More about alkaloids

Cystisus scoaprius is known to contain a volatile alkaloid, sparteine and a non-volatile alkaloid, sarothamnine. Abies webbiana contains a crystalline alkaloid, taxine (Fig. 5.7).

Asimina triloba contains benzyl isoquinoline alkaloid anolobine. Galipea officinalis is reported to contain quinoline alkaloids including (cusparine, galipine, galipoline, quinaldine, cuspareine, galipoidine, and l-methyl-2-quinolone). Vaccinium myrtillus contains quinolizidine alkaloids: myrtine and epimyrtine.

Alkaloids (atidine, atisine, hetidine, hetisine, heteratisine, heterophylline, heterophyllisine, heterophyllidine, isoatisine), are present in Aconitum heterophyllum (Fig. 5.8).

Steroidal alkaliods (Azosteroids)

Steroidal alkaliods (Azosteroids)

Nitrogen is in steroid nuclear skeleton

Nitrogen is in noe or more side chain

Saussurine

Solanum alkaloids Solanine

Veratrum alkaloids

Pregnane alkaloids Funtumine Cyclobuxine D Polchystermine A

Solanum alkaloids Solanine

Veratrum alkaloids

Salmandra alkaloids Salmandraine

Jerveratum Cerveratum

Fig. 5.4 Classification of steroidal alkaloids.

III-

III-

Saussurine
Aconitine

Atropine oh h3co

Saussurine

och3

Berberine o

Saussurine

Codeine n^chb h3c—o

Codeine oh ch3 o h3c\

ch3 o

Saussurine

nh h3c Colchicine nh h3c Colchicine h3c nh h3c nh oh Ephedrine oh Ephedrine ch3 n

Saussurine

Hyoscine o

Hyoscine

Saussurine

Hyoscyamine Fig. 5.5 Structure of important alkaloids.

o oh

Hyoscyamine Fig. 5.5 Structure of important alkaloids.

Pelosine or cissampeline is an amorphous alkaloid present in Cissampelos pareira. It is related to berberine. Protoberberine alkaloids, bebeerine, d-isochondrodensrine, menismine, hayatine (dl-bebeerine), hayatidine and cissamine or cyclanoline (Fig. 5.9), pareirine, are reported from the roots of Cissampelos pareira. Cissampareine has an inhibitory action against human carcinoma cells of the nasopharynx in cell culture. dl-curine is used as a muscle relaxant.

Cyclea peltata contains alkaloids including d-tetrandrine, dl-tetrandrine, isotetrandrine, limacine, berbamine, bomoarmoline, cycleapeltine, cyleadrine, cycleacurine, cycleanorine and cycleahomine. Tetrandrine is an irritant to mucosa, produces hypoglycemia in rats and emesis in pigeons. It is also a cardiac depressant. Coscinium fenestratum contains alkaloids including berberine, jatorrhizine, berbaruine, N,N-di-Me-lindacarpine, thalifendine and palmitine.

Saussurine
Nicotine

Piperine

CH3 Theophylline h3c h3c

Saussurine

n h3c Papaverine n

Saussurine

Piperine h3c Papaverine

Theobromine

Vasicine

Fig. 5.6 Structure of important alkaloids continued.

Structure Punarnavine

Fig. 5.7 Structure of Taxine.

Fig. 5.7 Structure of Taxine.

Saussurine
Atisine
SaussurineSaussurine

Hetisine Heteratisine

Fig. 5.8 Structure of major alkaloids of Aconitum heterophyllum.

Saussurine

o ch3

Fig. 5.9 Structure of Cissamine.

o ch3

Fig. 5.9 Structure of Cissamine.

Ervatamia heyneana contains alkaloids including, coronaridine, heyneanine, voacangine, y-indoxy voacangine, and ibogamine. Isovoacrisitine is anticholinergic and antihistaminic. Coronaridine, on oral administration, prevents pregnancy in rats. It is cytotoxic against P 388 lymphocytic leukemia. It also contains camptothecine. Rutaecarpine and dehydroevodiamine from Euodia rutaecarpa show, in vitro, uterotonic effect on the rat uterus. It also contains a sympathomimetic alkaloid, synephrine. Alkaloidal fraction of Fritillaria imperialis containing imperialine which reduces blood pressure and shows relaxant and antispasmodic activity. Bulb of Fritillaria royeli contains alkaloid, kashmirine.

Celatrus paniculatus, popularly known as Jyotishmati in Ayurveda, is reported to contain two alkaloids, celastrine (Fig. 5.9) and paniculatine. The former is recorded to be powerful stimulant and pyrogenic. Some authors report the presence of celopagine, celophanigine, and cepapanine. Eclipta alba is reported to contain ecliptine and nicotine (0.078%).

