Plant Toxins as Sources of Drugs - rd.springer.com · areorganiccompoundsthatarenotdirectlyinvolvedinthenormalgrowth,development,orreproduction of plants. These compounds are also

Plant Toxins as Sources of Drugs

Stela Maris Kuze Rates*, Andresa Heemann Betti, Liz Girardi M€uller and Jéssica de Matos NunesPrograma de Pós Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

Abstract

Plant toxins are representative of a large group of structurally diverse small molecules that result from theplant secondary metabolism. These toxins can be synthesized by plants themselves or by nonpathogenicendophytic microorganisms living within plants. Among the plant secondary metabolites that exhibitevident toxicity to humans and animals, alkaloids, terpenes, steroids, and phenolic compounds have led todrugs or templates for drug design. Many of these molecules affect neural transmission or cell divisionprocesses, which have given rise to drugs for treating central nervous disorders and cancer. In addition tosecondary metabolites, toxic plant proteins such as lectins have emerged as tools for disease diagnosis andas candidates to develop new anticancer drugs. This text describes the most important plant toxins (from atherapeutic point of view), such as curare, ergot alkaloids, indole alkaloids, cardiac glycosides, andtaxanes, according to their main pharmacological properties and clinical uses. The most representativeexamples of plants are Papaver somniferum, Digitalis purpurea, Catharanthus roseus, and Taxusspp. Traditional uses laid the foundation for the development of the majority of these drugs. At present,analytical tools based on genomics, proteomics, metabolomics, bioinformatics, and other twenty-first-century technologies are accelerating the identification and characterization of natural products. On theother hand, many new bioactive compounds are failing due to a lack of efficacy in the clinic, whichdemands new strategies for pharmacological research. The fusion of ‘omics technologies’ with ethno-medicine, systems biology, and studies of plant endophytes are exciting approaches to search for newdrugs from natural sources.

Keywords

Plant toxins; Plant secondary metabolites; Toxic plant proteins; Drugs from plants

Introduction

Nature has been an important source of compounds that are currently used in the clinic or as research toolsto probe biological functions. Venoms are included in numerous systems of traditional healing sinceprimordial times, but the modern translation of toxins into medicines began only in the 1940s with theintroduction of tubocurarine, a vegetal compound, into anesthetic practice as a selective muscle relaxant.This compound is one of the key active ingredients in curare, a South American arrow poison. In fact, asignificant number of pivotal drugs still used in therapeutics originally came from toxic plants or fromplants used for magical/religious or intoxicant purposes by ancient communities (Rates 2001).

While the main constituents of most animal toxins are peptides and proteins that are often proteaseresistant due to their disulfide-rich architectures, plant toxins are representative of a large group ofstructurally diverse small molecules that result from plant secondary metabolism. Secondary metabolites

*Email: [email protected]

Plant ToxinsDOI 10.1007/978-94-007-6728-7_5-1# Springer Science+Business Media Dordrecht 2015

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are organic compounds that are not directly involved in the normal growth, development, or reproductionof plants. These compounds are also referred to as plant allelochemicals, and they can be synthesized byplants themselves and by nonpathogenic endophytic microorganisms living within plants. The secondarymetabolites help plants to survive environmental stresses, protect plants from microbial infections andenvironmental pollutants, provide them with a defense against insects and herbivorous organisms, andattract natural predators of such organisms, as well as luring pollinators and other symbionts of theseplants. Plant toxins, by definition, damage other organisms, and toxins are thus expected to be involvedonly in conflicting relationships between species. Nevertheless, they are not restricted to purely antago-nistic interactions and also play a significant role in mutualistic interactions. For instance, depending onthe ecological context, toxins can either increase insects’ vulnerability to parasitoids andentomopathogens or protect them, eventually leading to self-medication (Ibanez et al. 2012). Phytochem-icals can also prolong longevity in heterotrophic organisms transversely across phyla via evolutionarilyconserved mechanisms (Leonov et al. 2015).

This chapter intends to illustrate plant toxins as sources of drugs, but it also includes compoundsoriginating from plants that are not lethal stricto sensu and therefore cannot be classified exactly as toxins.These compounds were chosen based on their evident/acute or expected/delayed human toxicity and theircurrent or historical role in therapeutics. The first comments cover curare and D-tubocurarine due to theircardinal importance to the toxin research field in the search for new drugs. Thereafter, the text depicts themost important plant toxins (from a therapeutic point of view) according to their main pharmacologicalproperties and clinical uses.

Curare

Curare is the common name of various plant extract alkaloid toxins originating from Central and SouthAmerica. At first, it was known as “arrow poison” because the indigenes used it for hunting; it wasproduced by boiling diverse plants (e.g., Chondrodendron tomentosum, Menispermaceae, or Strychnos)according to traditional recipes. The resulting paste was applied to arrowheads and used to kill manyhumans and animals over the centuries. Hence, it was only a matter of time until the underlying molecularmechanism piqued the interest of European scientists and physicians.

