ISSN 1813-1107 (Print)
ЕҢБЕКҚЫЗЫЛТУОРДЕНДІ
«Ә. Б. БЕКТҰРОВ АТЫНДАҒЫ ХИМИЯ ҒЫЛЫМДАРЫ ИНСТИТУТЫ»
АКЦИОНЕРЛІК ҚОҒАМЫ
Қ АЗАҚСТАННЫҢ
Х ИМИЯ Ж УРНАЛЫ Х ИМИЧЕСКИЙ Ж УРНАЛ
К АЗАХСТАНА
C HEMICAL JOURNAL of K AZAKHSTAN
АКЦИОНЕРНОЕ ОБЩЕСТВО
ОРДЕНА ТРУДОВОГО КРАСНОГО ЗНАМЕНИ
«ИНСТИТУТ ХИМИЧЕСКИХ НАУК им. А. Б. БЕКТУРОВА»
3 (75)
ИЮЛЬ – СЕНТЯБРЬ 2021 г.
ИЗДАЕТСЯ С ОКТЯБРЯ 2003 ГОДА ВЫХОДИТ 4 РАЗА В ГОД
АЛМАТЫ 2021
Ж у р н а л д ы ң б а с р е д а к т о р ы Бас директор
Д. Е. Фишер, х.ғ.к.
Р е д а к ц и я к е ң е с і н і ң м ү ш е л е р і:
Ө.Ж. Жүсіпбеков, проф., т.ғ.д., ҚР ҰҒА корр.-мүшесі (Қазақстан Республикасы);
Б.Н. Абсадыков, проф., т.ғ.д., ҚР ҰҒА корр.-мүшесі (Қазақстан Республикасы);
А.Р. Хохлов, проф., ф.-м.ғ.д., РҒА акад. (Ресей); М.П.Егоров, проф., х.ғ.д., РҒА акад., (Ресей); В.С. Солдатов, проф., х.ғ.д., ҰҒА (Беларусь); М.Ж.Жұрынов, проф., х.ғ.д., ҚР ҰҒА академигі (Қазақстан Республикасы); И.К. Бейсембетов, проф., э.ғ.д., ҚР ҰҒА академигі (Қазақстан Республикасы); Қ.Ж. Пірәлиев, проф., х.ғ.д., ҚР ҰҒА академигі (Қазақстан Республикасы); Д.Х. Халиков, проф., х.ғ.д., ТРҒА академигі (Тәжікстан Республикасы); В.М. Дембицкий, проф., х.ғ.д.,
РЖҒА акад. (Ресей); Л.А. Каюкова, проф., х.ғ.д. (Қазақстан Республикасы);
В.К. Ю, проф., х.ғ.д. (Қазақстан Республикасы); Е.Ф. Панарин, проф., х.ғ.д., РҒА корр.-мүшесі (Ресей); Э.Б. Зейналов, проф., х.ғ.д., Әзірбайжан ҰҒА корр.-мүшесі;
(Әзірбайжан); Брахим Елоуди, PhD, проф., х.ғ.д., Де Ла Рошель университеті (Франция Республикасы); Х. Темель, проф., Дикле университеті (Түркия Респуб- ликасы); Б.С. Закиров, проф., х.ғ.д., Өзбекстан Республикасы ҒА (Өзбекстан Республикасы); Г.А. Мун, х.ғ.д., проф. (Қазақстан Республикасы); К.Б. Ержанов, х.ғ.д., проф. (Қазақстан Республикасы); Б.Т. Өтелбаев, х.ғ.д., проф. (Қазақстан Республикасы); А.Е. Малмакова, PhD докторы (Қазақстан Республикасы);
К.Д. Мустафинов (бас ғылыми хатшысы).
«Қазақстанныңхимия журналы»
ISSN 2710-1185 (Online); ISSN 1813-1107 (Print)
Құрылтайшы: Еңбек Қызыл Ту орденді Ә.Б. Бектұров атындағы Химия ғылымдары институты
Тіркеу: Қазақстан РеспубликасыныңМәдениет, ақпарат және қоғамдықкелісім министрлігінде № 3995-Ж 2003 жылғы 25-маусымдағы
2003 жылы құрылған. Жылына 4 рет шығады.
Редакцияның мекен-жайы: 050010 (A26F3Y1), Қазақстан Республикасы, Алматы қ.,
Ш. Уалиханов көшесі, 106. тел. 8 (727) 291-24-64, 8 (727) 291-59-31.
ics_rk@mail.ru
© АҚ «Ә.Б. Бектұров атындағы Химия ғылымдары институты», 2021
«Қазпошта» АҚ-ның газет-журналдар каталогында немесе оның қосымшаларында жазылуиндексі
Г л а в н ы й р е д а к т о р Генеральный директор
Д. Е. Фишер, к.х.н.