Loturine (Fig. 5.11), loturidine and colloturine, present in Symplocos racemosa, are chemically related to harmine found in Peganum harmala. Gentianine present in medicinal plants of Gentianaceae has been reported to have antipsychotic, antimalarial and antiamoebic activities (Fig. 5.11). Other alkaloids distributed in medicinal plants of gentianaceae are gentianaine, gentianadine, gentialutine, gentiocrucine and gentianamine (Fig. 5.10). Erthyrocentaurine is a monoterpene alkaloid reported from Swertia laurii and Enicostemma hyssopifolium.

Phyllantidine and phyllantine (Fig. 5.11) are reported from leaves, fruits, and in vitro tissue cultures of Emblica officinalis.

Saussurine

Gentianaine

Gentianadine

Gentianamine

Fig. 5.10 Structure of alkaloids reported from Gentianaceae.

Gentianaine

Gentianadine

Gentianamine

Fig. 5.10 Structure of alkaloids reported from Gentianaceae.

Ryania speciosa, indigenous to South America, contains an insecticidal alkaloid, ryanodine. Alstonia scholaris is known to contain antimalarial

Saussurine

Celastrine o

Saussurine

Loturine ch2

Saussurine

Gentianine

Celastrine

Loturine

Gentianine oh oh oh oh

Saussurine

Phyllantine oh hoh2c

-cooch hoh2c

-cooch

Echitamine

Phyllantine

Saussurine

Echitamine

Saussurine

oh ch3

ooch3

Alsotinine Scholaricine

Fig. 5.11 Structure of alkaloids reported from Indian medicinal plants.

alkaloids including alsotinine, ditamine, echitamine and echitanine (Fig. 5.11). Ditamine possesses anti-periodic properties equal to the best quinine sulfate. A.scholaris also contains an alkaloid called scholaricine (Fig. 5.11). Alstonia constricta contains indole alkaloids including reserpine, deserpidine, alstonine, tetrahydroalstonine, alstonidine, and yohimbine. N-isobutyl 2, 4 decadieamide, a waxy alkaloid from Piper longum has antitubercular activity (Fig. 5.12).

CH3(CH2)4 ch=ch-ch=ch-co-nhch2 CH (CH3)2

Fig. 5.12 Structure of N-isobutyl 2, 4 decadieamide.

Actinidine is present in Nardostachys jatamansi. Coptine, copsine, coptisine and palmatine are reported from Coptis teeta. Mimosine is present in Mimosa pudica and is a protoplasmic poison. Moringine reported from Moringa olifera acts as a cardiac stimulant, bronchodilator, and has a depressant action on smooth muscle fibers and an inhibitory effect on the tone and movements of the intestine in rabbits and guinea pigs (Fig. 5.13).

Saussurine

Actinidine

Coptisine

Saussurine

Palmatine

Actinidine

Coptisine

Palmatine

ch2n2

ch2n2

Mimosine Moringine

Fig. 5.13 Structure of alkaloids reported from medicinal plants.

Strychnine, Brucine, icajine and vomicine (Strychnos nux vomica), carpaine (Carica papaya), colchicine (Colchium luteum), diaboline and novacine (Strychnos potatorum), lycorine (Crinum latifolium), noroxyhydrastinine (Coscinium fenestratum), piperlongumine, piperlonguminine and piperlatine (Piper longum), precatorine (Abrus precatorius) and asparagamine (a polycyclic alkaloid from Asparagus racemosus) are other examples of alkaloids isolated from medicinal plants (Fig. 5.14).

Experiments conducted with tylpohorine, a phenanthroindalizidine alkaloid, present in Tylophora asthmatica in various animal models, has shown significant anti-inflammatory, anti-anaphylactic and anti-spasmodic activities (Fig. 5.15).

Carbazole Alkaloid

Novacine

Precatorine

Novacine

Precatorine

Plant Antibacterial Alkaloids
Piperlonguminine Fig. 5.14 Structures of alkaloids reported from medicinal plants.
Stem Bark Clausena Heptaphylla
Fig. 5.15 Structure of Tylpohorine.

Imidazole alkaloid, chaksine isolated from Cassia absus has antibacterial activity. In a test for antifungal activity, chaksine iodide at 0.5% inhibited all fungi tested (Fig. 5.16). Isochaksine has similar activities to chaksine, but usually at higher doses.

A new carbazole alkaloid, clausenol, isolated from an alcoholic extract of the stem bark, of Clausena anisata was found to be active against Grampositive and Gram-negative bacteria and fungi (Fig. 5.17). Alkaloids; 3-formylcarbazole, mukonal (Fig. 5.18), 3-methoxycarbonylcarbazole,

Structure Alkaloid

Fig. 5.16 Structure of Chaksine.