Curare was taken to the Old World by Spanish conquistadors. In 1846, Claude Bernard demonstratedthat curare injected into a limb prevented muscle contraction in response to nerve stimulation. In the1860s, the scientists Thomas Richard Fraser and Alexander Crum Brown, working on the relationshipbetween chemical structure and biological activity, discovered that when alkaloids such as atropine,brucine, codeine, morphine, and nicotine had their nitrogen atoms changed from the tertiary to thequaternary form, they acquired curare-like activity. This was the precursor to much of the work onneuromuscular blocking drugs that took place after the Second World War. Harold King isolatedD-tubocurarine from a museum sample of curare, and in 1942, Oscar Wintersteiner and James Dutcherisolated the alkaloid D-tubocurarine (Fig. 1a) from the plant Chondrodendron tomentosum. Curare wasnot used clinically for muscle relaxation until that year. Its first clinical use as a muscle relaxant during anoperation was reported on January 23, 1942, when the anesthesiologist Harold Griffith injected a syntheticpreparation of curare into a young man before an appendectomy.

It was during the SecondWorldWar that John Halton and Cecil Gray used the drug on patients and werehighly gratified by the obtained results. Their experiences with curare were reported in 1946 and laid thebasis of what became known as the Liverpool technique – a triad of narcosis, analgesia, and musclerelaxation that remains in use (in essence) today. In addition, the molecular mechanism of curare as acompetitive antagonist of nicotinergic neuromuscular synaptic junctions was finally elucidated in the


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twentieth century. This non-depolarizing muscle relaxant, once in the circulation, quickly leads toparalysis including respiratory paralysis. The era of muscle relaxants in surgery had begun. The searchsoon began for new agents that lacked the cardiovascular side effects of tubocurarine. Because tubocu-rarine was known to contain a relatively rigid core structure carrying two functional groups, mostdiscovery studies have focused on synthetic compounds with curarimimetic actions: the toxin providedthe template for drug design. With the ongoing rapid development of medical science, new derivatives,such as atracurium (Fig. 1b), succinylcholine, gallamine, pancuronium, rocuronium, vecuronium, andmivacurium, could be synthesized with better pharmaceutical characteristics, and thus the original curarefrom Amazonia lost its relevance to modern medicine. The most successful of the newmuscle relaxants isatracurium. Two somewhat innocuous moieties were linked to build the active molecule. Its chemicalbridge was designed to break down rapidly in plasma to provide elimination that was not dependent onliver or kidney function and thus make the agent short acting, which facilitates the control of the extent ofparalysis. By chance, atracurium also lacks the cardiovascular side effects of other muscle relaxants (i.e., ablockade of nicotinic receptors in sympathetic ganglia that leads to a marked fall in blood pressure and/ora block of muscarinic cholinoceptors innervated by the cardiac vagus that could trigger arrhythmias).Atracurium was introduced in 1983, followed by cisatracurium (a defined isomer) in 1995. Still, muchresearch was necessary to develop the modern drugs in current use, but there is no doubt that curare and itsderivatives are the oldest muscle relaxants in use. For further readings, see Czarnowski et al. (2007) andRaghavendra (2002).

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Fig. 1 The muscle relaxant isolated from curare, (a) D-tubocurarin, and (b) atracurium, one of its derived molecules


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Drugs Acting on the Central Nervous System

MorphineMorphine’s history begins with the use of opium poppy plants (Papaver somniferum), which are native toEurasia and have been cultivated for more than 5,000 years. Opium ingestion was used for pain relief andsedation, and its poisonous effects are characterized by lethal respiratory depression at high doses. Themolecule was discovered in 1805 by Friedrich Wilhelm Adam Sert€urner (1783–1841), a pharmacy pupilin Germany who was working on active opium compound isolation. Morphine (Fig. 2a) is a morphinanisoquinoline alkaloid. Its molecular structure is the archetypal opioid, which consists of a centralquaternary carbon, a phenyl group or isostere attached to this carbon atom, a tertiary nitrogen atom,and a two-carbon bridge separating the tertiary nitrogen atom and the central carbon atom. A quaternarynitrogen considerably diminishes the desired effect because the drug will need to be transported into thecentral nervous system. Moreover, modifications to the methyl group on the nitrogen will decreaseanalgesia as well, as observed in the antagonist nalorphine. After morphine, a number of other alkaloids,such as codeine and papaverine, were isolated from opium. Currently, codeine (Fig. 2b) is obtained frommorphine and used as an analgesic and antitussive drug. Papaverine formed the basis for developingverapamil, a calcium channel blocker used to treat hypertension.

The analgesic effect of morphine occurs through the opioid system by binding the m receptor, which isprimarily found in the brainstem and medial thalamus. Unfortunately, most of its side effects are mediatedthrough m-opioid as well. Respiratory depression, antinociceptive tolerance, physical dependence, andconstipation are some of the undesired consequences that may accompany the potent analgesic effect ofmorphine.

Currently, morphine is approved by the FDA in sulfate form and is still accepted as the most effectivetreatment for pain as the gold standard when the effects of other analgesic drugs are compared. Morphinewas also the prototype for several opioid receptor agonists also in clinical use, such as fentanyl,oxycodone, and methadone. For further readings, see Rinner and Hudlicky (2012), Heydariet al. (2013), Everett and Gabbra (2014), and Sipahi et al. (2015).