Р е д а к ц и о н н а я к о л л е г и я:
У.Ж. Джусипбеков, проф., д.т.н., член-корр. НАН РК (Республика Казахстан);
Б.Н. Абсадыков, проф., д.т.н., член-корр. НАН РК (Республика Казахстан);
А.Р. Хохлов, проф., д.ф.-м.н., акад. РАН (Россия); М.П. Егоров, проф., д.х.н., акад.
РАН (Россия); В.С. Солдатов, проф., д.х.н., акад. НАН Беларуси (Беларусь);
М.Ж.Журинов, проф., д.х.н., акад. НАН РК (Республика Казахстан);
И.К. Бейсембетов, проф., д.э.н., акад. НАН РК (Республика Казахстан);
К.Д. Пралиев, проф., д.х.н., акад. НАН РК (Республика Казахстан); Д.Х. Халиков, проф., д.х.н., акад. АН Республики Таджикистан (Таджикистан); В.М. Дембицкий, проф., д.х.н., акад. РАЕН (Россия); Л.А. Каюкова, проф., д.х.н. (Республика Казахстан); В.К. Ю, проф., д.х.н. (Республика Казахстан); Е.Ф.Панарин, проф., д.х.н., член-корр. РАН (Россия); Э.Б. Зейналов, проф., д.х.н., член-корр. НАН Азербайджана (Азербайджан); Брахим Елоуди, проф., д.х.н., Ph.D, Университет Де Ла Рошель (Французская Республика); Х.Темель, проф., Университет Дикле (Турецкая Республика); Б.С. Закиров, проф. , д.х.н., (Республика Узбекистан);
Г.А. Мун, проф., д.х.н. (Республика Казахстан); К.Б. Ержанов, проф., д.х.н.
(Республика Казахстан); Б.Т. Утельбаев, проф., д.х.н. (Республика Казахстан);
А. Е. Малмакова, доктор PhD, А.Е. Малмакова, доктор Ph.D (Республика Казахстан); К.Д. Мустафинов (отв. секретарь).
«Химический журнал Казахстана».
ISSN 2710-1185 (Online); ISSN 1813-1107 (Print)
Учредитель: Ордена Трудового Красного Знамени Институт химических наук им. А.Б. Бектурова.
Регистрация: Министерство культуры, информации и общественного согласия Республики Казахстан № 3995-Ж от 25 июня 2003 г.
Основан в 2003 г. Выходит 4 раза в год.
Адрес редакции: 050010 (A26F3Y1), г. Алматы, ул. Ш. Уалиханова, 106, тел. 8 (727) 291-24-64, 8 (727) 291-59-31.
ics_rk@mail.ru
© АО «Институт химических наук им. А. Б. Бектурова», 2021 Подписной индекс 75241 в Каталоге газет и журналов АО «Казпочта» или в дополнении к нему.
E d i t o r i n C h i e f General director
D.E. Fisher, Candidate of Chemical Sciences
E d i t o r i a l b o a r d:
U.Zh. Dzhusipbekov, Prof., Doctor of Technical Sciences, Corr. Member of NAS RK (Republic of Kazakhstan); B.N. Absadykov, Prof., Doctor of Technical Sciences, Corr.
Member of NAS RK (Republic of Kazakhstan); A.R. Khokhlov, Prof., Doctor of
Physical and Matematical Sciences, Academician of RAS (Russia), M.P. Egorov, Prof., Doctor of Chemical Sciences, Academician of RAS (Russia), V.S. Soldatov, Prof., Doctor of Chemical Sciences, Academician of NAS of Belarus (Belarus);
M.Zh. Zhurinov, Prof., Doctor of Chemical Sciences, Academician of NAS RK (Republic of Kazakhstan); I.K. Beisembetov, Prof., Doctor of Economic Sciences, Academician of NAS RK (Republic of Kazakhstan); K.D. Praliyev, Prof., Doctor of
Chemical Sciences, Academician of NAS RK (Republic of Kazakhstan);
D.Kh. Khalikov, Prof., Doctor of Chemical Sciences, Academician of ASRT (Tajikistan);
V.M. Dembitsky, Prof., Doctor of Chemical Sciences, Academician of the RANS;
L.A. Kayukova, Prof., Doctor of Chemical Sciences (Republic of Kazakhstan);
V.K. Yu, Prof., Doctor of Chemical Sciences (Republic of Kazakhstan); E.F.Panarin, Prof., Doctor of Chemical Sciences, Corr. Member of RAS (Russia); E.B. Zeynalov, Prof., Doctor of Chemical Sciences, Corr. Member of NAS of Azerbaijan (Azerbaijan);
Brahim Elouadi, PhD, Prof., De La Rochelle University (French Republic); H. Temel, Prof., Dicle University (Republic of Turkey); B.S. Zakirov, Prof., Doctor of Chemical Sciences (Republic of Uzbekistan); G.A. Moon, Prof., Doctor of Chemical Sciences (Republic of Kazakhstan); K.B. Erzhanov, Prof., Doctor of Chemical Sciences (Republic of Kazakhstan); B.T. Utelbaev, Prof., Doctor of Chemical Sciences (Republic of Kazakhstan); A.E. Malmakova, Doctor PhD (Republic of Kazakhstan);
K.D. Mustafinov (executive sekretary).
