoformans. Scheme 17. An alternative method for the synthesis of tetracyclicglycoluril derivatives.
An alternative method for the synthesis of hexaazatetracyclanes 79 [38] is based on the catalytic heterocyclization of glycoluril 76 a with N,N-bis-(methoxymethyl)-N-alkylamines (Scheme 17). Scheme 17. An alternative method for the synthesis of tetracyclicglycoluril derivatives.
In continuation of these studies, a selective synthesis of 2,7-disubstituted 4,9-dimethylperhydro-2,3a,5a,7,8a,10a-hexaazapyrenes 86 and 87 was implemented (Scheme 22) by multicomponent condensation of adamantylamines [44] and (het)arylamines [45] with formaldehyde and isomeric tetraazadecalins in the presence of Ymmm zeolite in the Hform or ytterbium (III) chloride. The use of available secondary metabolites with pronounced pharmacological activity as the starting compounds for the subsequent chemical transformations is an efficient approach to the synthesis of semisynthetic drugs. An example is the synthesis of dimeric terpenoid with a perhydropyrene spacer 88 (Scheme 23) [46]. The reaction occurred only in the "strong" acid sites of the H-Ymmm zeolite. High efficiency of the zeolite catalyst is due to the presence of a hierarchical porosity (micro-, meso, and macropores), which provided for the improved diffusion of reactants towards the active sites inside the zeolite pores and the release of the reaction products from the pores to the reaction medium, thus creating conditions for the formation of bulky molecules. The use of available secondary metabolites with pronounced pharmacological activity as the starting compounds for the subsequent chemical transformations is an efficient approach to the synthesis of semisynthetic drugs. An example is the synthesis of dimeric terpenoid with a perhydropyrene spacer 88 (Scheme 23) [46]. The reaction occurred only in the "strong" acid sites of the H-Ymmm zeolite. High efficiency of the zeolite catalyst is due to the presence of a hierarchical porosity (micro-, meso, and macropores), which provided for the improved diffusion of reactants towards the active sites inside the zeolite pores and the release of the reaction products from the pores to the reaction medium, thus ity as the starting compounds for the subsequent chemical transformations is an efficient approach to the synthesis of semisynthetic drugs. An example is the synthesis of dimeric terpenoid with a perhydropyrene spacer 88 (Scheme 23) [46]. The reaction occurred only in the "strong" acid sites of the H-Ymmm zeolite. High efficiency of the zeolite catalyst is due to the presence of a hierarchical porosity (micro-, meso, and macropores), which provided for the improved diffusion of reactants towards the active sites inside the zeolite pores and the release of the reaction products from the pores to the reaction medium, thus creating conditions for the formation of bulky molecules. Compound 88 exhibited moderate cytotoxic effects against normal cells [human embryonic kidney cell line (HEK293)] and tumor cells [colon adenocarcinoma (HTC-116), human monocytic leukemia (THP-1), breast carcinoma (MCF-7), lung adenocarcinoma (A549), T-cell leukemia (Jurkat), and human neuroblastoma SH-SY5Y)]. Scheme 23. The synthesis of dimeric terpenoid with a perhydropyrene spacer.

Pentacyclanes with One Endocyclic Nitrogen Atom
The shrubs and trees of the Daphniphyllum genus, occurring mainly in the subtropical and tropical Asia, are highly valuable sources of natural alkaloids. Several hundred compounds have been isolated from these plants [47,48], but only some pentacyclic compounds, which are shown in Figure 3, had a fully saturated polycyclic core. The key approaches to the preparation of synthetic analogues of Daphniphyllum alkaloids have been reported [49].

