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15Chemical Journal of Kazakhstan ISSN 1813-1107, eISSN 2710-1185
Volume 3, Number 75 (2021), 67 - 82
https://doi.org/10.51580/2021-1/2710-1185.40
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 3FSAEIof HE "Tyumen State University", Russia E-mail: [email protected]
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 pharmacological 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 compounds 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 simultaneously 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 carbohydrate 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 condensation 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:
Sug(OH) +
N H EtOH, 65-70 0C ---►
O
1-4
O
Sug :
OH
OH
OH
OH
(D-Glc) (1)
(D-Gal) (2)
(D-Csy) (3)
(L-Ara) (4)
3
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-p-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.
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-p-D-glucopyranosyl-iso-thiocyanate 5 in an alcohol solution at an equimolar ratio of the reagents used.
N O I
C^C^
p
NHNH.
CHOAc
N=C=S
+ IVpAc AcO
5 OAc
AcOH2C
HN—C-NHNH-C_CH,,-
OAc
N
N
8
In [28], the results of hybrid synthesis of molecules combining fragments of two alkaloids in the structure are presented. The synthesized hybrid derivatives of /-ephedrine and J-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-/-ephedrine 9 and N-lupinan-J-pseudoephedrine 10, and epilupinine bromide was used for N-epilupinan-/-ephedrine 11 and N-epilupinan-J-pseudoephedrine 12 synthesis. The reactions were carried out in a sealed ampoule in a metal container (bomb) filled with glycerol.
—ch
C~C
ho n ch3
c6h5 |ch3
\ r
-,C-tch
/
ho n—ch3
hov.h^c6h5
h Jh
ch2~n v
ch3
ch
ho^ jic6h5
hc
^ch ^^ vch3 ch
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.
Ph/fc,
Me
\
JP-N(C2H5)2
N
I
Me 13
N
- (C2H5)2NH
Ph/,„
Me
Ph //„,,, rv
Me N /=
1 / Me
15
h
+
N
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.
C2H5OOC.
COOCjH5
H3C N CH3 H
C2H5OOC.
BrH2C N CH2Br H
+ 2HN.
0
EtOOC
COOEt
18-20
QH,
N_ C6H5 CH3
(19); Vh_H^ (20).
CH
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 warmblooded animals [34]. In [7,8,35], the authors synthesized previously unknown phenothiazine derivatives of cytisine, anabasine, /-ephedrine, and J-pseudoe-phedrine 21-24 alkaloids:
2 5
2NBS
N
H
+ClCH2COCl
+ HN.
<J
-I Л
о—CCH2-N^J
21-24
o-
N (21,
_ CiH^ ^CH3 CH-HC
(22), / \ (23),
HO N—CH,
C6H5
%
•CH3
yCH-HC^
HO N—CH,
(24).
Alkylation of cytisine, anabasine, /-ephedrine, and J-pseudoephedrine alkaloids with 10-(2-chloroacetyl) phenothiazine was carried out in boiling toluene in the presence of triethylamine. Column chromatography and re-precipitation 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].
25
J ГТ
--CCH2CH2-N^ ^
26
J
O-CCH2CH2-N'
r
27
/ ^CH: N—Г
HO
I
O-CCH2CH2'
CH3
/ ^CH3 N-С
/'"""C6
HO 6
N
O
6 5
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 semiconductor 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:
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.
+
о
о
The synthesis of hybrid molecules, including fragments of natural compounds 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 transformation 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 according 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.
OH
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.
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.
OH OH
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.
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.
34
Funding: The work was carried out within the framework of the project No. AP08855433 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; e-mail: [email protected]; ORCID ID: https://orcid.org/0000-0003-1878-2787
Mukusheva Gulim Kenesbekovna (corresponding author) - Candidate of chemical sciences, Associated Professor; e-mail: [email protected]; ORCID ID: https://orcid.org/0000-0001-6706-4816
Minayeva Yelena Viktorovna - Candidate of chemical sciences, e-mail: [email protected]; ORCID ID: https://orcid.org/0000-0001-9382-5965
Zhasymbekova Aigerym Rysbekovna - PhD student, e-mail: [email protected]; ORCID ID: https://orcid.org/0000-0003-1272-9096
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Тушндеме
АЛКАЛОИДТАРДЬЩ НЕГ1З1НДЕГ1 ГИБРИДТ1 МОЛЕКУЛАЛАР
О.А. Нуркенов1, С.Д. Фазылов1'2, Г.К. Мщышева*2, Е.В. Минаева2, И.В. Кулаков3, Ж.С. Нурмаганбетов1, А.С. Кшкентаева1, А.Р. Жасымбекова 2
1 "Органикалъщ синтез жэне KOMip химиясы институты"ЖШС, Караганды, Казахстан
2«Академик Е.А. Бекетов атындагы Караганды университетi» КЕАК, Караганды, Казахстан
3«Тюмень мемлекеттжуниверситетi» ФМА ЖОО, Ресей E-mail: [email protected]
¥сынылган шолуда алкалоид молекулаларына непзделген жаца гибридп туындылардьщ сиш^ туралы мэлiмeттeр жинакталган. Б^л ретте жана бiрeгeй дэрiлiк препараттарды жасау максатында жана фармакологиялык к¥ВДы агент-тeрдi эзiрлeу Yшiн кешбасшы косылыстар рeтiндe баска биологиялык бeлсeндi всiмдiк мeтаболиттeрi мен Yйлeсiмдe табиги косылыстар молекулаларынын фраг-мeнттeрi бар гибридтi к¥рылымдарды алу эдiстeрi талданган. Табиги алкалоид-тардын нуклeозидтi жагдайындагы эр тYрлi ароматты жэне гeтeроциклдi алмас-тыргыштардыц бiр молекуладагы Yйлeсiмi алынган полифункционалды туынды-ларды кeйiнгi химиялык модификациялаудын жана мYмкiндiктeрiн жэне олардын жана эр тYрлi биологиялык бeлсeндiлiгiн ашады. Осы косылыстардын багытталган тYрлeндiрулeрi нeгiзiндe синтездщ тиiмдi эдiстeрi эзiрлeндi. Осы катарда бiрiктiрiл-ген косылыстарынын фармакологиялык касиеттершщ кен спeктрi перспективалы болып табылады. Алкалоид молекулалары нeгiзiндe бiрiктiрiлгeн туындыларды алу жeткiлiктi зeрттeлмeгeнiн ескере отырып, жана косылыстардын багытталган синтeзi жана дэршк заттарды алу т^ргысынан да, органикалык синтeздiн жана эдiстeрiн жасау, сондай-ак косылыстардын жана катарындагы молекулалардын стереохи-миясын аныктау т^ргысынан да кызыгушылык тудырады.
ТYЙiндi сездер: алкалоидтар, алкалоидтар туындылары, гибридтi молекулалар, химиялык тYрлeндiру, 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: [email protected]
В представленном обзоре обобщены данные синтеза новых гибридных производных на основе молекул алкалоидов. При этом проанализированы методы получения гибридных структур, содержащих фрагменты молекул природных соединений в сочетании с другими биологически активными растительными метаболитами, 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 ароматических и гетероциклических заместителей в нуклеозидномположении природных алкалоидов раскрывает новые возможности как последующей химической модификации полученных полифункциональных производных, так и новую разнообразную 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 алкалоидов изучено недостаточно, направленный синтез новых соединений представляет 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.