«Chemical Journal of Kazakhstan»
ISSN 2710-1185 (Online);
ISSN 1813-1107 (Print)
Founder: Order of the Red Banner of Labor Institute of Chemical Sciences named after A.B. Bekturov.
Registration: Ministry of Culture, Information and Public Accord of the Republic of Kazakhstan No. 3995-Ж dated June 25, 2003 year.
«Chemical Journal of Kazakhstan» was founded in 2003 year, publishes four issues in a year.
Address of the Editorial board: 050010 (A26F3Y1), Republic of Kazakhstan, Almaty, Sh. Ualikhanov str., 106, A.B. Bekturov Institute of chemical sciences awarded by the Order of Red Banner of Labor, Fax: 8(727)291-24-64.
ics_rk@mail.ru
© JSC «Institute of Chemical Sciences named after A.B. Bekturov», 2021.
Chemical Journal of Kazakhstan
ISSN 1813-1107, еISSN 2710-1185 https://doi.org/10.51580/2021-1/2710-1185.40 Volume 3, Number 75 (2021), 67 – 82
UDC547.94:547.99:577.124
HYBRID MOLECULES BASED ON ALKALOIDS
O.A. Nurkenov1, S.D. Fazylov1,2, G.K. Mukusheva*2, Ye.V. Minayeva2, I.V. Kulakov3, Zh.S. Nurmaganbetov1,
A.S. Kishkentaeva1, A.R. Zhasymbekova2
1LLC “Institute of Organic Synthesis and Coal Chemistry”, Karagandy, Kazakhstan
2NLC Karaganda Buketov University, Karagandy, Kazakhstan
3FSAEI of HE “Tyumen State University”, Russia E-mail: mukusheva1977@list.ru
Abstract: This review has been summarized the data on the synthesis of new hybrid derivatives based on alkaloid molecules. At the same time, there have been analyzed methods for obtaining hybrid structures containing fragments of natural compounds molecules in combination with other biologically active plant metabolites, as leading compounds for the development of new pharmacologically valuable agents, with the aim of creating new original drugs. The combination of pharmacophoric residues in one molecule, namely various aromatic and heterocyclic substituents in the nucleoside position of natural alkaloids, opens up new possibilities for both the subsequent chemical modification of the polyfunctional derivatives obtained and their new diverse biological activity. Effective methods of synthesis have been developed on the basis of directed transformations of these compounds (or their precursors). A wide range of pharmaco- logical properties of combined compounds of these series with a combination of low toxicity is promising. Considering that the preparation of combined derivatives based on alkaloid molecules has been insufficiently studied, the targeted synthesis of new com- pounds is of interest both in terms of new medicinespreparation and the development of new methods of organic synthesis, as well as the molecules stereochemistry determination of a new series of compounds.
Key words: alkaloids, alkaloids derivatives, hybrid molecules, chemical modification, cytisine, anabasine, ephedrine.
1. Introduction
Molecular hybridization is one of the modern widely used approaches in the search for new and improvement of known medicines with a high level of action ___________
Citation: Nurkenov O.A., Fazylov S.D., Mukusheva G.K., Minayeva Ye.V., Kulakov I.V., urmaganbetov Zh.S., Kishkentaeva A.S., Zhasymbekova A.R. Hybrid molecules based on alkaloids. Chem. J. Kaz., 2021, 3(75), 67‒82. DOI: https://doi.org/10.51580/2021-1/2710- 1185.40
selectivity [1-4]. The combination in one molecule of two non-identical pharmacophores, covalently linked into one molecule, leads to a new compound that has the properties of both components. Hybrid molecules acting simulta- neously on the receptor and on the enzyme can lead to powerful synergistic effects. Thus, the design of hybrid compounds and their use as medicines is a promising approach in the treatment of complex physiological disorders of the body.