Pentacyclanes with One Endocyclic Nitrogen Atom
The shrubs and trees of the Daphniphyllum genus, occurring mainly in the subtropical and tropical Asia, are highly valuable sources of natural alkaloids. Several hundred compounds have been isolated from these plants [47,48], but only some pentacyclic compounds, which are shown in Figure 3, had a fully saturated polycyclic core. The key approaches to the preparation of synthetic analogues of Daphniphyllum alkaloids have been reported [49].  Out of the Daphniphyllum alkaloid family, special mention should be made of the group of compounds with a non-classical structure [50,51]. This group includes, in particular, longeracemine 95 and angustimine 96 (Figure 4). A specific feature of longeracemine 95 is the presence of the C-7/C-9 bond and the 5/6/6/6/5 type ring system. In turn, angustimine 96 is an intramolecular salt containing a non-trivial hexacyclic moiety resulting from the cleavage of the C-6/C-7 bond to the C-6-N bond. Some Daphniphyllum alkaloids exhibited anticancer, antioxidant, and anti-HIV activities and stimulated wheat growth. The biological activity of natural Daphniphyllum alkaloids has not been exhaustively studied, since pharmacological assays prove to be costly due to low contents of the alkaloids. Out of the Daphniphyllum alkaloid family, special mention should be made of the group of compounds with a non-classical structure [50,51]. This group includes, in particular, longeracemine 95 and angustimine 96 (Figure 4). A specific feature of longeracemine 95 is the presence of the C-7/C-9 bond and the 5/6/6/6/5 type ring system. In turn, angustimine 96 is an intramolecular salt containing a non-trivial hexacyclic moiety resulting from the cleavage of the C-6/C-7 bond to the C-6-N bond. Some Daphniphyllum alkaloids exhibited anticancer, antioxidant, and anti-HIV activities and stimulated wheat growth. The biological activity of natural Daphniphyllum alkaloids has not been exhaustively studied, since pharmacological assays prove to be costly due to low contents of the alkaloids. ular, longeracemine 95 and angustimine 96 (Figure 4). A specific feature of longeracemine 95 is the presence of the C-7/C-9 bond and the 5/6/6/6/5 type ring system. In turn, angustimine 96 is an intramolecular salt containing a non-trivial hexacyclic moiety resulting from the cleavage of the C-6/C-7 bond to the C-6-N bond. Some Daphniphyllum alkaloids exhibited anticancer, antioxidant, and anti-HIV activities and stimulated wheat growth. The biological activity of natural Daphniphyllum alkaloids has not been exhaustively studied, since pharmacological assays prove to be costly due to low contents of the alkaloids.

Pentacyclanes with Three Endocyclic Nitrogen Atoms
The stereoselective synthesis of the decahydropyrrolo[2,1,5-cd]indolizine system has been reported [53]. The 1,3-dipolar cycloaddition of glycine methyl ester and cinnamaldehyde to N-phenylmaleimide resulted in the formation of pyrrolidine derivative. The sub- 95 is the presence of the C-7/C-9 bond and the 5/6/6/6/5 type ring system. In turn, angustimine 96 is an intramolecular salt containing a non-trivial hexacyclic moiety resulting from the cleavage of the C-6/C-7 bond to the C-6-N bond. Some Daphniphyllum alkaloids exhibited anticancer, antioxidant, and anti-HIV activities and stimulated wheat growth. The biological activity of natural Daphniphyllum alkaloids has not been exhaustively studied, since pharmacological assays prove to be costly due to low contents of the alkaloids.

Pentacyclanes with Three Endocyclic Nitrogen Atoms
The stereoselective synthesis of the decahydropyrrolo[2,1,5-cd]indolizine system has been reported [53]. The 1,3-dipolar cycloaddition of glycine methyl ester and cinnamaldehyde to N-phenylmaleimide resulted in the formation of pyrrolidine derivative. The sub-Scheme 24. The synthesis of monoazapentacyclic compound.

Pentacyclanes with Three Endocyclic Nitrogen Atoms
The stereoselective synthesis of the decahydropyrrolo[2,1,5-cd]indolizine system has been reported [53].  It was shown that (-)-cytisine derivatives of this type exhibited a moderate antiviral activity against the H1N1 serotype influenza A virus [55].
A group of researchers reported [54] the synthesis of pentacyclic adducts 101 a-d. The method included [4+2]-cycloaddition of N-substituted maleimides to N-benzyl (-)cytisine and the subsequent hydrogenation on the palladium catalyst. The complete reduction of compound 101 d enabled the synthesis of saturated triamine 102 in 66% yield (Scheme 26). It was shown that (-)-cytisine derivatives of this type exhibited a moderate antiviral activity against the H1N1 serotype influenza A virus [55]. Scheme 26. The formation of pentacyclic adducts.

Pentacyclanes with Six and More Endocyclic Nitrogen Atoms
An example of the synthesis of cage pentacyclanes 104 is reported in a study headed by A. Kravchenko [56] (Scheme 27). Having replaced glyoxal, which is traditionally used for glycoluril synthesis, by cyclohexane-1,2-dione, the authors obtained derivative 103 with the goal to use it as a synthon for the synthesis of fused polyheterocyclic glycolurils.