"h

Fig. 5.16 Structure of Chaksine.

2-hydroxy-3-formyl-7-methoxycarbazole, and clauszoline J from Clausena excavata eliminates Mycobacteria with MIC values ranging from 50-200^g/ mL. 3-Formylcarbazole, mukonal, 3-methoxycarbonylcarbazole, and 2-hydroxy-3-formyl-7-methoxycarbazole show antifungal activity with IC50 values of 13.6, 29.3, 9.5, and 2.8^g/mL, respectively. Carbazole alkaloids of the Clausena species and Rutaceae in general are related in structure to the antitumor alkaloid ellipticine and hold some potential as cytotoxic and antiviral agents.

Fig. 5.17 Structure of Clausenol.

Fig. 5.17 Structure of Clausenol.

'cho oh

Fig. 5.18 Structure of Mukonal.

Fig. 5.18 Structure of Mukonal.

Mahanine (Fig. 5.19), a carbazole alkaloid, isolated from Micromelum minutum, induces apoptosis in the human myeloid cancer cell HL-60 at 10^M via activation of caspase-3 through a mitochondrial dependent pathway.

Fig. 5.19 Structure of Mahanine.

Bicuculline acts as an antagonsit at GABA receptor. It has been shown to compete with GABA for specific sites on synaptosomes (Fig. 5.20). The alkaloid is reported from Corydalis govniana. The trans-conformation of GABA fits the structure of (+)-bicuculline.

Hydrastis Canadensis

Hydrastine from Hydrastis canadensis is a potent GABAa competitive antagonist, twice as potent as biccuculline (Fig. 5.21).

Corydalis Transs
Fig. 5.21 Structure of Hydrastine.

Isoquinoline alkaloid, liriodenine, isolated from Fissistigma glaucescens is known to block the muscarinic receptors and therefore impede the secretion of gastric juices and the contraction of gastric smooth muscles. Isoquinoline alkaloid, cryptofolione (Fig. 5.22), isolated from Cryptocarya tomentosa seems to have anxiolytic potential as it resembles Kawain, the active principle of Piper methysticum.

Hydrastis Canadensis Root Anatomy
Fig. 5.22 Structure of Cryptofolione.

Chelerythrine from Sanguinaria canadensis is a narcotic (Fig. 5.23). Corycavine isolated from Corydalis tuberosa is anthelmintic (Fig. 5.24). Corydaline isolated from Corydalis govaniana is antiperiodic (Fig. 5.25).

Corydalis GovanianaCorydalis Govaniana

HsC\

Cholera Morphological Shape

Fig. 5.25 Structure of Corydaline.

Fig. 5.25 Structure of Corydaline.

Berberine (Fig. 5.26) is the chief alkaloid from roots and stem-bark of Berberis aristata, B. asiatica, B.lycium, B. vulgaris and B. umbellata. Berberine has diverse pharmacological activites including antibacterial, antihypertensive, and cholagouge.

Fig. 5.26 Structure of Berberine.

Fig. 5.26 Structure of Berberine.

Berberine sulfate has been shown to inhibit the growth of Entamoeba histolytica, Giardia lamblia and Trichomonas vaginalis, in vitro. The parasites all exhibited morphological changes after exposure to berberine sulfate. In one experiment, berberine hydrochloride reduced the cholera toxin-induced secretion of water, sodium and chloride in perfused rat ileum. Berberine was also found to inhibit the intestinal secretory response of Vibrio cholerae and Escherichia coli enterotoxins without causing histological damage to the intestinal mucosa.

Berberine is also active against other intestinal infections that cause acute diarrhea such as Shigella dysenteriae,Salmonella paratyphi and various Klebsiella species. Berberine sulfate has been shown to block the adherence of Streptococcus pyrogenes and E. coli to host cells, possibly explaining it's mechanism of action against numerous pathogens.

Berberine was found to be the active constituent in an extract of Hydrastis canadensis root that demonstrated activity against a multiple drug-resistant strain of Mycobacterium tuberculosi. Berberine also inhibits Helicobacter pylori. Berberine has a long history of use for eye infections. In one study that looked at the effectiveness in treating trachoma, berberine was better than sulfacetamide in eradicating Chlamydia trachomatis from the eye and preventing a relapse of symptoms.

Berberine has a choleretic (bile-stimulating) effect and has been shown to lower bilirubin levels. Berberine inhibited the effects of tumor promotors on the skin using a mouse model. There is evidence that berberine also has a direct tumor killing effect and has the ability to stimulate production of white blood cells.

Berberine has hypotensive, antisecretory and sedative effects. The mechanism for these effects may be explained by the fact that berberine has platelet a 2 adrenoceptor agonist activity that is similar to that of clonidine.