One of the promising directions of this strategy can be, in our opinion, the combination of heterocyclic systems of natural alkaloids and pharmacophore groups of other natural compoundsin one structure. The numerous data on the manifestation by alkaloids derivatives of a wide spectrum of bioactivity [5-7] are good prerequisites.Taking into account the valuable biological properties of alkaloids and their derivatives, the search for new ways of chemical modification of alkaloids is undoubtedly relevant, and the attention of researchers is attracted by the obtaining of more and more complexly constructed heterocyclic systems.
Therefore, the introduction of alkaloids, fragments with biological activity into the molecules composition, is an urgent task and is of scientific and practical interest.
The methods development for the hybrid synthesis of various combined derivatives of the known alkaloids, namelycytisine, anabasine, lupinine, etc. is poorly studied and promising [7-10]. This approach allows us to expand the possible ways to search for new medicines.
2. Results and discussion
In this article, we present some of the results of many years of research on the chemical modification of quinolizidine and pyridine alkaloids with the participation of carbohydrate molecules, flavonoids, dihydroquercetin, fullerene and their modified derivatives. The combination of two physiological effects in a hybrid molecule is intended to produce a synergistic effect (increased efficacy) in the treatment of a disease or disorder. For example, the introduction of carbo- hydrate fragments into the structure of physiologically active substances not only increases their water solubility, but also significantly reduces toxicity, which makes it possible to recommend the method of glycosylation of a physiologically active compound at the glycosidic center of sugars as one of the possible ways to obtain low-toxic drugs [10-20]. It is also known that carbohydrates in the form of various derivatives are part of the cells of any living organism, playing here the role of a structural material, a supplier of energy, substrates and regulators of specific and biochemical processes. Carbohydrates, combining with nucleophilic acids, proteins and lipids, constitute high-molecular complexes that underlie subcellular structures and constitute the basis of living matter [19]. They are widely used in the treatment of cardiovascular diseases, used as antitumor, antimicrobial, and anticholinesterase agents [20].
In this regard, it was of interest to obtain N-glycosylamines based on the alkaloid cytisine and some monosaccharides for the subsequent study of their biological properties. The synthesis of N-glycosylamines 1-4 was carried out by the well-known classical method proposed by V. Sorokin in [21]. The conden- sation of the cytisine molecule with the monosaccharides D-glucose, D-galactose, D-xylose, and L-arabinose was carried out in the medium of absolute ethyl alcohol (without the addition of a catalyst) 1-4:
N
N
O
H
Sug(OH) + Sug
EtOH, 65-700C
6
N N
7
8
9 1
2 3 4 5
O
10 11
12 13
O HO
OH OH CH2OH
HO O
OH OH CH2OH Sug =
O HO
OH OH
HO O
OH OH
; ; ;
2' 1' 3' 4'
5' 6'
(D-Glc) (1) (D-Gal) (2) (D-Csy) (3) (L-Ara) (4) 1-4
N-glycosylcytisines obtained 1-4 have good solubility in polar solvents and may be of interest as analogs of the respiratory analeptic “cytiton”, remedies for smoking cessation “lobesil”, “tabex”, since, undoubtedly, they will have much lower toxicity and prolongation actions due to their gradual hydrolysis in the body.
As is known, glycosylisothiocyanates are important intermediate synthons in the synthesis of various biologically active compounds [22]. The isothiocyanate method makes it possible to introduce a thioamide group into the structure of amines (alkaloids) and hydrazides with the formation of thioureas and thiosemicarbazides, which not only expands the boundaries of these compounds modification, but can also lead to the emergence of new types of bioactivity.
Glycosylthioureas are usually obtained by the Fischer reaction, that is interaction of the corresponding amino compounds with glycosylisothiocyanate [22-24].
We carried out the interaction of 1-isothiocyano-1-deoxy-2,3,4,6-tetra-O- acetyl-β-D-glucopyranose 5 with cytisine and anabasine [7, 8]. It was found that glycosylisothiocyanate 5 reacts quite easily with the indicated alkaloids in o- xylene solution at room temperature. The compounds synthesized 6, 7 have been obtained in 70-80% yields.
O CH2OAc
AcO OAc
OAc N C S
+
O CH2OAc
AcO OAc
OAc HN C
S
5
N
NH
O
N NH +
N O
CH2OAc
AcO OAc
OAc HN C
S
N
O N
N 6
7
The addition of hydrazides to isothiocyanates is one of the convenient methods for the synthesis of thiosemicarbazides. It is known [25-27] that thiosemicarbazide derivatives have a wide range of biological actions, namely anticonvulsant, glypoglycemic, anti-inflammatory, and antibacterial ones.
Therefore, it was of interest to synthesize a new thiosemicarbazide derivative 8 based on N-anabasinylacetic acid hydrazide. Thus, a thiosemicarbazidederivative 8 based on N-anabasinyl-acetic acid hydrazide was synthesized by the condensation of N-anabasinylacetic acid hydrazide with 1-deoxy-2,3,4,6-tetra-O- acetyl-β-D-glucopyranosyl-iso-thiocyanate 5 in an alcohol solution at an equimolar ratio of the reagents used.