Pentacyclanes with Six and More Endocyclic Nitrogen Atoms
An example of the synthesis of cage pentacyclanes 104 is reported in a study headed by A. Kravchenko [56] (Scheme 27). Having replaced glyoxal, which is traditionally used for glycoluril synthesis, by cyclohexane-1,2-dione, the authors obtained derivative 103 with the goal to use it as a synthon for the synthesis of fused polyheterocyclic glycolurils.
A group of researchers reported [54] the synthesis of pentacyclic adducts 101 a-d. The method included [4+2]-cycloaddition of N-substituted maleimides to N-benzyl (-)cytisine and the subsequent hydrogenation on the palladium catalyst. The complete reduction of compound 101 d enabled the synthesis of saturated triamine 102 in 66% yield (Scheme 26). It was shown that (-)-cytisine derivatives of this type exhibited a moderate antiviral activity against the H1N1 serotype influenza A virus [55].

Pentacyclanes with Six and More Endocyclic Nitrogen Atoms
An example of the synthesis of cage pentacyclanes 104 is reported in a study headed by A. Kravchenko [56] (Scheme 27). Having replaced glyoxal, which is traditionally used for glycoluril synthesis, by cyclohexane-1,2-dione, the authors obtained derivative 103 with the goal to use it as a synthon for the synthesis of fused polyheterocyclic glycolurils.

Hexacyclanes with One Endocyclic Nitrogen Atom
A large group of penta-and hexacyclic saturated nitrogen-containing compounds belonging to the family of diterpene alkaloids were isolated from various species of Aconitum, Delphinium, and Garrya plants ( Figure 5). In terms of the chemical structure, they have been classified as C18-, C19-, or C20-diterpene alkaloids without multiple bonds in the molecular core. Most of C19-diterpene alkaloids belong to the aconitine and lycoctonine types. The main representatives of C20-diterpene alkaloids correspond to atisine and napelline types [58][59][60][61][62][63]. Diterpene alkaloids exhibited a pronounced cytotoxic effect against human tumor cells (A-549, DU-145, MDA-MB-231, MCF-7, HER2, and KB) [64,65]. The anti-inflammatory activity was studied for some representatives of Aconitum diterpene alkaloids [66]. In 2014, Japanese researchers headed by T. Fukuyama performed the first total synthesis of (−)-lepenine 113 [67]. The denudatine molecular skeleton of this product represented a hexacyclic system comprising tetradecahydrophenanthrene, a polycyclic system containing a nitrogen atom, and a bicyclo [2.2.2] cage. The multistep synthesis started with the conversion of methyl L-lactate 108 to alcohol 109, which was transformed to tetracyclic lactone 110 via a sequence of reactions. The subsequent transformations were directed towards the formation of polycyclic system 112 containing a nitrogen atom. The final goal, which was successfully solved, was related to the construction of bicyclo [2.2.2] cage and its subsequent fuctionalization, resulting in the target polycyclane 113 (Scheme 30). In 2014, Japanese researchers headed by T. Fukuyama performed the first total synthesis of (−)-lepenine 113 [67]. The denudatine molecular skeleton of this product represented a hexacyclic system comprising tetradecahydrophenanthrene, a polycyclic system containing a nitrogen atom, and a bicyclo [2.2.2] cage. The multistep synthesis started with the conversion of methyl L-lactate 108 to alcohol 109, which was transformed to tetracyclic lactone 110 via a sequence of reactions. The subsequent transformations were directed towards the formation of polycyclic system 112 containing a nitrogen atom. The final goal, which was successfully solved, was related to the construction of bicyclo [2.2.2] cage and its subsequent fuctionalization, resulting in the target polycyclane 113 (Scheme 30).

Hexacyclanes with Two and Three Endocyclic Nitrogen Atoms
D. Trauner and B.M. Williams proposed [68] a synthetic route to alkaloid (+)-lycopalhine A 121, which features a complex hexacyclic ring system consisting of one C-6 and two C-5 carbocycles and single pyrrolidine, piperidine, and perhydropyrimidine moieties. L-Glutamic acid ester 114 was used as the starting compound in the multistep synthesis. Using a number of successive transformations, compound 114 was converted to amino ketone 117, which reacted with aldehyde 118. The treatment of the resulting imine 119 with L-proline promoted an intramolecular 5-endo-trig Mannich cyclization, resulting in the synthesis of product 120 with the S-configuration at C-7. The subsequent intramolecular cyclization enabled the formation of diazapolycyclane 121 (Scheme 31).

Scheme 31. A synthetic route to alkaloid (+)-lycopalhine A.
A study of Li's research group [69] describing new representatives of Myrioneuron alkaloids with a non-trivial hexacyclic core deserves attention ( Figure 6). The structures of the products were determined by a combination of spectroscopic data and a single crystal X-ray diffraction analysis. Compound 123 is the first Myrioneuron alkaloid featuring a unique trans-decahydroquinoline motif and containing a rare cyano group. Compounds 122 a,b inhibited the hepatitis C virus in vitro. Scheme 30. The first total synthesis of (-)-lepenine.