Berberine inhibits the growth of HepG2 cells by direct interaction with DNA in which it intercalates. Berberine, extracted from Arcangelisia flava, inhibits the enzymatic activity of Plasmodium falciparum telomerase dose-dependently at doses ranging from 30-300mM. Palmatine (Fig. 5.87), berberine, jatrorrhizine (Fig. 5.87), and dihydroberberine (Fig. 5.27) inhibit the growth of Babesia gibsoni cultured in vitro at very small doses.

Chemical Str Saussurine

och3

Fig. 5.27 Structure of Dihydroberberine.

och3

Fig. 5.27 Structure of Dihydroberberine.

Berbamine (Fig. 5.28) obtained from the root of B. poiretii increases leucocytosis. Oxycanthine (Fig. 5.29) is considered to be less potent as compared to berberine. Other alkaloids distributed among Berberis species include oxyberberine, berbinine, berbericine and berbericinine. Berbericine is identical with berberine-acetone complex.

h3c h3c

oh o ph3

o h3c o

Fig. 5.28 Structure of Berbamine.

Fig. 5.28 Structure of Berbamine.

Chemical Structure Christembine
Fig. 5.29 Structure of Oxycanthine.

Alkaloids of Uncaria tomentosa include rhynchophylline (antihypertensive), hirsutine (local anesthetic) and mitraphylline (diuretic) (Fig. 5.30). The plant also contains 5-a-carboxystrictosidine, isopteropodine, isomitraphyllin and isorynchophylline.

Rhynchophylline

Rhynchophylline

Rhynchophylline o o

Structure Rhynchophylline Hirsutine

Hirsutine

Fig. 5.30 Structure of alkaloids of Uncaria tomentosa.

Hirsutine

Fig. 5.30 Structure of alkaloids of Uncaria tomentosa.

Pausinystalia yohimbe contains stimulant alkaloid, yohimbine or quebrachine (Fig. 5.31). Yohimbine causes an increase in epinephrine release from the adrenal gland and results in a dose-dependent increase in plasma epinephrine. Yohimbine, given in moderate doses; increases systolic blood pressure in patients with orthostatic hypotension due to primary autonomic failure.

Yohimbine significantly enhanced the overall analgesic effect of morphine with post operative dental pain. One study demonstrated yohimbine reversed sedation and shortened the duration of analgesia associated with clonidine administered post operatively.The alkaloid has been investigated clinically in erectile dysfunction, post traumatic stress disorder and Parkinson's disease.

Adrenal Gland Parkinson Disease
Fig. 5.31 Structure of Yohimbine.

Sanguinaria canadensis contain isoquinoline alkaloids, sanguinarine, chelerythrine and oxysanguinarine: protoberberine-type: berberine, coptisine: protopine-type:protopine. a- and ß-allocryptopine. Sanguinarine is antimicrobial and anti-inflammatory. Its use as an antiplaque agent and for gingivitis is plausible and has been documented in diverse studies.

The alkaloids initially act as a narcotic, causing severe cramps followed by local paralysis of sensitive nerve endings. Caulophyllum thalictroides contain isoquinoline alkaloid, magnoflorine.

Brahmine (0.01%) is a highly toxic alkaloid obtained from Hydrocotyle asiatica. In therpaeutic dosage, it resembles strychnine. It does not produce reflex irritation. Herpestine is another alkaloid from same plant. Adifoline, alkaloid obtained from acetone fraction of wood of Adina cordifolia is a central nervous sytem depressant and hypotensive in experimental animals.

Punarnavine, an alkaloid present in Boerrhavia diffusa (punarnava) is bitter in taste. Punarnavine hydrochloride is the salt in crystalline form. Punarnavine sulfate is a needle shaped crystalline form brownish-white in color. Yeild of punarnavine sulfate from the plant is 0.053%. Punarnavine is a diuretic and its acts chiefly on renal epithelium. It is non-toxic, however the nature of the alkaloid is not known.

Himbacine, obtained from Gabulimina baccata is a muscarinic antagonist (Fig. 5.32). Aegeline from Aegle marlemols is reported to be a cardiac tonic and useful in asthma (Fig. 5.33). Aegelenine is identical with fagarine isolated from Zanthoxylum acanthopodium. The plant, in addition, contains alkaloids including; skimmianine (Fig. 5.34), shahidine, O-methylhalfordinol and isopentylhalfordinol. a-pederine and fi-pederine are obtained from Paederia foetida.

^xs^chs

Structure Skimmianine

Fig. 5.32 Structure of Himbacine.

Fig. 5.32 Structure of Himbacine.

och3

ch3o och3

Fig. 5.34 Structure of Skimmianine.

och3

ch3o ch3o

Fig. 5.33 Structure of Aegeline.

ch3o och3

Fig. 5.34 Structure of Skimmianine.

