Life regulation through the high and low cytotoxicity

Alkaloids from the plant family Amaryllidaceae are known to have a wide range of biological activities. They have analgesic, antiviral, anti-malarial, antineoplastic properties and display effects on the CNS. Elgorashi et al.354 have studied 25 Amaryllidaceae alkaloids for possible inhibitory activity of their acetylcholinesterase enzyme (AChE). This enzyme is biologically very important. According to the cholinergic hypothesis Alzheimer's disease symptoms result from AChE activity, which reduces brain acetylcholine activity. Crinine, crinamidine, epivittatine, 6-hydroxycrinamine, N-desmethyl-8a-ethoxypretazettine, N-desmethyl-8ft-ethoxypretazettine, lycorine, 1-O-acetyllycorine, 1,2-di-O-acetyllycorine and cherylline have been shown to inhibit AChE354. Lycorine-type alkaloids are the most active against AChE354 355. The action mechanism of these alkaloids on AChE inhibition is still not exactly known, although it has been reported that the crystal structures of the acetylcholinesterase inhibitors such as galanthamine, huperzine A, tacrine and edrophonium demonstrated binding to the active site gorge of AChE354 356. Studies on steroid alkaloids such as saracocine, saracodine, saracorine and alkaloid-C isolated from Sarcococca saligna351 suggest that these alkaloids are also calcium antagonists and AChE inhibitors. The AChE is known to be located on the acetylcholine receptor (AChR), which is also bound by such alkaloids as anabasine, arecoline, coniine, C-toxiferine, cytisine, hyoscyamine, lobeline, lupanine, muscarine, nicotine, pilocarpine, tubocurarine, scopolamine, sparteine

Figure 81. Alkaloids in the acetylcholine receptor. Abbreviations: AChE - acetylcholine enzyme; AChR - acetylcholine receptor; Xj (red) - inactivity of AChE.

and so on. These alkaloids can activate AChE or inhibit it by influence of enzyme AChE (Figure 81). As in cases of the Amaryllidaceae alkaloids, AChE can be inhibited. As a result of this, acetylcholine activity increases. Acetyl-choline activity is needed for human brain function. It seems that Amaryllidaceae alkaloids have a wide biological regulatory ability. It is known that lycorine, one of the most important Amaryllidaceae alkaloids, is actively antiviral. Pseu-dolycorine and pretazettine are active against several types of leukaemia by the inhibition of protein synthesis and prevention of peptide-bond formation358. Galanthanine has analgesic, anticholinergic and anticholinesterase properties. The minor Amaryllidaceae alkaloids studied by Abd El Hafiz et al358 are also biologically active. The lycorine-type alkaloid (pratorinine) and the crinine-type alkaloid (6a-hydroxybuphanisine) showed a moderate cytotoxic activity. Moreover, (—)-spectaline, apiperedine alkaloid isolated from the legume Cassia leptophylla Vog.359, has been proved in studies by Alexandre-Moreira et al.360 to have no significant toxicity effects but rather antinociceptive traits. In these experiments conducted on mice, (—)-spectaline was able to significantly inhibit abdominal writhing in the mice in comparison to the control animals. It was suggested that this bioactivity of (—)-spectaline was connected to a direct interaction of the binding of the vanilloid system or excitatory amino acid on its receptors360. This is a promising research direction when considering possible bioapplications of this alkaloid.

Neolitsine, dicentrine, cassythine and actinodaphine are aporphine alkaloids isolated from Cassytha filiformis. These alkaloids have been studied by Stevigny et al.361 for their cytotoxic activities on cancerous and non-cancerous cell lines in vitro. Neolitsine was very active against HeLa and 3T3 cells and cassythine and actinodaphnine showed activity against Mel-5 and HL-60 cells. Dicen-trine was previously reported to be cytotoxic against several tumour cells and has been shown to inhibit DNA and RNA biosynthesis775. Dicentrine also acts as a topoisomerase II inhibitor362. Chen et al.363 have researched aporphine alkaloids isolated from the trunk bark of Hernandia nymphaeifolia. These alkaloids also showed potent cytotoxities against P-388, KB16, A549 and HT-29 cell lines. Similar results have been previously noted in the case of dimeric aporphine alkaloids isolated from the same species364.

Very interesting results concerning the cytotoxicity of alkaloids isolated from the flowers of ornamental legume plant Senna spectabilis have been noted by Sriphong et al.365. N,O-diacetylcassine, 3(R)-benzoyloxy-2(R)-methyl-6(R)-(1T-oxododecyl)-piperidine and 5-hydroxy-2-methyl-6-(1T-oxododecyl)-pyridine N-oxide exhibited cytotoxicity against KB cell lines.

One of the most common biological properties of alkaloids is their cytotoxicity against cells of foreign organisms. These activities have been widely studied for their potential use in the elimination and reduction of human cancer cell lines. Wu et al.366 have studied the cytotoxicity of 53 isoquinoline alkaloids and their N-oxides against A-549, HCT-8, KB, P-388 and L-1210 cells. The isoquinoline alkaloids represent a different structural type of alkaloids. Among all structural types investigated (tetrahydroprotoberbirines, protoberberines, apor-phines, morphinadienone, oxoaporphines, phenanthrenes and their N-oxides), the most active were some of the oxoaporphines. Liriodenine especially showed potent and wide spectrum activity against all the cell lines tested366. Moreover, it has been evident in this research that human KB cells appear to be the most sensitive in detecting active compounds of different alkaloids. The same result has been noted by Jagetia et al.367 in the case of echitamine, which is a monoterpene indole alkaloid. This research investigated HeLA, HepG2, HL60, KB and MCF-7 cells in vitro and in mice. Jegetia et al.367 reported anti-tumour properties of echitamine in vitro and in vivo. Moreover, Long and Li368 have noted the anti-tumourous characteristics of alkaloid extracted from Oxytropis ochrocephala, and concluded that the activity is dose dependent. This anti-tumour effect is associated with the expression of inhibition of proliferating cell nuclear antigen (PCNA) and mutant p53 protein368.

The cytotoxic activity of phenanthroquinolizidine alkaloids has also been reported369. Of two studied alkaloids (boehmeriasin A and boehmeriasin B) isolated from Boehmeria siamensis Craib (Utricaceae), only boehmeriasin A possessed cytotoxicity against 12 cell lines from 6 types of cancer, including lung, colon, breast, prostate, kidney cancer and leukaemia. The anti-mitotic and cytotoxic activities of guattegaumerine, a bisbenzylisoquinoline alkaloid isolated from the bark of Guatteria gaumeri, have been studied by Leclerq et al.370 According to the results, guattegaumerine exerts activity on B16 melanoma, which is a relatively resistant tumour. Cytotoxic activity of 8-O-Cinnamoylneoline, an alkaloid isolated from flower bud of Aconitum carmichaeli (Ranunculaceae), was studied by Taki et al.371 This alkaloid was detected only in flower buds. These acute toxicity and analgesic activities are connected with the presence of C-8 substituent in its ring. The tubers of the Aconitum species have been known to be biologically very active. In China and Japan these species are known as herbs with strong bioactive potential. They contain masconitine, hypaconitine and aconitine that are extremely toxic371. Taki et al.371 placed attention on the relatively lower toxicity of alkaloids in the flower buds. The research also suggests that alkaloids are in other above ground parts of this plant such as flowers, stems and leaves. Alkaloids from other plant parts may have lower acute toxicities compared to the tubers. Biologically active alkaloids are regulators not only of endogenous life processes in the organisms that produce them, but also in the organism to which has consumed them.

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