Hexacyclanes with Two and Three Endocyclic Nitrogen Atoms
D. Trauner and B.M. Williams proposed [68] a synthetic route to alkaloid (+ palhine A 121, which features a complex hexacyclic ring system consisting of one C two C-5 carbocycles and single pyrrolidine, piperidine, and perhydropyrimidine ties. L-Glutamic acid ester 114 was used as the starting compound in the multiste thesis. Using a number of successive transformations, compound 114 was conver amino ketone 117, which reacted with aldehyde 118. The treatment of the resulting 119 with L-proline promoted an intramolecular 5-endo-trig Mannich cyclization, res in the synthesis of product 120 with the S-configuration at C-7. The subsequent in lecular cyclization enabled the formation of diazapolycyclane 121 (Scheme 31).

Scheme 31. A synthetic route to alkaloid (+)-lycopalhine A.
A study of Li's research group [69] describing new representatives of Myrio alkaloids with a non-trivial hexacyclic core deserves attention ( Figure 6). The stru of the products were determined by a combination of spectroscopic data and a singl tal X-ray diffraction analysis. Compound 123 is the first Myrioneuron alkaloid featu unique trans-decahydroquinoline motif and containing a rare cyano group. Comp 122 a,b inhibited the hepatitis C virus in vitro.

Scheme 31. A synthetic route to alkaloid (+)-lycopalhine A.
A study of Li's research group [69] describing new representatives of Myrioneuron alkaloids with a non-trivial hexacyclic core deserves attention ( Figure 6). The structures of the products were determined by a combination of spectroscopic data and a single crystal X-ray diffraction analysis. Compound 123 is the first Myrioneuron alkaloid featuring a unique trans-decahydroquinoline motif and containing a rare cyano group. Compounds 122 a,b inhibited the hepatitis C virus in vitro.

Hexacyclanes with Six Endocyclic Nitrogen Atoms
The cyclocondensation of 4-aminopiperidine, paraformaldehyde, and tetraazaperhydrotetracene 124 in the presence of the highly acidic Lewatit cation exchange resin [70] enabled the synthesis of N,N -disubstituted hexaazaperhydrodibenzotetracene 125, the stereoconfiguration of which was not indicated (Scheme 32).

Hexacyclanes with Six Endocyclic Nitrogen Atoms
The cyclocondensation of 4-aminopiperidine, paraformaldehyde, and tetraazaperhydrotetracene 124 in the presence of the highly acidic Lewatit cation exchange resin [70] enabled the synthesis of N,N′-disubstituted hexaazaperhydrodibenzotetracene 125, the stereoconfiguration of which was not indicated (Scheme 32).