Fig. 5.33 Structure of Aegeline.

Christembine is obtained from Embelia ribes. Hymenodictyoline is one of the few alkaloids which do not contain oxygen and is obtained from Hymenodictyon excelsum. Fagamide, an alkaloid present in Zanthoxylum acanthopodium is the possible irritating principle. Nishindine is extracted from Vitex negundo. Viola odorata yields violine, which is emetic. Anistrocladinine isolated from Ancistrocladus heyneanus has antispasmodic acitivity on isolated guinea pig ileum comparable with papaverine.

Achilleine, an alkaloid of Achillea millefolium is considered to be an active haemostatic. It reduces blood-clot in rabbits. The total alkaloidal content (mucuadine, mucuadinine, mucucuadinine,pruriendine, mucunine, mucunadine and nicotine) of Mucuna prurita demonstrated increased spermatogenesis in albino rats. O-methylsolanocapsine isolated from Solanum pseudocapsicum leaves possess strong cytotoxic properties (Fig. 5.35).

Saussurine, an alkaloid isolated from Saussurea lappa is a potent bronchodilator. It has depressant action on the involuntary muscle fibers of the bronchioles and gastrointestinal tract. Saussurine tartrate has been shown to produce a definite relaxation of the bronchioles in the same way as adrenaline does. Saussurine has a positive inotropic action on the heart muscle.

Saussurine Chemica Structure

Fig. 5.35 Structure of O-methylsolanocapsine.

Fig. 5.35 Structure of O-methylsolanocapsine.

The hydrochloride of alkaloid, evolvine present in Evolvulus alsinoides is reported to exhibit lobeline-like action on the cardiovascular system. In cats, the drug has significant sympathomimetic activity. The blood pressure remains elevated for a longer duration as compared to adrenaline. Increase in peripheral pressure is observed on local injection of the drug. Phaeanthus ebracteolatus contains bis-benzylisoquinoline known as phaeantharine which has exhibited some levels of antibacterial activity.

Lycoriside, at lower concentrations (1-20 ^g/ml), in vitro, produces statistically significant protection against Tween 80-induced degranulation, as also to sensitized mast cells challenged with an antigen (horse serum). It also provided protection against compound 48/80-induced degranulation of mast cells when administered in vivo in a dose of 1-5 mg/kg, po.

Cerpegin, a novel furopyridine alkaloid isolated from Cerpegia juncea demonstrates dose-related analgesic effect in mice. Cerpegin do not produce any autonomic or behavioral changes up to a dose of 200 mg/ kg but doses of more than 400 mg/kg produced excitation and later convulsions in mice (Fig. 5.36).

Premnazole, an isoxazole alkaloid isolated from Premna integrifolia a. and Gmelina arborea has significant anti-inflammatory activity in reducing cotton pellet-induced granuloma formation in rats (Fig. 5.37). The anti-inflammatory activity is comparable to that of phenylbutazone.

The water-soluble alkaloid, achyranthine, isolated from Achyranthes aspera has been screened for its anti inflammatory and antiarthritic activity against carrageenin-induced foot oedema, granuloma pouch, formalin induced arthritis and adjuvant arthritis in rats. It shows significant anti-inflammatory activity in all the four models employed but is less active

Fig. 5.36 Structure of Cerpegin.

Fig. 5.37 Structure of Premnazole.

Fig. 5.37 Structure of Premnazole.

than phenylbutazone and betamethasone. Incidence of gastric ulcers is maximum with betamethasone and minimum with achyranthine.

Anti-inflammatory activity of crotalaburnine (anacrotine) isolated from Crotalbria laburnifolia has been investigated against several models of inflammation (Fig. 5.38). The effect has been compared with the activity of hydrocortisone, phenylbutazone, sodium salicylate and cyproheptadine against different types of inflammation.

In normal rats crotalaburnine (10 mg/kg s.c.), phenylbutazone (100 mg/kg oral) and sodium salicylate (500 mg/kg i.p.) inhibits hyaluronidase-induced oedema. However, in adrenalectomized rats, there is a reduction of the inhibitory effect of sodium salicylate but not of phenylbutazone or crotalaburnine.

Solkhasianine is a new glycoalkaloid from Solanum khasianum. Solasodine, an alkaloid of Solanum xanthocarpum demonstrates antifertility activity in males and dogs (Fig. 5.39). The alkaloid on oral administration results in inhibition of spermatogenesis and sperm motility. The mechanism of action of solasodine may be attributed to inhibition of testosterone release. Yuehchukene, an alkaloid from Murraya paniculata is used to regulate fertility in China.

