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Figure 6.
General synthesis methods of cantharimide and norcantharimides (R
derivative to be synthesized).
0
: Primary amine containing the desired
dimethylmaleimide) is made by initially synthesizing maleimides and adding DielsAlder with furan (Figure 6).
2. Cantharimides
Cantharidine is found in Cantharis vesicatory, Lytta caraganae, Mylabris phalerata,
Meloidae, Oedemeridae, and various other insect species. Derivatives of cantharidin are
synthesized to reduce their blistering effects on the skin, reduce their toxic properties,
and benefit from their antitumor activity. Since the 1950s, it has been determined that
various anhydride and imide derivatives exhibit a wide range of biological activities
(antidepressant, anticonvulsant) as well as antitumor properties [33–43]. For this
reason, cantharimide, which has an imide structure, attracted the attention of GuangSheng WANG reported that he synthesized cantharimide and N-methyl cantharimide
in an article he prepared in 1989 and conducted an activity study in KB cell culture. As
a result of his study, he stated that both compounds showed antitumor activity [10].
Pen-Yuan Lin and his group synthesized 10 different cantharimide derivatives
using various tryptamine, indolyl, naphthyl, and pyridyl amines [34]. Lin used
Zhang’s method in his synthesis. In this method, in the presence of triethyl amine at
high pressure, the related amine compound gives cantharimides as a result of an
addition reaction under pressure at 200°C (Figures 7 and 8) [44].
Another of the cantharimide derivatives is the derivatives obtained by the addition
of heterocyclic groups. These derivatives were synthesized for cytotoxicity tests
against human hepatocellular carcinoma cells. In this synthesis, N-thiazolyl and Nthiadiazolyl cantharimides were synthesized by the method used above. According to
the results of the study, they observed that the side groups attached to N-Thiazolyl
and N-Thiadiazolyl amine compounds showed higher cytotoxicity than cantharidin in
Figure 7.
Synthesis of tryptamine, indolyl, naphthyl, and pyridyl canthrimidines [44].
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Figure 8.
Synthesis of cantharimides at high pressure [44].
Alkaloids: Cantharidin Derivatives
the area of electron-withdrawing (such as -NO2), whereas a decrease in cytotoxic
activity was observed in methyl-substituted compounds (Figure 9) [45].
In 2007, a new cantharimide derivative was synthesized by Chan et al. Its structure
was elucidated and its cytotoxicity on SK-Hep-1 hepatoma cells was determined. In
this study, two cantharimides were synthesized with 2-amino benzothiazole derivatives. Cantharidin and 2-amino benzothiazole derivatives were added to a tube
containing dry toluene and triethylamine (TEA), and related derivatives were synthesized at 200°C [45]. As a result of cytotoxic studies of the study group, it was
determined that the compounds showed inhibition on SK-Hep-1 hepatoma. Using the
results from the study, the group is also designing new (Figure 10) molecules [46].
Cantharimide derivatives were also synthesized using aliphatic primary amines,
phenethyl amines, aniline, and pyridine components by high-pressure addition reaction method. In the synthesis, the product was obtained with a yield of 29—96%. It is
thought that the primary factor affecting the efficiency is the inductive effect of
electron-negative groups. Another factor affecting the yield is the nucleophilic and
basicity strength of the amines. Again, cytotoxicity studies of the compounds obtained
in this synthesis were performed in human hepatocellular carcinoma (Hep G2) and
myeloid leukemia cells (HL-60). In the evaluation, it was determined that compounds
(10 and 16) with electron-withdrawing NO
groups in the pyridyl and benzene rings
2
showed strong inhibitory effects in both cell lines. Methyl-containing compounds
Figure 9.
The synthesis of the N-thiazolyl- and N-thiadiazolyl cantharimides [45].
Figure 10.
The synthesis of the (Me/-OMe)-2-amino benzothiazole cantharimides [46].
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Figure 11.
Cantharimides are synthesized by the high-pressure addition reaction method [33].
Figure 12.
Dimeric-canthraimides isolated from M. Phaletata [34].