Scheme 32. The synthesis of hexaazaperhydrodibenzotetracene.
A number of studies, addressed the possibility of preparing hexaazaperhydrodibenzotetracenes from tetracyclanes 124 a,b as the starting building blocks, which were obtained from (±)-cis-1,2-diaminocyclohexane or (±)-trans-1,2-diaminocyclohexane. Heterocyclization [71] of 1,6,7,12-tetraazaperhydrotetracene 124 a, generated in situ from (±)-ciscyclohexane-1,2-diamine, with N,N-di(methoxymethyl)alkylamines or 1,3,5-tricycloalkyl-1,3,5-triazinanes under optimized reaction conditions led to the selective formation of the corresponding 2,9-di(cyclo)alkyl-substituted hexaazaperhydrodibenzotetracenes 126 in 72-82% yields (Scheme 33). The hexaazaperhydrodibenzotetracene skeleton has the trans,trans,anti,trans,trans-configuration, in which two piperazine and two triazinane rings are in a chair conformation and are fused in the trans-form. A distinctive feature of the synthesis based on (±)-cis-1,2-diaminocyclohexane is the formation of perhydrotetracenes with S*,R*,R*,S* relative configuration of the chiral centers at the C-3b, C-7a, C-10b, and C-14a carbon atoms. The possibility of incorporating amino derivative of the methyl maleopimarate into the hexaazaperhydrodibenzotetracene core (Scheme 34) has been reported [46]. Compound 127 exhibits moderate cytotoxic effects against HTC-116, THP-1, MCF-7, Jurkat, and SH-SY5Y tumor cells. The suggested synthesis opens a way to new potentially biologically active hybrid molecules. Combining several moieties with proven pharmacological activity in one molecule is a promising approach to the development of organic compounds with a targeted biological action. This strategy may give rise to compounds possessing a new spectrum of pharmacological properties compared to initial molecules [72]. The possibility of incorporating amino derivative of the methyl maleopimarate into the hexaazaperhydrodibenzotetracene core (Scheme 34) has been reported [46]. Compound 127 exhibits moderate cytotoxic effects against HTC-116, THP-1, MCF-7, Jurkat, and SH-SY5Y tumor cells. The suggested synthesis opens a way to new potentially biologically active hybrid molecules. Combining several moieties with proven pharmacological activity in one molecule is a promising approach to the development of organic compounds with a targeted biological action. This strategy may give rise to compounds possessing a new spectrum of pharmacological properties compared to initial molecules [72]. Scheme 34. The incorporation amino derivative of the methyl maleopimarate in to the hexaazaperhydrodibenzotetracene core.
An efficient one-pot method for the synthesis of previously undescribed 2,9-disubstituted hexaazaperhydrodibenzotetracenes 128 has been developed [73]. The synthesis was based on tetraazaperhydrotetracene 124 b derived from (±)-trans-1,2-diaminocyclohexane (Scheme 35). The six-membered carbo and aza rings in the hexaazaperhydrodibenzotetracene moiety exist in the chair conformation. The piperazine rings are cis-fused, while the piperazine and cyclohexane rings are trans-fused. A structural pecularity of the synthesized hexaazaperhydrodibenzotetracenes is the presence of the R*,R*,R*,R*-relative configuration of chiral centers at the C-3b, C-7a, C-10b, C-14a carbon atoms and a cis-junction of the rings along the C14c-C14d bond. No data on configurations of compounds formed in the reactions of 1,2-diaminocyclohexane isomers with glyoxal are available from the literature. Still, it was reported that the reactions of trans-diaminocyclohexane [74,75] with 2,3-dihydro-5,6-dimethylpyrazine give tetraazapolycyclane compounds with cis-junction of piperazine rings. The products obtained in the reactions of triethylenetetramine [76] with glyoxalare characterized by similar stereochemistry. It is noteworthy that perhydropyrene polyazapolycycles also have both trans- [71] and cis-junctions [77] of the piperazine rings. An efficient one-pot method for the synthesis of previously undescribed 2,9-disubstituted hexaazaperhydrodibenzotetracenes 128 has been developed [73]. The synthesis was based on tetraazaperhydrotetracene 124 b derived from (±)-trans-1,2-diaminocyclohexane (Scheme 35). The six-membered carbo and aza rings in the hexaazaperhydrodibenzotetracene moiety exist in the chair conformation. The piperazine rings are cis-fused, while the piperazine and cyclohexane rings are trans-fused. A structural pecularity of the synthesized hexaazaperhydrodibenzotetracenes is the presence of the R*,R*,R*,R*-relative configuration of chiral centers at the C-3b, C-7a, C-10b, C-14a carbon atoms and a cis-junction of the rings along the C14c-C14d bond. No data on configurations of compounds formed in the reactions of 1,2-diaminocyclohexane isomers with glyoxal are available from the literature. Still, it was reported that the reactions of trans-diaminocyclohexane [74,75] with 2,3-dihydro-5,6-dimethylpyrazine give tetraazapolycyclane compounds with cis-junction of piperazine rings. The products obtained in the reactions of triethylenetetramine [76] with glyoxalare characterized by similar stereochemistry. It is noteworthy that perhydropyrene polyazapolycycles also have both trans- [71] and cis-junctions [77] of the piperazine rings. The possibility of incorporating amino derivative of the methyl maleopimarate into the hexaazaperhydrodibenzotetracene core (Scheme 34) has been reported [46]. Compound 127 exhibits moderate cytotoxic effects against HTC-116, THP-1, MCF-7, Jurkat, and SH-SY5Y tumor cells. The suggested synthesis opens a way to new potentially biologically active hybrid molecules. Combining several moieties with proven pharmacological activity in one molecule is a promising approach to the development of organic compounds with a targeted biological action. This strategy may give rise to compounds possessing a new spectrum of pharmacological properties compared to initial molecules [72]. Scheme 34. The incorporation amino derivative of the methyl maleopimarate in to the hexaazaperhydrodibenzotetracene core.
An efficient one-pot method for the synthesis of previously undescribed 2,9-disubstituted hexaazaperhydrodibenzotetracenes 128 has been developed [73]. The synthesis was based on tetraazaperhydrotetracene 124 b derived from (±)-trans-1,2-diaminocyclohexane (Scheme 35). The six-membered carbo and aza rings in the hexaazaperhydrodibenzotetracene moiety exist in the chair conformation. The piperazine rings are cis-fused, while the piperazine and cyclohexane rings are trans-fused. A structural pecularity of the synthesized hexaazaperhydrodibenzotetracenes is the presence of the R*,R*,R*,R*-relative configuration of chiral centers at the C-3b, C-7a, C-10b, C-14a carbon atoms and a cis-junction of the rings along the C14c-C14d bond. No data on configurations of compounds formed in the reactions of 1,2-diaminocyclohexane isomers with glyoxal are available from the literature. Still, it was reported that the reactions of trans-diaminocyclohexane [74,75] with 2,3-dihydro-5,6-dimethylpyrazine give tetraazapolycyclane compounds with cis-junction of piperazine rings. The products obtained in the reactions of triethylenetetramine [76] with glyoxalare characterized by similar stereochemistry. It is noteworthy that perhydropyrene polyazapolycycles also have both trans- [71] and cis-junctions [77] of the piperazine rings. The broad spectrum of biological activity of the heterosystems with an adamantane moiety [78] attracts the attention of researchers and