Mechanism Action Chloroquine

Fig. 5.38 Structure of Crotalaburnine.

Fig. 5.38 Structure of Crotalaburnine.

Fig. 5.39 Structure of Solasodine.

Fig. 5.39 Structure of Solasodine.

Pergularinine, tylophorinidine and deoxytubulosine isolated from the Indian medicinal plants Pergularia pallida and Alangium lamarckii respectively, inhibits (IC50 = 50 microM) the elevated TS activity of leukocytes in cancer patients with clinically diagnozed chronic myelocytic leukemia (n = 10), acute lymphocytic leukemia and metastatic solid tumors (Figs. 5.40 and 5.41).

Structure Tylophorinidine
Fig. 5.40 Structure of Tylophorinidine.
Achilleine Alkaloid Structure

Cryptolepine (Fig. 5.42) is an indolisoquinoline antimalarial alkaloid with IC50 value approximately half of chloroquine. It was shown that the alkaloid might interact with DNA, and it appeared that two nitrogen atoms N and N-CH3 of cryptolepine interact with adenine-thymine base pair. There is also a possibility of formation of p-p charge transfer complex between purine-pyrimidine bases and cryptolepine and electron environment.

Another interesting antimalarial compound, tubulosine was found active in vitro against both sensitive and resistant strains of P. falciparum. The indole moiety in tubulosine enhances the affinity for protozoan receptor, when compared with psychotrine and cephaeline. Extracts from Triphophyllum peltatum led to the isolation of dioncophylline B and dioncophylline C both exhibiting high antiplasmodial activity (Fig. 5.43). Dioncophylline C cured malaria-infected mice completely after a 4-d oral treatment with 50 mg kg-1 d-1 without noticeable toxic effects.

Ancistrocladus Korupensis

A bisbenzylisoquinoline alkaloid dehatrine isolated from the wood of Beilschmiedia madang, exhibited potent inhibitory activity (IC50 0.017 ^ M) against the proliferation of malaria pathogen P. falciparum, which was comparable to quinine. Recently, a novel dimeric naphthylisoquinoline alkaloid heterodimer with antiplasmodial activity, korundamine A has been isolated from Ancistrocladus korupensis (Fig. 5.44).

Achyranthine Chemical Structure
Fig. 5.44 Structure of Korundamine A.

Topotecan, an analog of a plant alkaloid, camptothecin discovered in the Chinese tree species Camptotheca acuminata, for the treatment of ovarian and small cell lung cancers (Fig. 5.45). Irinotecan, another chemical analog which has been developed from another plant alkaloid discovered in the same tree, C. acuminata, is used for the treatment of metastatic colorectal cancer.

Topotecan Tree Images
Fig. 5.45 Structure of Camptothecin.

(+)-Calanolide A and (-)-Calanolide B (costatolide) isolated from Calophyllum lanigerum and Calophyllum teysmanii, respectively. (+)-Calanolide A is currently in early clinical trials in the United States. Maytansine from Maytenus ilicifolia exhibits significant cytotoxic and antitumoral efficacy. Additionally, an ulcer-preventing effect has been demonstrated in both animal and human studies.

Michellamine B, from the leaves of Ancistrocladus korupensis, a vine found in the Korup rainforest region of southwest Cameroon, has undergone extensive preclinical study, but is considered too toxic for advancement to clinical trials (Fig. 5.46).

Korupensis

Homoharringtonine from Cephalotaxus harringtonia is used in acute nonlymphoblastic leukemia and chronic myelogenus leukemia (Fig. 5.47).

Korupensis

Ellipticine (Fig. 5.48) and related alkaloids, e.g. 9-methoxyellipticine are found in the bark of Ochrosia elliptica. Clinical trials with these alkaloids and a number of synthetic analogues showed them to be potent inhibitors of several cancerous disorders, but pre-clinical toxicology indicated a number of side-effects, including haemolysis and cardiovascular effects.

Evodia Extract Side Effects
Fig. 5.48 Structure of Ellipticine.

Evodiamine (Fig. 5.49) extracted from Evodia elleryana, inhibits cell proliferation and migration of several types of cancer cell lines, including leukemia human caucasian acute lymphoblastic leukaemia cell-line (CCRF-CEM) cells in a concentration-dependent manner with an IC50 of 0.57^M via apoptosis following microtubular cytoskeleton abrogation. Methanol extracts of various parts of Euodia elleryana inhibits the growth of a broad spectrum of bacteria. While the antibacterial principle here is unknown, one could reasonably expect that evodiamine and rutaecarpine (Fig. 5.50)-like quinazoline alkaloids are involved.