(6, 7, and 9) have less effect, while halogen-containing compound (8) has a moderate
effect. Compound 10 with the 2-(3-nitro pyridyl) group showed stronger cytotoxicity.
Para-Pyridyl imide 4 showed greater potency than ortho- or meta-pyridyl imide. 3Pyridyl (5) and N-phenyl imides (14 and 16) also showed strong cytotoxicity. Compounds with planar side chains (12, 14, and 20) and N-azaethyl or N-aryl compounds
(17, 18, 19, and 21) showed moderate cytotoxicity on both Hep G2 and HL-60.
However, aliphatic chain imides (1, 2, and 3) were found to have very low effects in
the studied cell lines (Hep G2, HL-60) (Figure 11) [33].
Until 2017, about thirty cantharidin derivativeshave been isolated from insects of
the genus Mylabris and Hycleus. As cantharimide compounds are known to exist in
different insects from Mylabris and Hycleus species, thirteen new cantharidin derivatives have been isolated from the whole body of Mythicomyia phalerata as part of
studies to discover new potential antitumor agents [34]. During this purification,
dimeric cantharimides were also obtained. The cytotoxic effects of the isolated derivatives against HepG2, MDA-MB-231, and A-549 cell lines were investigated, and it
was determined that all isolated compounds showed high activity, except for the
compound called Canthaminomide F (Figure 12) [34].
Due to the presence of dimeric products in cantharimides obtained from natural
sources, some researchers have included these compounds in their synthesis. In a
study conducted in this way, cantharimide dimers were synthesized and the structure
was determined. The dimers synthesized in the same study were also isolated from
natural sources. Along with these dimers, two different cantharimides were purified
(Figure 13) [35].
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Figure 13.
Cantharimide dimers from the Chinese Blister Beetle [35].
Alkaloids: Cantharidin Derivatives
3. Norcantharimides
Studies on norcantharimides are examined by dividing them into two groups
distribution methods and medicinal chemicals. Compounds such as norcantharimide
[36] and norcantharidin dimer [37] belong to the class of medicinal chemicals.
Norcantharimides are made from either the imide ring [38] or the cyclohexyl ring [39]
in their medicinal chemical derivative synthesis. Then, new derivatives [40] were
obtained by opening the imide ring in these derivatives (Figures 14 and 15).
In addition, when dimer products were detected in cantharimide derivatives purified in natural sources, dimer structures in norcantharimide derivatives were included
in the synthesis [36]. Norcantharidin-dimer analogs as analogs of norcantharidin,
norcantharidin with lactose acid, norcantharidin with amantadine, water-soluble
norcantharidin with chitosan analogs, esterification of norcantharidin, amino acid
norcantharimides, N-substituted dehydronortharimid analogs, immune liposomes,
and modifications of norcantharidin show potential in the anticancer field [36].
Some norcantharidin analogs are known to have very good PP1 and PP2A inhibitory activity [22, 41–43]. In addition, studies by McCluskey et al. reported that some
norcantharidin analogs, which have no toxic effect on human cell lines, kill
trichostrongylid nematode Trichostrongylus vitrinus and Haemonchus contortus
larvae [47].
McCluskey synthesizes a large number of norcantharimide in his studies and
conducts various activity studies. In one of these studies, he synthesized 54
norcantharimide compounds and conducted a toxicity study against H. Contortus,
which showed serine–threonine phosphatases (PP1 and PP2A) [48]. As a result of the
study, it was determined that three of the 54 analogs synthesized were almost
completely lethal against H. contortus and showed at least five times more inhibition
Figure 14.
Examples of norcantharimide as a medicinal chemical [36–40].
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Figure 15.
(A) Reagents and conditions: (a) Et
reflux, 24–36 h (d) RNH
sealed tube 200°C, 36 h.
,THF, rt [41]. (B) Reagents and conditions: (a) CH3OH, rt. 30 min; (b) PhCH3,
2
O, rt., 48 h; (b) acetone, 10% Pd–C, H2(g) 50 psi, 18 h; (c) RNH2, PhCH3,
2
than the control compounds. McCluskey’ reported that he synthesized 54 compounds
by the methods given below Figure 14 [47].