O AcO
OAc OAc CH2OAc
N=C=S
N N CH2C
O NHNH2
O AcO
OAc OAc AcOH2C
HN C S
NHNH
8
2' 1' 3' 4'
5' 6'
C O
CH2 N
N
2 3 4
9
5 6
7 8
1
+
5
In [28], the results of hybrid synthesis of molecules combining fragments of two alkaloids in the structure are presented. The synthesized hybrid derivatives of l-ephedrine and d-pseudoephedrine with lupinine and epilupinine are of interest not only for studying their biological properties.They are also interesting as chiral catalysts in the formation of a new carbon-carbon bond in the production of chiral pheromones.
Bromolupinine was used as a synthonfor the synthesis of N-lupinan-l- ephedrine 9 and N-lupinan-d-pseudoephedrine 10, and epilupinine bromide was used for N-epilupinan-l-ephedrine 11 and N-epilupinan-d-pseudoephedrine 12 synthesis. The reactions were carried out in a sealed ampoule in a metal container (bomb) filled with glycerol.
HC CH C6H5
HO
CH3
N CH3 H2C
N H
CH CH HO
C6H5 CH3
N CH3 H2C
N H
9 10
HC CH
C6H5 HO
CH3 N
CH3 H
N
CH2
11
HC C6H5
CH HO
CH3 N
CH3 H
N
CH2
12
The authors of [29] studied a hybrid reaction of transamidation of d- pseudoephedrine cycloamidophosphite 13 with anabasine alkaloid. It was found that cycloamidophosphite 13 is an effective phosphorylating agent, the use of which makes it possible to introduce the oxazaphospholane cycle into the backbone of the anabasine alkaloid. Further, the cycloamidophosphite 14 obtained was modified by interaction with sulfur into a 2-thione-derivative of amidophosphate 15.
N P Ph O
Me
Me
N(C2H5)2
+ S
- (C2H5)2NH
N P Ph O
Me
Me
+
13
N
NH
N
N
N P Ph O
Me
Me N
N S
14 15
Recently, a new class of heterocyclic compounds with a basic 1,4-dihydro- pyridine base, possessing high antihypertensive and nootropic activity, has begun to be widely used in medical practice [30].
The Hantzsch method applied for the synthesis of symmetric 1,4-dihydro- pyridines has a wide variation of used practically available aliphatic, aromatic or heterocyclic aldehydes, various derivatives of acetoacetic ester and ammonia (or primary amines), which makes it very promising for further search for new biologically active compounds and their chemical modification.
In [31], the corresponding diethyl 4-(4-phenyl)-2,6-dimethyl-1,4-dihydro- pyridino-3,5-dicarboxylate 16, which was used further for the subsequent reaction of halogenation and substitution,was synthesized by the Hantzsch method, in 60%
yield by the three-component condensation of 2 moles of acetoacetic ester, benzaldehyde and 25% aqueous ammonia solution. Bromi-nationof compound 16 was carried out using a mild brominating agent, namely bromosuccinimide, at room temperature in methanol according to the method described in [32]. Using a double excess of bromosuccinimide, the corresponding dibromomethyl derivative was obtained 17. The resulting dibromomethyl 1,4-dihydropyridine derivative 17 turned out to be quite reactive in the nucleophilic substitution reaction. Thus, the products of alkylation 18-20 were isolated in the interaction of a benzene solution of 14 with a double amount of alkaloids anabasine, cytisine, and d-pseudoephe- drine. The reactions were carried out in the presence of an excess of triethylamine at room temperature and vigorous stirring during the day.
N H3C CH3
COOC2H5 C2H5OOC
H
H
N
BrH2C CH2Br COOC2H5 C2H5OOC
H
H 2 NBS
16 17
MeOH
+ 2HN
CH2 N H2C COOEt EtOOC
H
H
N N
18-20
N =
N
N (18),
N N
O
(19), CH HC HO
C6H5 CH3
N CH3 (20).
Phenothiazine with a condensed tricyclic system isone of the poorly studied objects in combination synthesis with alkaloids. It is widely studied in the synthesis of insecticidal and antihelminthic drugs [33]. In addition, phenothiazine itself, like many sulfur-containing derivatives, has very low toxicity for warm- blooded animals [34]. In [7,8,35], the authors synthesized previously unknown phenothiazine derivatives of cytisine, anabasine, l-ephedrine, and d-pseudoe- phedrine 21-24 alkaloids:
N
S +ClCH2COCl
N S
CCH2Cl O
N S
CCH2
O N
H
21-24
+ HN
N =
N
N (21, N
N
O
(22),
CH HC HO
C6H5 CH3
N CH3 (23),
CH HC HO
C6H5 CH3
N CH3 (24).