Structure EvodiamineStructure Ellipticine

Rhizome of Nuphar pumilum contains dimeric sesquiterpene thioalkaloids, such as 6-hydroxythiobinupharidine, 6, 6"-dihydroxythiobinupharidine, and 6-hydroxythionuphlutine B (Figs. 5.51, 5.52), which inhibited the invasion of B16 melanoma cells across collagen-coated filters in vitro with IC50 0.029, 0.087, and 0.36^ M, respectively, indicating a clear antimetastatic potential.

B16 CollagenBacteria B16

Nelumbo nucifera elaborates antiviral isoquinolines (+)-1(R)-coclaurine (Fig. 5.53) and 1(S)- norcoclaurine, which inhibits the replication of HIV in vitro with EC 50 values of 0.8 and <0.8g/ ^L, and therapeutic index values of >125 and >25, respectively. Liensinine (Fig. 5.54) and isoliensinine showed potent anti-Human Immunodeficiency Virus (HIV) activities with EC50 values of <0.8g/^ L and Therapeutic Index values of >9.9 and >6.5g/^ L.

Fig. 5.53 Structure of Coclaurine.
Fig. 5.54 Structure of Liensinine.

Nuciferine (Fig. 5.55), an aporphine alkaloid, had an EC50 value of 0.8g/ ^ L and a Therapeutic Index value of 36. Isoliensinine exhibited a significant inhibitory effect on bleomycin-induced pulmonary fibrosis in male mice. The alkaloid lowered the hydroxyproline content and limited the lung histological injury induced by bleomycin, and also inhibited the overexpression of TNF-a and TGF-ß induced by bleomycin, and showed potent activity against bleomycin-induced pulmonary fibrosis.

Structure Aporphine

Cappamansin A (Fig. 5.56), from the roots of Capparis sikkimensis subsp. formosana has encouraged potently the survival of ovarian (1A9), lung (A549), ileocecal (HCT-8), breast (MCF-7), nasopharyngeal (Kb), and vincristine resistant (KB-VIN) human tumor cell lines cultured in vitro.

Fig. 5.56 Structure of Cappamansin A.

Fig. 5.56 Structure of Cappamansin A.

Tetrandrine (Fig. 5.57), a bis-benzyl isoquinoline alkaloid, isolated from the roots of Stephania tetrandra, showed that it not only inhibits Hep G2 growth but also induced apoptosis and blocked cell cycle progression in the GI phase.

h3c h3c

Structure Tetrandrine

o ch3

Fig. 5.57 Structure of Tetrandrine.

o ch3

Fig. 5.57 Structure of Tetrandrine.

Cassaine is a cardiotoxic alkaloid in Erythhrophloeum guinnense (Fig. 5.58). It causes anorexia, defective vision, increases heart sounds and dyspnoea.

CH3\N^CH3

ho ho

Testosterona

CH3 ch3

Fig. 5.58 Structure of Cassaine.

CH3 ch3

Fig. 5.58 Structure of Cassaine.

Frangulanine, a cyclopeptide alkaloid from Hovenia dulcis induces mitochondrial swelling in 0.5 M Kcl solution at the concentration at 6.5^M. The alkaloid showed ion selectivity on the induction of mitochondrial swelling. Ion specific pores are involved in sodium-potassium transport. Ion specific pores in the membrane are blocked by frangulanine, which acts as an ionophore for potassium. Vertine the principal alkaloid of Heimia salicifolia has anti-inflammatory activity.

Dicentra cucullaria contains isoquinoline alkaloids: including bicuculline, corlumine, protopine, cryptopine, and cularine. Liriodendron tulipifera contains isoquinoline alkaloids (0.1%), particularly of the aporphine type: including remerine, lysicamine, liriodenine, and lanugosine. The alkaloid violine from Viola odorata has an emetine-like effect. Quassia amara contains indole alkaloids of:-beta-carboline type, including l-vinyl-4, 8-dimethoxy-betacarboline and canthinone type, including 2-methoxy-6-one, 3-methylcanthine-5, 6-dione.

Sambucus ebulus is reported to quinolizidine alkaloids: cytisine, methylcytisine, anagyrine, isosparteine, lupanine, and tinctorine. Lupinus luteus contains quinolizidine alkaloids including sparteine, lupinine and p-cumaroyllupinine. Lupinine and benzolylupinine are reported to be anthelmintic.

Areca alkaloids

The major stimulant alkaloid of Areca catechu is arecoline (up to 0.2%) (Fig. 5.59), the remainder of the alkaloid content (total about 0.45%) being composed of arecaidine, guvacine, and guvacoline. Arecoline is an agonist for muscarinic acetylcholine receptors. Arecoline has been employed in veterinary practice as a vermicide to eradicate worms.

Arecoline

Arecaidine Guvacoline

Fig. 5.59 Structure of Areca alkaloids.