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Fig. 2 The archetypal opioid structure of (a) morphine and its C-3 esterified analogue, (b) codeine


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CannabinoidsCannabinoids belong to terpenophenolic class and are the main active compounds isolated fromCannabissativa. Although the plant is the most commonly used illicit drug in Europe, it is generally regarded ascausing low acute toxicity. The recreational purpose of the smoked plant gives pleasure and relaxingperception that may be followed by dysphoria, anxiety, and panic episodes. Acute psychoactive effects ofcannabinoids are impairment of memory, reductions in psychomotor, and cognitive performance, whileextremely high consumption might impair cognitive and memory performance, especially in children andadolescents. The current data at least assures thatCannabis consumption by adolescents doubles their riskof developing schizophrenia in the future.

The first information on the therapeutic use of Cannabis spp. dates back to the third millennium B.C.,aiming to treat menstrual disorders, gout, rheumatism, malaria, constipation, and absent-mindedness.Among the active compounds in Cannabis extracts (Fig. 3), tetrahydrocannabinol (THC) is the strongestpsychotropically active component, followed by cannabidiol (CBD), cannabigerol, and cannabichromene.

A number of studies conducted using controlled trials with standardized and/or synthetic cannabinoidpreparations indicate beneficial results in alleviating symptoms such as spasticity, pain, nausea, vomiting,and loss of appetite. Continued studies on their pharmacological activity led to the first approval of acannabis-based medication in Germany in 2011. This medicine contains THC and CBD in a 1:1 ratio andis used to treat moderate to severe refractory spasticity in multiple sclerosis. The FDA approved the studyof CBD effects on pediatric epilepsy in 2013. Recently, the Brazilian Health Surveillance Agency(Anvisa) reclassified the CBD as a controlled medicine. Furthermore, the CBD is effective in models ofneuronal injury, neurodegeneration, and psychiatric disorders, such as schizophrenia, and the antipsy-chotic potential of this compound has already been demonstrated.

To date, two endogenous cannabinoid receptors have been identified, giving rise to the understandingof cannabinoid action in the human body. The cannabinoid type 1 receptors (CB1 receptors), which arethe most widely distributed G protein-coupled receptor in the central nervous system, are mainly locatedat the terminals of central and peripheral neurons and inhibit the release of several neurotransmitters:acetylcholine, noradrenaline, dopamine, 5-hydroxytryptamine, g-aminobutyric acid, glutamate,D-aspartate, and cholecystokinin. On the other hand, CB2 receptors are predominantly expressed byimmune cells, modulating the release of cytokines and cell trafficking. For further readings, seeDi Marzo (2006), Devinsky et al. (2014), Grotenhermen and M€uller-Vahl (2012), and Di Marzoet al. (2015).

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Fig. 3 Cannabis sativa active compounds: (a) tetrahydrocannabinol, (b) cannabidiol, (c) cannabigerol, and (d)cannabichromen


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CocaineThe white euphoria powder, cocaine (benzoylmethylecgonine), is a tropane alkaloid obtained from theleaves of the South American shrub Erythroxylum coca. This molecule is considered to be one of the mostfrequently used illegal recreational drugs worldwide, obviously imposing several health problems andeven life-threatening cardiotoxicity.

The therapeutic use of cocaine (Fig. 4) dates back to 1884, when Karl Koller used it in an ophthalmicsurgery and attempted to determine the molecule’s properties with his colleague Sigmund Freud, whoused to self-administer the substance as a stimulant. In fact, cocaine is the only local anesthetic withvasoconstrictor properties. The local anesthetic effect then occurs by blocking the action of axonalmembrane sodium channels. The vasoconstrictor activity is imparted by its additional capacity to induceneuronal catecholamine release. It acts mainly by increasing dopamine levels by binding to the dopaminetransporter and blocking the reuptake of dopamine into the presynaptic cell. It potentiates not only theeffects of endogenous catecholamines but also those from exogenous sources.

Aside from the reported benefits, continued studies have demonstrated that cocaine is not an anestheticagent of choice, and alternative compounds have become more accepted. Its potential harmful effects andrisk of addiction (a consequence of the increase in dopamine in the nucleus accumbens and the associatedrewarding effects) have strictly limited cocaine’s therapeutic purposes to topical anesthesia in ophthal-mological and nasal surgery, even though the possible hazards of this local anesthesia are not fullyexplored yet.

The identification of the benzoyl moiety of cocaine enabled the synthesis of different molecules, suchas benzocaine, which is the cocaine benzoic acid ester (in 1890 by Ritsert); procaine, which is the cocainepara-aminobenzoic acid (more soluble and less toxic than benzocaine) (in 1905 by Einhorn and Braun);and, finally, lidocaine (in 1943 by Löfgren), the diethyl-aminoacetic acid derivative of cocaine that startedthe amide-type local anesthetic age.

At present, cocaine’s therapeutic heritage can be observed in its derived formulations: co-phenylcaineforte (5 % lignocaine and 0.5 % phenylephrine), lignocaine alone or as 4 % lignocaine with 1:1000adrenaline, amethocaine, and oxymetazoline. For further readings, see Alañón et al. (2014) and Kecket al. (2015).

Ergot AlkaloidsPrimarily responsible for ergotism or St. Anthony’s fire disease, which is transmitted by the ergot parasitefungus of rye and other grains, ergot alkaloids are currently used in the treatment of a broad array ofdiseases, especially as psychoactive and vasoconstricting agents. This class of molecules belongs to theindole alkaloid group and can be classified according to their structures, namely, clavines, lysergic acidamides (ergoamides), and peptides (ergopeptines). All of them share the first biosynthetic steps, whichlead to the formation of the tetracyclic ergoline ring system, except the simplest one, the tricycliccompound (Fig. 5).