Alkylation of cytisine, anabasine, l-ephedrine, and d-pseudoephedrine alkaloids with 10-(2-chloroacetyl) phenothiazine was carried out in boiling toluene in the presence of triethylamine. Column chromatography and re-preci- pitation of hydrochlorides into the base were used to purify the target products.
In order to further study the structure-activity relationship, N-alkaloid- propionyl derivatives of phenothiazine were also obtained 25-28, since 10-ami- nopropionyl derivatives of phenothiazine have high cholinergic and adrenolytic activity, antianginal and antiarrhythmic action [34].
N S
CCH2CH2
O N
N S
CCH2CH2
O N
CH3
HO CH3
C6H5 25
27 N
N S
CCH2CH2
O N N
O
N S
CCH2CH2
O N
CH3
HO CH3
C6H5 28
26
A very new and interesting direction in the alkaloids hybrid synthesis is their fullerene derivatives. Fullerenes attract the attention of researchers by their potential for practical application in science, biology, and medicine, in semicon- ductor technology and nanoelectronics [36-38]. The main directions of obtaining new materials and biologically active compounds based on fullerenes are associated with their functionalization using various reagents. Analysis of the literature data shows that the synthesis of organic fullerene C60 derivatives containingpharmacophore groups is of the greatest interest [39-43]. Fullero- pyrrolidines obtained by the Prato reaction are the most widely studied in the fullerene chemistry. There is very little information in the scientific literature on the chemical modification of natural compounds with the participation of C60
fullerene. In [44, 45], we described the synthesis of a new fullerene-containing derivative of the alkaloid cytisine 29. The synthesis of a new fulleropyrrolidine compound with the participation of fullerene C60 was carried out in a three- component medium with sarcosine and 4-cytisinobenzaldehyde in boiling toluene for 4 h according to the following scheme:
C60
+ CH3NHCH2COOH + C O H
N N
O
CH2 CH
N CH3 N
N
O 29
After the reaction, unreacted starting materials and the reaction product 29 were separated by column chromatography on SiO2, eluting with toluene and then with pyridine. In this case, the starting unreacted fullerene C60wasisolated, and then the target fulleropyrrolidine 29 was isolated with a yield of 38%.
A probable scheme for the formation of fulleropyrrolidine 29 was proposed as a 1,3-dipolar addition to fullerene C60 through the intermediate formation of active azomethinylides: condensation of aromatic aldehyde with sarcosine occurs at the first stage of the reaction as a result of nucleophilic addition of the amino group of sarcosine to the carbonyl group of the aldehyde. Further, water is first eliminatedin the adductformed, and then decarboxylation occurs with the formation of azoylide, which nucleophilically attacks the fullerene core at the bond (6-6). As a result of the azoylideaddition to the bond (6-6) of the fullerene core, a pyrrolidine ring appears.
The synthesis of hybrid molecules, including fragments of natural com- pounds with the participation of flavonoids and alkaloids, can open the way to a wide range of new compounds with potential biological activity. Flavonoids represent a large group of natural compounds, among which dihydroquercetin (DHQ) and quercetin (Q) and their derivatives, possessing powerful antioxidant, hepatoprotective, antitumor, immunomodulating, and other properties, occupy a special place [46]. Interest in dihydroquercetin and quercetin is due to the fact that these flavonoids are actively used in the food industry and medicine. Both flavonoids belong to the group of phenolic compounds with antioxidant effects. In medical practice, dihydroquercetin and quercetin are used to treat radiation sickness, septic endocarditis, to prevent capillary lesions, etc. [47]. In recent years, quercetin has been found to be active against HIV-1 reverse transcriptase and integrase, as well as an inhibitory effect against the herpes virus [48]. The high biological activity and low toxicity of dihydroquercetin compounds make it possible to refer them to the group of leading compounds for chemical trans- formation in order to synthesize new hybrid polyfunctional pharmacologically active compounds.
N.V. Koshelevoy et al. [49] obtained a mixture of mono- and disubstituted derivatives 30 and 31 in a ratio of 2:1 (according to the HPLC method data), using the example of the interaction of DHQ, cytisine and formaldehyde accor- ding to the Mannich reaction in a molar ratio of 1: 1.4: 1.4 by adding a mixture of reagents to the substrate. Authors obtained a mixture of mono- and disubstituted DHQ derivatives in a 2:1 ratio with a two-fold excess of reagents and the reverse addition. It was shown that the formation of the disubstituted derivative 31 is associated with the higher basicity of the alkaloid cytisine.