In another study published by McCluskey in 2011, eighteen phosphate esters of the
side group attached to the imide nitrogen were synthesized. It has bioscreened them in
nine human cancer cell lines (HT29 ve SW480, MCF-7, A2780, H460, A431, DU145,
BE2-C, SJ-G2). As a result of the study, he stated that he obtained a new series of
norcantharidin analogs with broad-spectrum antiproliferative activity [41]. Another
important finding from the study is the relative ease of Phosphate ester hydrolysis. Of
the phosphates studied, diphenyl and bis-trichloroethyl analogs showed the highest
level of cell death ( Figure 16) [49].
McCluskey also conducted biological activity studies by synthesizing
norcantharidin-dimer analogs. McCluskey explained the relationship between
heterocyclic substituted (nor)cantharidin analogs and PP1 and PP2A as a result of
his studies. McCluskey et al. synthesized many norcantharidin analogs, including two
bis-norcantharimides. Among the compounds it synthesized were compounds
containing 10, 12, and 14 alkyl chains attached to the imide nitrogen, 1,2-diol units,
and two norcantharimide attached to dodecyl. Among these groups, two
norcantharimide (Bis-Norcantharimide) bound to dodecyl showed the highest activity in the cell line [42].
Evaluating the results obtained from this study, Cuifang Cai showed that the
compound containing N-C
(Figure 17) side group has a longer half-life and
14H29
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Alkaloids: Cantharidin Derivatives
Figure 16.
Reagents and conditions: (a) H
Figure 17.
N-C
and norcantharimide, whose physical and chemical stability was determined by Cuifang Cai [50].
14H29
N–X–OH, D, 18 h; (b) ClP(O)(OR)2, n-Bu2O, Et3N, rt [49].
2
higher volume of distribution (Vss) compared to norcantharidin, as a result of the
pharmacokinetic study performed by injecting it into rats. The results obtained from
this study suggested that the formulation to be prepared with N-C
is a promising
14H29
alternative with its high encapsulation efficiency, significant physical and chemical
stability, and long half-life (Figure 17) [50].
Dimeric compounds norcantharidin compounds have been synthesized and studied by many researchers for the treatment of cancer, HIV, Alzheimer’s, malaria, and
various parasitic diseases. Some of the scientists who carried out these studies are
Gervais [51], McCluskey [42], T. Nakatani [35], Tang [52], and Tan [38].
When Xue-Jie Tan and his group realized that good results were obtained both in
extract analysis and in many synthesis and activity studies, they used four dimeric
norcantharimide directly synthesized in their studies. Two of these compounds were
synthesized for the first time by Xue-Jie Tan and his group, while the remaining two
were synthesized by Dominic V. McGrath’s group. However, Xue-Jie Tan and his
group presented the crystal structure, spectroscopic properties, and anticancer activities of these four unsaturated dimeric norcantharimides to the knowledge of
researchers (Figure 18) [38].
Figure 18.
Dimer-norcantharimides synthesized by Tan et al. [38].
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4. Conclusion
Alkaloids are defined as amine compounds naturally produced by plants. In addition, alkaloids are defined as secondary metabolites with important biological properties. It is also known that some alkaloids are beneficial for some diseases. In light of
this information, we can evaluate cantharimide and norcantharimide derivatives in
the alkaloid class, even if they are not of plant origin. Considering the information, we
have briefly compiled above, the starting compound is a product of natural origin.
Later, all of the synthesized derivatives contained nitrogen atoms, and positive test
results were obtained on many disease-causing agents. After obtaining a large number
of alkaloid cantharimide derivatives by extraction, it has also begun to be synthesized
as a medicinal chemical. Researchers at the
In this review, it was concluded that medicinal chemical-synthesized derivatives of an
insect-derived alkaloid can be used for pharmaceutical purposes.
time sought to improve previous methods.
Acknowledgements
We would like to thank Atatürk University (Project number: 2012/470 and FBG2018-6476) for its financial support of this work.
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Alkaloids: Cantharidin Derivatives
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