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Fig. 4 Cocaine


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Convolvulaceae, Poaceae, and Polygalaceae are the three families of higher plants in which thesemetabolites are found, but their production is often dependent on the presence of plant-associated fungi.Moreover, fungi from the Ascomycota phylum, such asClaviceps, Epichloë, Penicillium, and Aspergillusspp., are the main producers of ergot alkaloids. Claviceps purpurea is the most studied species related toergotism, and during the Middle Ages, it was able to trigger gangrene in limbs, disturbances in thefunction of the central nervous system, and ultimately death.

The ergot alkaloids possess a strong interaction with serotonin, dopamine, and adrenergic receptors inthe central nervous system and also with adrenergic receptors in blood vessels. Due to this observation, itsvery specific uterotonic action was explored, and ergotamine, previously isolated in 1932, started to beused for the prevention and treatment of postpartum hemorrhages. In the beginning of the nineteenthcentury, due to repeated cases of associated intrapartum ergometrine use and tetanic uterine contractionsthat led to fetal asphyxia, stillbirth, and uterine rupture, their role changed from pulvis ad partum (thepowder of birth) to pulvis ad mortem (the powder of death), and their use was restricted to postpartumhemorrhage treatment.

In addition to their use as vasoconstrictors, ergot alkaloids were the first antimigraine drug available.Dihydroergotamine is an ergotamine analogue administered as a nasal spray or by injection. Ergotamine isavailable in oral and sublingual tablet formulations and rectal suppositories.

Currently, natural and semisynthetic ergot alkaloids are used as a second-line intervention in theabsence of contraindications, if uterine atony persists after oxytocin administration during caesareandelivery, and as blood pressure modulators and pituitary hormone regulators for migraine prevention andas dopaminergic agents. For further readings, see Gerhards et al. (2014) and Tepper (2013).

Atropine, Scopolamine, and HyoscyamineAtropine, scopolamine, and hyoscyamine are alkaloids found in plants of the Solanaceae botanical familysuch as Atropa belladonna, Datura stramonium, Hyoscyamus niger, and Hyoscyamus muticus. Atropine(Fig. 6a) and scopolamine (Fig. 6b) are esters derived from aromatic acid (tropic acid) and tropine(tropanol) or scopine. Scopine differs from tropine only in having an oxygen bridge between the carbon

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Fig. 5 General molecular structure of ergot alkaloids: (a) ergoline ring, (b) clavines, (c) ergoamides, (d) ergopeptides, and (e)chanoclavine


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atoms designated as 6 and 7. On the other hand, hyoscyamine is the tropine ester of tropic acid. It is anasymmetric molecule and forms atropine when (-)-hyoscyamine is racemized into the (�)-compound.

Preparations of belladonna were known to the ancient Hindus and have been used by physicians formany centuries. During the Roman Empire and in theMiddle Ages, Atropa belladonna (also called deadlynightshade) was frequently used to poison people, with ingestion. Also, it is the major cause of poisoningcurrently.

These compounds are muscarinic receptor antagonists, which compete with acetylcholine and othermuscarinic agonists for a common binding site at the muscarinic receptor. Due to this capacity, their actionin the central nervous system is highlighted by the parkinsonism treatment and prevention of motionsickness and postoperative nausea and vomiting; scopolamine is the most effective form, with a newtransdermal preparation recently approved by the FDA in 2015. The adoption of atropine in ophthalmictreatment is restricted to the induction of complete cycloplegia. Atropine has also been used in anesthesiaprocedures, and other belladonna alkaloids and muscarinic receptors can also be employed in therespiratory, gastrointestinal, and cardiovascular systems. Moreover, toxicity symptoms of atropine,scopolamine, hyoscyamine, and other belladonna alkaloids, such as skin rash, skin flushing, mouthdryness, and eye perturbations, can occur along with their therapeutic use. For further readings, seeGrynkiewicz and Gadzikowska (2008), Renner et al. (2005), and Rossignol and Frye (2014).

Physostigmine and Other Acetylcholinesterase InhibitorsPhysostigmine (Fig. 7a) is a tertiary amine belonging to the indole alkaloid class. This substance is ahighly unstable white powder that becomes red upon exposure to light, air, and heat. Physostigmine ispresent in the ripe seeds of Physostigma venenosum from Western Africa. Its dried ripe seeds, known asesere by the old Calabar natives, were formerly used as an “ordeal poison” to determine the guilt or the

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Fig. 6 (a) Atropine (D,L-hyoscyamine) and (b) scopolamine

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Fig. 7 Physostigmine (a) and (b) galanthamine


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innocence of a person accused of a crime. If the accused merely vomited after ingesting the seeds, he wasinnocent, but those who succumbed to the muscarinic effects were deemed guilty.

The first therapeutic use of the drug dates from 1877, when Ludwig Laqueur used it in the treatment ofglaucoma. Further studies in 1929 led Dr. Stedman to identify the mechanism of its parasympathomimeticeffect through acetylcholinesterase inhibition, thus acting as a substrate and facilitating carbamylation ofthe enzyme. The use of physostigmine for myasthenia gravis underlies this principle because the moleculestimulates almost all involuntary muscles in the body, effectively increasing the concentration ofacetylcholine at the sites of cholinergic transmission. Other reported uses include reversing atropineanticholinergic toxicity.