HO +
OH O
O OH
OH OH
O
OH OH O
HO
OH OH
+ CH2O
H2C
HN
N
O
N
N
O
O
OH OH O
HO
OH OH
H2C N
N O
N
N O
H2C
+
30 31
In order to simplify the direction of the reactionstudied, we introduced a significant change: dihydroquercetin was replaced by a complex with cytisine.
Complex 32 was obtained by short-term contact of equimolecular amounts of the starting reagents and it spontaneously separates from the reaction mixture.
According to its properties, the adduct is not a salt like ammonia derivatives formed due to the interaction of one of the phenolic hydroxyls of dihydro- quercetin with the nitrogen atom of the cytisinealkaloid.
Complex 32 was reacted with formaldehyde at room temperature in 2- propanol. In this case, the expected reaction product was isolated in the form of an individual yellowish powder 30.
+ HO
OH O
O OH
OH OH
+ CH2O HN
N O
30 HO
OH O
O OH
OH
OH HN
N
32 O
The presence of several hydroxyl groups, two aromatic rings and a pyrone ring in the quercetin molecule allows its chemical modification in order to obtain a number of new biologically active derivatives of interest for medicine. Thus, we were interested in the synthesis of an aminomethyl derivative of quercetin 33 based on the physiologically active alkaloid cytisine. The synthesis was carried out in a dioxane medium by adding an equimolar amount of a mixture of paraform and cytisine in dioxaneto quercetin.
O
OH OH O
HO
OH OH
H2C
N
N
O +
HO
OH O
O OH
OH OH
N
NH
O
33
Recently, 1,2,3-triazoles have been actively used as a linker fragment connecting two pharmacophores due to their exceptional pharmacokinetic characteristics: the ability to form hydrogen bonds and increase the solubility of
compounds, stability in vivo [50, 51]. The attractiveness of 1,2,3-triazoles is due to the versatility of their reactivity, as well as the practical use of derivatives of 1,2,3-triazoles as drugs, technical reagents and “building blocks” in supramolecular chemistry. It should be noted that the 1,2,3-triazole fragment has established itself as the most significant pharmacophore group; therefore, the modification of alkaloids by introducing such a substituent is one of the priority areas of organic and medicinal chemistry. In this regard, we have synthesized a new biologically active compound 34 containing simultaneously fragments of the alkaloids cytisine, lupinine and pharmacophoric 1,2,3-triazole. We have chosen an effective modern method of azide-alkyne cycloaddition catalyzed by copper compounds. N-propargylcytisine was used as an alkyne component of this cycloaddition reaction. The starting lupinineazide was obtained by the reaction of nucleophilic substitution with the azide ion of the corresponding mesylate of the lupinine derivative. The reaction of lupinineazide with N-propargylcytisine was carried out by heating (85°C) the reagents in DMF in the presence of CuSO4*5H2O and sodium ascorbate. The combination of Cu (II) with sodium ascorbate provided regioselective formation of 1,2,3-triazole; in this case, sodium ascorbate acted as a reducing agent, excluding the homocombination product formation.
N CH2 N3
N H2C N
N N
CH2
34
DMFA (85oC) AscNa / CuSO4* 5 H2O
N
N O N
N O
CH2C CH +
Thus, the material presented in this article testifies to the feasibility and prospects of searching for new hybrid biologically active compounds based on plant alkaloids.
Hybrid synthesis with the participation of natural alkaloids and fragments of various physiologically active compounds is a new promising scientific direction.
Hybrid molecules acting simultaneously on the receptor and on the enzyme can lead to powerful synergistic effects. Hybrid synthesis medicines can be obtained by combining ligands belonging to completely different pharmacophores. Hybrid molecules can be obtained by combining two components with different activity (associative synthesis) or from a compound with a double action. The combination of two non-identical pharmacophores in one molecule leads to a new compound that has the properties of both components.
Funding: The work was carried out within the framework of the project No. АР08855433 on grant financing of the Science Committee of the Ministry of Education and Science of the Republic of Kazakhstan.
Conflicts of Interest: The authors declare no conflict of interest.