stimulates the development of efficient methods for the synthesis of new cage molecules. In this regard, the same authors [73] performed the one-pot cyclocondensation of adamantylamines with formaldehyde and tetraazaperhydrotetracene 124 b in the presence of granulated H-Ymmm zeolite to give previously undescribed diadamantyl-substituted hexaazaperhydrodibenzotetracenes 129 (Scheme 36). The hydroxyadamantane-substituted hexaazaperhydrodibenzotetracenew is shown to possess a cytostatic activity (a proliferation-restrictive activity) against six tumor cell cultures (Jurkat, K562, U937, A549, A2780, and T74D). The most pronounced effect was observed in U937 cells. The broad spectrum of biological activity of the heterosystems with an adamantane moiety [78] attracts the attention of researchers and stimulates the development of efficient methods for the synthesis of new cage molecules. In this regard, the same authors [73] performed the one-pot cyclocondensation of adamantylamines with formaldehyde and tetraazaperhydrotetracene 124 b in the presence of granulated H-Ymmm zeolite to give previously undescribed diadamantyl-substituted hexaazaperhydrodibenzotetracenes 129 (Scheme 36). The hydroxyadamantane-substituted hexaazaperhydrodibenzotetracenew is shown to possess a cytostatic activity (a proliferation-restrictive activity) against six tumor cell cultures (Jurkat, K562, U937, A549, A2780, and T74D). The most pronounced effect was observed in U937 cells. The catalytic cyclocondensation of tetraazaperhydrotetracene 124 b [79,80] with formaldehyde and some (het)arylamines led to the corresponding 2,9-bis(hetaryl) derivatives 130 a,b (Scheme 37). The condensation of heterocycle 124 b with formaldehyde in the presence of a catalyst involves the stage of formation of tetrakis(hydroxymethyl) derivative. Probably, YbCl3 × 6H2O or Sm(NO3)3 × 6H2O is coordinated, as a hard Lewis acid, to the oxygen atom of intermediate to give a carbocation. The subsequent nucleophilic addition of the primary (het)arylamine to the carbocation results in di(het)aryl-substituted hexaazaperhydrodibenzotetracenes. Scheme 37. The catalytic cyclocondensation of tetraazaperhydrotetracene with formaldehyde and some (het)arylamines.
The ability of N,N,N′,N′-tetramethylmethanediamine to form new C-N bonds in the catalytic synthesis of heterocyclic compounds has been reported [81]. With this in mind, at the next stage, authors [82] made an attempt to use tetramethylmethanediamine as a synthetic equivalent of formaldehyde in the synthesis of hexaazaperhydrodibenzotetracenes 130 a,b (Scheme 38). The condensation of tetraazaperhydrotetracene 124 b with N,N,N′,N′-tetramethylmethanediamine and substituted anilines was performed in the presence of NiCl2 × 6H2O as the most active catalyst. According to the hard and soft acids Scheme 36. The formation of diadamantyl-substituted hexaazaperhydrodibenzotetracenes.
The catalytic cyclocondensation of tetraazaperhydrotetracene 124 b [79,80] with formaldehyde and some (het)arylamines led to the corresponding 2,9-bis(hetaryl) derivatives 130 a,b (Scheme 37). The condensation of heterocycle 124 b with formaldehyde in the presence of a catalyst involves the stage of formation of tetrakis(hydroxymethyl) derivative. Probably, YbCl 3 × 6H 2 O or Sm(NO 3 ) 3 × 6H 2 O is coordinated, as a hard Lewis acid, to the oxygen atom of intermediate to give a carbocation. The subsequent nucleophilic addition of the primary (het)arylamine to the carbocation results in di(het)aryl-substituted hexaazaperhydrodibenzotetracenes. The broad spectrum of biological activity of the heterosystems with an adamantane moiety [78] attracts the attention of researchers and stimulates the development of efficient methods for the synthesis of new cage molecules. In this regard, the same authors [73] performed the one-pot cyclocondensation of adamantylamines with formaldehyde and tetraazaperhydrotetracene 124 b in the presence of granulated H-Ymmm zeolite to give previously undescribed diadamantyl-substituted hexaazaperhydrodibenzotetracenes 129 (Scheme 36). The hydroxyadamantane-substituted hexaazaperhydrodibenzotetracenew is shown to possess a cytostatic activity (a proliferation-restrictive activity) against six tumor cell cultures (Jurkat, K562, U937, A549, A2780, and T74D). The most pronounced effect was observed in U937 cells. The catalytic cyclocondensation of tetraazaperhydrotetracene 124 b [79,80] with formaldehyde and some (het)arylamines led to the corresponding 2,9-bis(hetaryl) derivatives 130 a,b (Scheme 37). The condensation of heterocycle 124 b with formaldehyde in the presence of a catalyst involves the stage of formation of tetrakis(hydroxymethyl) derivative. Probably, YbCl3 × 6H2O or Sm(NO3)3 × 6H2O is coordinated, as a hard Lewis acid, to the oxygen atom of intermediate to give a carbocation. The subsequent nucleophilic addition of the primary (het)arylamine to the carbocation results in di(het)aryl-substituted hexaazaperhydrodibenzotetracenes. Scheme 37. The catalytic cyclocondensation of tetraazaperhydrotetracene with formaldehyde and some (het)arylamines.
The ability of N,N,N′,N′-tetramethylmethanediamine to form new C-N bonds in the catalytic synthesis of heterocyclic compounds has been reported [81]. With this in mind, at the next stage, authors [82] made an attempt to use tetramethylmethanediamine as a synthetic equivalent of formaldehyde in the synthesis of hexaazaperhydrodibenzotetracenes 130 a,b (Scheme 38). The condensation of tetraazaperhydrotetracene 124 b with N,N,N′,N′-tetramethylmethanediamine and substituted anilines was performed in the presence of NiCl2 × 6H2O as the most active catalyst. According to the hard and soft acids Scheme 37. The catalytic cyclocondensation of tetraazaperhydrotetracene with formaldehyde and some (het)arylamines.
The ability of N,N,N ,N -tetramethylmethanediamine to form new C-N bonds in the catalytic synthesis of heterocyclic compounds has been reported [81]. With this in mind, at the next stage, authors [82] made an attempt to use tetramethylmethanediamine as a synthetic equivalent of formaldehyde in the synthesis of hexaazaperhydrodibenzotetracenes 130 a,b (Scheme 38). The condensation of tetraazaperhydrotetracene 124 b with N,N,N ,N -tetramethylmethanediamine and substituted anilines was performed in the presence of NiCl 2 × 6H 2 O as the most active catalyst. According to the hard and soft acids and bases principle [83], Ni(II) chloride hexahydrate, being an "intermediate" Lewis acid, is preferably coordinated to the intermediate N-donor ligand to give the most stable acid-base complex. and bases principle [83], Ni(II) chloride hexahydrate, being an "intermediate" Lewis acid, is preferably coordinated to the intermediate N-donor ligand to give the most stable acidbase complex. Scheme 38. An alternative method for the synthesis of hexaazaperhydrodibenzotetracenes.
Hexaazaperhydrodibenzotetracenes 130 a,b were evaluated for cytotoxicity in a panel of human cancer cell lines (HepG2, HTC116, SH-SY5Y, MCF-7, A549, Jurkat, THP-1) and in tentatively normal cells (HEK293) by the MTT assay [82]. Tetracenes containing 3-methoxyphenyl and 4-nitrophenyl substituents exhibited a moderate cytotoxicity against tentatively normal HEK293 cells only. The compound containing a pyridine substituent was most active amongst the series of substances studied, inhibiting the viability of cancer and non-cancer cells with IC50 values ranging from 25 to 52 μM, depending on the cell line tested.