The chemical structure of physostigmine has provided a template for the development of othermolecules with highly significant anticholinesterase activity. Acetylcholinesterase inhibitors, such asrivastigmine, are licensed for use in the UK for the symptomatic treatment of mild to moderately severeAlzheimer’s disease.

The antidote properties of a number of plants against central nervous system intoxication induced byanticholinergic agents were empirically recognized in ancient times, and these observations could beconsidered as the basis for discovering new important drugs acting on the cholinergic system. Homer, inhis epic poem the Odyssey, described a plant, “moly,” used by Odysseus as an antidote against Circe’spoisonous drugs. Centrally acting anticholinergic agents are thought to have been used by Circe to induceamnesia and a delusional state in Odysseus’ crew. There is evidence supporting the hypothesis that“moly” might have been a plant named snowdrop (Galanthus nivalis), which contains galanthamine(Fig. 7b), a centrally acting anticholinesterase. Therefore, the description of “moly” as an antidote inHomer’s Odyssey may represent the oldest recorded use of an anticholinesterase agent to reverse centralanticholinergic intoxication.

Currently, the alkaloid galanthamine (Fig. 7b) is well known as a selective and rapidly reversibleacetylcholinesterase inhibitor with simultaneous allosteric modulation of neuronal nicotinic receptorbinders. Within this panorama, the development of the cholinergic hypothesis for Alzheimer’s disease,which consists of an expressive deficit of acetylcholine in the brain that thus impairs cholinergic synapses,led to the investigation of galanthamine use in Alzheimer’s disease treatment. Preclinical and clinicaltrials succeeded between the 1980s and 1990s, and even though the benefits of acetylcholine inhibitorslast for a maximum of 12–24 months, the meaningful symptomatic benefits maintain this class as themainstay of pharmacotherapy in Alzheimer’s disease.

The regulation of the cholinergic system can also be used as a strategy for the treatment of other relateddiseases, such as the reversal of neuromuscular blockades and some central nervous disorders. Moreover,the investigation of galanthamine as an option in autism treatment has been highlighted since thismolecule was observed to decrease both core and associated symptoms of the disease, indicative of itsefficacy. Nevertheless, both require larger controlled studies.

Another alkaloid, huperzine A, derived from the Chinese herb Huperzia serrata, was identified in the1980s as a potent, reversible, selective inhibitor of acetylcholinesterase. Huperzine A appears to havebeneficial effects on the improvement of cognitive function, daily living activity, and global clinicalassessment in patients with Alzheimer’s disease. However, its effectiveness for Alzheimer’s treatmentremains controversial. For further readings, see Čolović et al. (2013), Moore et al. (2015), and Watkinset al. (2014).


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Antitumor Agents

Podophyllotoxin: EtoposidePodophyllotoxin (Fig. 8a) is an aryltetralin-type lignan isolated from podophyllin, a resin produced byspecies belonging to the Podophyllum genus, such as P. emodi and P. peltatum (Berberidaceae). Becauseof its cytotoxicity, the resin is currently used topically in the treatment of genital warts and condylomata.Podophyllin resin contains numerous compounds, but its toxicity has been attributed to podophyllotoxin,which is well known for its cytotoxic and neurotoxic properties. Patients intoxicated by podophyllotoxinpresent several clinical signs and symptoms, such as vomiting, diarrhea, abdominal pain, and abnormalhepatic functions, in addition to the neurological disturbance.

Podophyllotoxin is included in many pharmacopoeias and is used as an antiviral agent against thehuman papillomavirus (HPV), cytomegalovirus, Sindbis virus, and other venereal warts. Podophyllotoxinis effective in the treatment of molluscum contagiosum, a benign skin disease that primarily affectschildren, young adults, and patients infected by human immunodeficiency virus (HIV). Additionally, theantitumor activity of podophyllotoxin has been demonstrated; it is effective in the treatment of some typesof genital tumors and in non-Hodgkin’s and other lymphomas, as well as in lung cancer.

Podophyllotoxin irreversibly binds to tubulin and therefore inhibits its polymerization, inducing cellcycle arrest at the G2/M phase. Some limitations of the clinical use of podophyllotoxin are its poorselectivity against tumor cells and its narrow therapeutic window. Therefore, derivatives ofpodophyllotoxin, such as the semisynthetic derivative etoposides (Fig. 8b) synthesized in 1963, weredeveloped. These compounds present good clinical effects against several types of neoplasms.

The first clinical trial of etoposide was reported in 1971, and it was approved by the FDA in 1983.Etoposide’s toxicity is lower than podophyllotoxin’s toxicity because of the introduction of a glucose unitin the structure of podophyllotoxin and the subsequent acetylation of the hydroxyl at positions 4 and 6. It

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Fig. 8 Molecular structures of (a) podophyllotoxin and (b) etoposide. Note the presence of a glucose unit in the structure ofetoposide molecule


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acts by inhibiting deoxyribonucleic acid (DNA) topoisomerase II, which causes double strand breaks inDNA and prevents DNA synthesis at the premitotic stage. Etoposide is used in combination with otherchemotherapeutic agents for the treatment of refractory testicular tumors, small-cell lung cancer, lym-phoma, nonlymphocytic leukemia, and glioblastoma multiforme. For further readings, see Canelet al. (2000) and Gordaliza et al. (2004).