Guvacine

Ashwagandha alkaloids (see Solanaceae alkaloids also)

Withania somnifera contains alkaloids including anagrine, anaferine, cuscohygrine, hygrine, isopelletriene, pseudopelletriene, 3a-togloxytropine, 3-tropyltigloate, tropine and withasomnine and visamine (Fig. 5.60). Acute toxicity of W. somnifera alkaloids is modest. A 180-day study involving rats found unfavorable increases in catecholamine content of the heart and decreases in the adrenal glands.

Anagyrine

Anagyrine

Hygrine

Fig. 5.60 Structure of Ashwagandha alkaloids.

Ephedra alkaloids

The plants typically contain 0.5-2.0% of alkaloids, according to species, and from 30-90% of the total alkaloids is (-)-ephedrine. Related structures, including thendiastereoisomeric (+)-pseudoephedrine and the demethyl analogues (-)-norephedrine and (+)-norpseudoephedrine are also present. In Ephedra intermedia, the proportion of pseudoephedrine exceeds that of ephedrine. Ephedrine (Fig. 5.61) is an indirectly acting sympathomimetic amine with effects similar to noradrenaline. Lacking the phenolic groups of the catecholamines, it has only weak action on adrenoreceptors, but it is able to displace noradrenaline from storage vesicles in the nerve terminals, which can then act on receptors. It also has bronchodilator activity, giving relief in asthma. It has vasoconstrictor action on mucous membranes, making it an effective nasal decongestant.

Fig. 5.61 Structure of Ephedrine.

Fig. 5.61 Structure of Ephedrine.

Pseudoephedrine is also widely used in compound cough and cold preparations and as a decongestant.

Ergot alkaloids (Claviceps purpurea)

The ergot sclerotia contain from 0.15-0.5% alkaloids, and more than 50 have been characterized. The medicinally useful compounds are derivatives of (+) - lysergic acid. There are three classes of ergot alkaloids: the ergotamine group consisting of ergotamine, ergosine and the corresponding isomers the ergotoxine group consisting of ergocornine, ergocristine, ergokryptine and their isomers ergometrine and its isomer. Ergotamine (ergonovine) finds application in anti migraine prescriptions (Fig. 5.62). It is a partial agonist of a-adrenoceptors and 5-HT receptors. It is not suitable for obstetric use because it also produces a pronounced peripheral vasoconstrictor action. Ergometrine is used as an oxytocic, and is injected during the final stages of labor and immediately following childbirth, especially if hemorrhaging occurs. Bleeding is reduced because of its vasoconstrictor effects, and it is valuable after Caesarian operations.

Structure Cinchonine
Fig. 5.62 Structure of Ergotamine.

Cevadilla alkaloids

They are obtained from Schoenacaulon officinale. The alkaloids include cevadine (veratrine), veratridine (veraine), sabadilline (cevadilline), sabadine and sabadinine. Cevadine is toxic and used externally as an insecticidal.

Cinchona alkaloids

A considerable number of alkaloids have been characterized in the cinchona bark, four of which account for some 30-60% of the alkaloid content. These are quinine, quinidine, cinchonidine, and cinchonine (Fig. 5.63).

Fig. 5.63 Structure of Cinchona alkaloids.

Fig. 5.63 Structure of Cinchona alkaloids.

Quinine is extremely bitter, and also possesses antipyretic, analgesic and anti-inflammatory properties. While quinine is still the drug of choice for the treatment of Falciparum malaria, it can be also used to treat nocturnal leg cramps and arthritis. It can cause various side-effects like nausea, vomiting, cinchonism, and rarely, pulmonary oedema.

Quinidine is used in the treatment of cardiac arrhythmia. Intravenous injection of quinidine is also used in the treatment of Plasmodium falciparum malaria. Thrombocytopenia is the major adverse effect.

Coca alkaloids

Coca leaves are obtained from species of Erythroxylum coca and E. truxillense. Coca leaf contains 0.7-2.5% of alkaloids, the chief component (-)-cocaine (Fig. 5.64). It is a potent central nervous system stimulant and appetite suppressant. For its euphoretic effect, cocaine is often used recreationally, and it is one of the most common drugs of abuse and addiction. Cocaine is used as a topical anaesthetic in eye, throat and nose surgery. In overdose, it leads to tachyarrhythmia and hypertension.

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Responses

  • grimalda
    Can Ecliptine blocks acetlcholine?
    6 years ago
  • adonay
    What is the structural formula of galipoline?
    4 years ago
  • Paula
    What is the chemical formula of galipoline?
    4 years ago
  • stephanie
    What is the chemical structure of galipoline?
    4 years ago
  • ross hunter
    Which alkaloid is present in zanthoxylum?
    10 months ago

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