Heptacyclic Saturated Nitrogen-Containing Compounds
Only a few examples of the synthesis of heptacyclanes with endocyclic nitrogen atoms can be found in the literature. Thus the synthesis of methylene-bridged glycoluril dimer 132 has been proposed [84]. Glycoluril dimer was prepared in two steps. First, a precursor of glycoluril dimer was synthesized and then two precursor molecules 131 were linked via the condensation with formaldehyde (Scheme 39). Scheme 39. The synthesis of methylene-bridged glycoluril dimer.

Conclusions
The scope of applicability of nitrogen compounds is ever expanding. The molecular cores of N-polycyclic compounds possess high structural diversity and attract interest in relation to the search for new medicinal agents. In this review, we considered and described the modern trends in the chemistry of saturated azapolycyclic molecules with promising biological properties such as anticancer, anti-inflammatory, antibacterial, antifungal, antiviral, and other properties. On the one hand, the development of synthetic routes to new original polycyclic systems and the targeted modification of polyheterocycles substantially expand the potential for the synthesis of these compounds. On the other hand, it is of considerable interest to incorporate pharmacologically significant groups and natural metabolites with pronounced biological activity into the polycyclic core in Scheme 38. An alternative method for the synthesis of hexaazaperhydrodibenzotetracenes.
Hexaazaperhydrodibenzotetracenes 130 a,b were evaluated for cytotoxicity in a panel of human cancer cell lines (HepG2, HTC116, SH-SY5Y, MCF-7, A549, Jurkat, THP-1) and in tentatively normal cells (HEK293) by the MTT assay [82]. Tetracenes containing 3methoxyphenyl and 4-nitrophenyl substituents exhibited a moderate cytotoxicity against tentatively normal HEK293 cells only. The compound containing a pyridine substituent was most active amongst the series of substances studied, inhibiting the viability of cancer and non-cancer cells with IC 50 values ranging from 25 to 52 µM, depending on the cell line tested.