TaxanesTaxanes gained popularity in the 1980s and 1990s as an innovation against cancer. Considered at the timeas the most promising new chemotherapeutic agents developed for cancer treatment, paclitaxel anddocetaxel dominated the scene. To date, several taxanes have been isolated and their structural analoguesdescribed.

Taxanes are modified diterpenes (also classified as non-heterocyclic pseudo-alkaloids) produced by theyew tree, belonging to Taxus spp. The poisonous nature of yew has been cited since the second century B.C., when yew “juice” used to be handled for poisoning and extracts were consumed in ritual suicides andas emmenagogues.

Chemical features of this class of compounds include a taxane ring with a four-member oxetane ringattached at positions C-4 and C-5 and a bulky ester side chain at C-13. The configuration of this ester chainis essential for the antitumor activity through a special mechanism of action.

The prototype of taxanes, paclitaxel (Fig. 9), was discovered as part of a National Cancer Instituteprogram in which extracts of thousands of plants were screened for anticancer activity. It was discoveredin 1979 and approved for clinical use against ovarian cancer in 1992 and against breast cancer in 1994.Paclitaxel was initially supplied from the bark of the Pacific yew, Taxus brevifolia, a small slow-growingevergreen coniferous tree, which is not a sustainable source due to plant scarcity. Further investigationsled to an approved semisynthetic molecule derived from a readily available precursor,10-deacetylbaccatin III obtained from the needles of Taxus baccata, which is the European and moreabundant yew species compared to the Pacific one and able to handle commercial demands.

Taxanes act by microtubule stabilization, interfering with the normal mitotic process due to induceddisintegration resistance to cell division. Both taxoids bind to the b-subunit of tubulin, but higher activityfor tubulin has been observed with docetaxel, which results in a longer intracellular period than paclitaxel.This may explain why docetaxel appears to be two to four times more potent than paclitaxel in studies ofantitumor efficacy. The transition between microtubule stabilization and cell death affected by taxanes isnot clear.

Regarding cautionary procedures, myelosuppression is the dose-limiting toxicity of both taxanes.Among them, neutropenia is the more reported complication, but diverse other toxicities are alsoencountered, such as hypersensitivity reactions, hematological toxicity, neurotoxicity, and cardiac effects.Currently, paclitaxel and docetaxel are widely prescribed antineoplastic agents for a broad range of

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Fig. 9 Paclitaxel


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malignant solid tumors despite their side effects. Poor drug solubility and drug resistance can also be listedas drawbacks, but studies are underway to develop new, less toxic, and more active analogues able toovercome these problems. For further readings, see Wang et al. (2015) and Yared and Tkaczuk (2012).

Vincristine and VinblastineThe vinca alkaloids are indole alkaloid molecules primarily encountered in the pink periwinkle plantCatharanthus roseus, known as the vinca plant that is native and endemic to Madagascar and alsoencountered in Europe, Northwest Africa, Southwest Asia, and Southern USA. They have dimericchemical structures containing an indole (catharanthine) and a dihydroindole nucleus (vindoline) joinedtogether with other complexes. The earlier therapeutic use of vinca is related to diabetes treatment in thepopulation of Madagascar. Further evaluation of the hypoglycemic activity of its extracts evidenced agranulocytopenia produced as a result of bone marrow suppression in animals, directing studies to modelleukemia and lymphoma treatment. Confirmation of such activity led to the isolation of vinblastine andvincristine alkaloids, which are currently used in the treatment of Hodgkin’s lymphoma, Kaposi’ssarcoma, ovarian cancer, and testicular and infant acute lymphoblastic leukemia.

Structurally, vinblastine and vincristine (Fig. 10) are identical except for the substituent found on theindoline nitrogen in the lower vindoline portion of the molecules. This modification does not alter theirmechanism of action, which is characterized by antimitotic action that interferes with microtubule

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O OCH3CH3

OH3CO

Fig. 10 The vinca alkaloids (a) vincristine and (b) vinblastine are structurally identical apart from the substituent attached inthe indoline nitrogen in the lower vindoline portion of the molecules, which are an aldehyde and a methyl group, respectively


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dynamics through tubulin binding and subsequent prevention of cell division, ultimately promoting celldeath. Nevertheless, this single structural difference distinguishes both the clinical activity and toxicityprofiles of these molecules.

Vincristine is primary used to treat pediatric malignancies and for children and adults is indispensablein the chemotherapy regimens for acute lymphocytic leukemia, lymphoid blast crisis of chronic myeloidleukemia, and both Hodgkin’s and non-Hodgkin’s lymphomas. On the other hand, vinblastine is the mainchemotherapeutic agent used against germ cell malignancies and some types of advanced lymphomas.Vincristine and vinblastine toxicity is characterized by peripheral neuropathy and neutropenia. Despitebeing less neurotoxic, vinblastine presents similar side effects to vincristine, particularly when it iscombined with or follows other neurotoxic agents such as taxanes.

Knowledge of the structure and functional groups, as well as the toxicity, of vinca alkaloids guidesstudies in a natural direction: the search for new analogues that are more active, less toxic, and exhibit abroader spectrum of anticancer efficacy. In this context, there are two other major vinca alkaloids inclinical use based on vincristine and vinblastine, vinorelbine and vindesine. As prototypes, vincaalkaloids led to the synthesis of vinflunine, which has been approved in Europe for the treatment ofsecond-line transitional cell carcinoma of the urothelium. For further readings, see Magge and De Angelis(2015) and Moudi et al. (2013).