Information about authors:
Nurkenov Oralgazy Aktayevich – Doctor of chemical sciences, Professor; е-mail:
nurkenov_oral@mail.ru; ORCID ID: https://orcid.org/0000-0003-1878-2787
Mukusheva Gulim Kenesbekovna (corresponding author) – Candidate of chemical sciences, Associated Professor; е-mail: mukusheva1977@list.ru; ORCID ID:
https://orcid.org/0000-0001-6706-4816
Minayeva Yelena Viktorovna – Candidate of chemical sciences, е-mail: yelenaminayeva@yandex.ru; ORCID ID: https://orcid.org/0000-0001-9382-5965
Zhasymbekova Aigerym Rysbekovna – PhD student, е-mail: aigera-93-93@mail.ru;
ORCID ID: https://orcid.org/0000-0003-1272-9096
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Түйіндеме
АЛКАЛОИДТАРДЫҢНЕГІЗІНДЕГІ ГИБРИДТІ МОЛЕКУЛАЛАР
О.А. Нүркенов1, С.Д. Фазылов1,2, Г.К. Мұқышева*2, Е.В. Минаева2, И.В. Кулаков3, Ж.С. Нұрмағанбетов1, А.С. Кішкентаева1, А.Р. Жасымбекова 2
1"Органикалық синтез және көмір химиясы институты" ЖШС, Қарағанды, Қазақстан
2«Академик Е.А. Бөкетов атындағы Қарағанды университеті» КЕАҚ, Қарағанды, Қазақстан
3«Тюмень мемлекеттік университеті» ФМА ЖОО, Ресей E-mail: mukusheva1977@list.ru
Ұсынылған шолуда алкалоид молекулаларына негізделген жаңа гибридті туындылардың синтезі туралы мәліметтер жинақталған. Бұл ретте жаңа бірегей дәрілік препараттарды жасау мақсатында жаңа фармакологиялық құнды агент- терді әзірлеу үшін көшбасшы қосылыстар ретінде басқа биологиялық белсенді өсімдік метаболиттері мен үйлесімде табиғи қосылыстар молекулаларының фраг- менттері бар гибридті құрылымдарды алу әдістері талданған. Табиғи алкалоид- тардың нуклеозидті жағдайындағы әр түрлі ароматты және гетероциклді алмас- тырғыштардың бір молекуладағы үйлесімі алынған полифункционалды туынды- ларды кейінгі химиялық модификациялаудың жаңа мүмкіндіктерін және олардың жаңа әр түрлі биологиялық белсенділігін ашады. Осы қосылыстардың бағытталған түрлендірулері негізінде синтездің тиімді әдістері әзірленді. Осы қатарда біріктіріл- ген қосылыстарының фармакологиялық қасиеттерінің кең спектрі перспективалы болып табылады. Алкалоид молекулалары негізінде біріктірілген туындыларды алу жеткілікті зерттелмегенін ескере отырып, жаңа қосылыстардың бағытталған синтезі жаңа дәрілік заттарды алу тұрғысынан да, органикалық синтездің жаңа әдістерін жасау, сондай-ақ қосылыстардың жаңа қатарындағы молекулалардың стереохи- миясын анықтау тұрғысынан да қызығушылық тудырады.
Түйіндісөздер: алкалоидтар, алкалоидтар туындылары, гибридті молекулалар, химиялық түрлендіру, цитизин, анабазин, эфедрин.
Резюме
ГИБРИДНЫЕ МОЛЕКУЛЫ НА ОСНОВЕ АЛКАЛОИДОВ
О.А. Нуркенов1, С.Д. Фазылов1,2, Г.К. Мукушева*2, Е.В. Минаева2, И.В. Кулаков3, Ж.С. Нурмаганбетов1, А.С. Кишкентаева1, А.Р. Жасымбекова 2
1«Институт органического синтеза и химии угля», Караганда, Казахстан
2НАО «Карагандинский университет имени Е.А. Букетова», Караганда, Казахстан
3ФГАОУ ВО «Тюменский государственный университет», Россия E-mail: mukusheva1977@list.ru
В представленном обзоре обобщены данные синтеза новых гибридных про- изводных на основе молекул алкалоидов. При этом проанализированы методы получения гибридных структур, содержащих фрагменты молекул природных соеди- нений в сочетании с другими биологически активными растительными метабо- литами, в качестве соединений-лидеров для разработки новых фармакологически ценных агентов, с целью создания новых оригинальных лекарственных препаратов.
Сочетание в одной молекуле фармакофорных остатков, а именно различных аро- матических и гетероциклических заместителей в нуклеозидномположении природ- ных алкалоидов раскрывает новые возможности как последующей химической модификации полученных полифункциональных производных, так и новую разно- образную их биологическую активность. На основе направленных превращений этих соединений (или их предшественников) разработаны эффективные методы синтеза. Перспективным является широкий спектр фармакологических свойств комбинированных соединений данных рядов при сочетании низкой токсичности.
Учитывая, что получение комбинированных производных на основе молекул алка- лоидов изучено недостаточно, направленный синтез новых соединений представ- ляет интерес как в плане получения новых лекарственных веществ, так и разработки новых методов органического синтеза, а также определения стереохимии молекул нового ряда соединений.
Ключевые слова: алкалоиды, производные алкалоидов, гибридные молекулы, химическая модификация, цитизин, анабазин, эфедрин.