Heptacyclic Saturated Nitrogen-Containing Compounds
Only a few examples of the synthesis of heptacyclanes with endocyclic nitrogen atoms can be found in the literature. Thus the synthesis of methylene-bridged glycoluril dimer 132 has been proposed [84]. Glycoluril dimer was prepared in two steps. First, a precursor of glycoluril dimer was synthesized and then two precursor molecules 131 were linked via the condensation with formaldehyde (Scheme 39). Hexaazaperhydrodibenzotetracenes 130 a,b were evaluated for cytotoxicity in a panel of human cancer cell lines (HepG2, HTC116, SH-SY5Y, MCF-7, A549, Jurkat, THP-1) and in tentatively normal cells (HEK293) by the MTT assay [82]. Tetracenes containing 3-methoxyphenyl and 4-nitrophenyl substituents exhibited a moderate cytotoxicity against tentatively normal HEK293 cells only. The compound containing a pyridine substituent was most active amongst the series of substances studied, inhibiting the viability of cancer and non-cancer cells with IC50 values ranging from 25 to 52 μM, depending on the cell line tested.

Heptacyclic Saturated Nitrogen-Containing Compounds
Only a few examples of the synthesis of heptacyclanes with endocyclic nitrogen atoms can be found in the literature. Thus the synthesis of methylene-bridged glycoluril dimer 132 has been proposed [84]. Glycoluril dimer was prepared in two steps. First, a precursor of glycoluril dimer was synthesized and then two precursor molecules 131 were linked via the condensation with formaldehyde (Scheme 39). Scheme 39. The synthesis of methylene-bridged glycoluril dimer.

Conclusions
The scope of applicability of nitrogen compounds is ever expanding. The molecular cores of N-polycyclic compounds possess high structural diversity and attract interest in relation to the search for new medicinal agents. In this review, we considered and described the modern trends in the chemistry of saturated azapolycyclic molecules with promising biological properties such as anticancer, anti-inflammatory, antibacterial, antifungal, antiviral, and other properties. On the one hand, the development of synthetic routes to new original polycyclic systems and the targeted modification of polyheterocycles substantially expand the potential for the synthesis of these compounds. On the other hand, it is of considerable interest to incorporate pharmacologically significant groups and natural metabolites with pronounced biological activity into the polycyclic core in Scheme 39. The synthesis of methylene-bridged glycoluril dimer.

Conclusions
The scope of applicability of nitrogen compounds is ever expanding. The molecular cores of N-polycyclic compounds possess high structural diversity and attract interest in relation to the search for new medicinal agents. In this review, we considered and described the modern trends in the chemistry of saturated azapolycyclic molecules with promising biological properties such as anticancer, anti-inflammatory, antibacterial, antifungal, antiviral, and other properties. On the one hand, the development of synthetic routes to new original polycyclic systems and the targeted modification of polyheterocycles substantially expand the potential for the synthesis of these compounds. On the other hand, it is of considerable interest to incorporate pharmacologically significant groups and natural metabolites with pronounced biological activity into the polycyclic core in order to obtain new classes of hybrid molecules as promising precursors for the development of modern medications for the treatment of socially significant diseases. Analysis of state-of-the-art studies addressing the synthesis of various saturated N-polycyclic molecules confirms their huge potential and implies a broad scope of practical application of these products.