Phorbol EstersPhorbol esters are tetracyclic diterpenoids in which two hydroxyl groups on neighboring carbon atoms areesterified to fatty acids. Numerous species belonging to the Euphorbiaceae botanical family, such asSapium indicum, S. japonicum, Euphorbia frankiana, E. coerulescens, E. ticulli, E. tirucalli, Crotonsparsiflorus, C. tiglium, C. ciliatoglandulifer, Jatropha curcas, Excoecaria agallocha, and Homalanthusnutans, contain toxic phorbols.

Plants of Euphorbiaceae have been consumed medicinally for two millennia, despite the fact thatphorbol esters represent the most powerful tumor promoters known. In Africa and Asia, the latex ofE. tirucalli has been used in folk medicine in the treatment of rheumatism, asthma, gastric disorders, andneuralgia. Notably, the endemic appearance of Burkitt’s lymphoma in Africa and of nasopharyngealcarcinoma in China coincides with the abundance of Euphorbia tirucalli.

The phorbol esters themselves are not able to induce tumors, but promote tumor growth followingexposure to a subcarcinogenic dose of a carcinogen. Phorbol esters and their derivatives are able to mimicthe action of diacylglycerol and interact with protein kinase C (PKC), affecting the activity of manyenzymes, the biosynthesis of proteins and DNA, the cell differentiation processes, and the gene expres-sion. The interaction with PKC is the mechanism whereby phorbol esters induce cell proliferation andtumor production. Additionally, the concomitant exposure of 4-deoxyphorbol ester with the Epstein–Barrvirus induced a high frequency of chromosomal changes in human B lymphocytes in vitro, which maylead to the neoplastic conversion of Epstein–Barr virus-transformed B lymphocytes. These observationsmight explain the occurrence of Burkitt’s lymphoma in communities that use the latex of E. tirucalli infolk medicine, as mentioned above.

The most commonly used phorbol ester, 4-b-12-O-tetradecanoylphorbol-13-acetate (TPA, Fig. 11),was first discovered in the croton plant (Croton tiglium) in Southeast Asia. It is a potent promoter of mouseskin tumors and has been used as a pharmacological tool in research models of oncogenesis. On the otherhand, some studies have demonstrated that TPA can be an effective cancer therapeutic agent in myelocyticleukemia patients and has been indicated as a potential colorectal cancer therapeutic. TPA has also beenshown to increase white blood cell and neutrophil counts in solid-tumor cancer patients. Additionally,TPA is an inhibitor of HIV-1-induced cytopathic effects and is also reported to produce structural changesin the parasite Leishmania amazonensis.


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Preclinical studies have shown that other phorbol esters, such as jatrophone – amacrocyclic diterpenoidisolated from Jatropha gossypifolia – and a phorbol diester and its delta 5,6,7-beta-hydroperoxidederivative isolated from Ostodes paniculata, present antileukemic activity under in vitro and in vivoconditions. Additionally, jatrophone is toxic to the promastigote forms of L. braziliensis, L. amazonensis,and L. chagasi. Despite these observations, no medical devices containing phorbol esters are currentlyapproved by the FDA. For further readings, see Ron and Kazanietz (1999) and Goel et al. (2007).

LectinsLectins are a highly diverse class of carbohydrate-binding proteins of nonimmune origin. They arebroadly distributed in almost all organisms including invertebrates, bacteria, and viruses, but among allof the sources, plants have been the most extensively studied. These macromolecules were initiallyidentified as toxic proteins, including ricin, one of the most toxic from the seeds of castor beans (Ricinuscommunis). Their toxicity is related to their capacity to cause digestion and immune distress throughinteraction of the lectins with the gut epithelial cells and agglutination of other cells, such as red bloodcells.

Regarding plants, this diverse category of molecules can be described as proteins containing at least onenon-catalytic domain, which allows them to selectively recognize and reversibly bind to specific glycansor free sugars present on glycoproteins and glycolipids without altering the carbohydrate structure. Due tothis property, plant lectins affect both apoptosis and autophagy by modulating representative signalingpathways, thus acting as potential new antitumor agents in cancer drug discovery.

Lectins have also been characterized as a useful tool for diagnostic and therapeutic purposes in cancerresearch. They have an active component that alters cancer initiation, promotion, and progression. Severaldifferent types of lectins reduce the malignant potential of cancer cells. The effects of lectins on humanhepatoma, human choriocarcinoma, mouse melanoma, and rat osteosarcoma cell lines have been studied.Pleurotus ostreatus lectins inhibited tumor growth and played a significant role in the survival time ofmice, which was ascribed to the improvement of the host immune system. Vicia faba agglutinin, the lectinpresent in broad beans, reduces the malignant phenotype of colon cancer cells. The capacity of lectins tobind to carbohydrates permits glycoproteins to be expressed on cancer cells. Wheat germ agglutinin(WGA) is considered toxic to human pancreatic carcinoma cells in vitro because exposure to this lectinresults in nuclear fragmentation, DNA release, and chromatin condensation, resulting in apoptosis.Furthermore, WGA influences the cell growth of human breast cancer cell lines in vitro. According tothe previously mentioned observations, lectins can be used as carriers for targeted drug deliverydepending on the glycosylation pattern of the cells and the specific lectin due to their biorecognition ofspecific carbohydrates.

OH

H3C

H

OH

HH

HOO

O

O

O

C13H27

O

Fig. 11 The phorbol ester 4-b-12-O-tetradecanoylphorbol-13-acetate


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Additionally, a number of algal lectins such as cyanovirin-N, microvirin, microcystis viridis lectin,scytovirin, Oscillatoria agardhii agglutinin, and griffithsin are considered potential microbicide candi-dates to prevent the sexual transmission of HIV through topical applications. They not only inhibitinfection of cells by cell-free viruses, but they can also efficiently prevent virus transmission from virus-infected cells to uninfected CD4(+) target T lymphocytes, dendritic cell-specific intercellular adhesionmolecule-3-grabbing nonintegrin (DC-SIGN)-directed capture of HIV-1, and transmission to CD4(+)T lymphocytes. Currently, there are approximately 500 lectins commercially available. For furtherreadings, see Jiang et al. (2015), Wu and Sun (2012), and Zarogoulidis et al. (2015).

Other Agents

Cardiac GlycosidesCardiac glycosides are a perfectly individualized chemical group with excellent structural homogeneity.They possess a b-lactone unsaturated ring at C-17 and are divided into cardenolides, such as ouabain anddigoxin, and bufadienolides, such as bufalin.

Although historical records indicate that extracts of the common foxglove Digitalis purpurea wereused (mainly as poisonous preparations) as early as in Egyptian and Roman times, the first scientificreports on the medical application of cardiac glycosides date back to 1785, stemming from the work of theEnglish botanist WilliamWithering. Withering was most impressed with their diuretic effects, but he alsoobserved that cardiac glycosides exerted power over the motion of the heart to a degree, which had neverbeen observed in any other medicine. In 1799, John Ferrier suggested the mechanism of action of cardiacglycosides on the heart, which was finally proven in 1910 by Wenckebach. In the nineteenth century, thecardiac glycosides began to be used in the control of tachyarrhythmia, despite being considered highlytoxic.

The main cardiac glycoside, digoxin (Fig. 12), is known to have complex modes of action. It remainsthe only drug for chronic heart failure that inhibits the sodium pump, which indirectly promotes calciuminflux by sodium–calcium exchange and thus gives rise to the well-known inotropic effect (increase inmyocardial contractility); at the same time, it sets the stage for calcium-mediated toxicity. Inhibition of theNa+/Ca+ exchanger alone is not powerful enough to achieve therapeutic or toxic intracellular levels ofcalcium. One of the major issues related to the medical use of cardiac glycosides originates from theirrather narrow therapeutic index, with most prominent adverse effects including anorexia, nausea,vomiting, diarrhea, and life-threatening alterations of cardiac rhythm (either bradycardia or tachycardia).Still, the prototypical cardiac glycosides digoxin and digitoxin have been approved by the FDA for thetherapy of atrial fibrillation, atrial flutter, and paroxysmal atrial tachycardia prior to 1982. In 1998, the

O

OO

O

O

17

O

O

OH

H

H

HOH

HO

HO

HHO

H

H

OH

Fig. 12 Digoxin


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FDA extended the indications of digoxin to congestive heart failure. Currently, digoxin is indicated for thetreatment of congestive heart failure, atrial fibrillation, and atrial flutter with rapid ventricular response,whereas the use of digitoxin has been discontinued in several Western countries. Although a number ofsophisticated management options and new therapeutic agents utilized to treat patients with heart failurehave been developed in recent years, digoxin remains one of the most frequently prescribed drugs.

The cardiac glycoside mechanism of action has also been meaningful as a tool to study Na+⁄K+-ATPaseactive molecules. Extensive advances in knowledge of the role of cardiotonic steroids in Na+/K+-ATPaseand general human physiology have resulted in an ongoing understanding of the same regulation ofintracellular and hormonal signaling processes, clarifying the comprehension of sodium homeostasis innormal and pathophysiological states. Recently, cardiotonic glycosides have been suggested to exertpotent antineoplastic effects, and they notably appear to increase the immunogenicity of dying cancercells. For further readings, see Kirilmaz et al. (2012), Menger et al. (2013), and Opie (2013).

ColchicineColchicine (Fig. 13) is an alkaloid originally extracted from the meadow saffron Colchicum autumnaleL. and approved in 2009 by the FDA as a monotherapy drug to treat familial Mediterranean fever andacute gout flares. Dioscorides was aware of the poisonous action of C. autumnale, and preparations of theplant were not recommended for pain treatment until the sixth century A.D. over fear inspired by itspoisonous nature (nevertheless, the drug was recommended in Arabian writings for use in gout).Additionally, it was only employed in Europe in the seventeenth century. In 1763, Colchicum wasintroduced for the treatment of gout by von Störck and was incorporated in several popularized “goutmixtures.”

At low doses (0.5–0.6 mg once or twice daily), colchicine is generally safe and well tolerated. Thisalkaloid modulates multiple pro- and anti-inflammatory pathways associated with gouty arthritis, which iscaused by excessive production (or inability to excrete) of uric acid that accumulates in the joints.Colchicine exerts its biological effects by inhibiting tubulin assembly and suppressing microtubuleformation and thereby disrupts microtubule-based inflammatory cell chemotaxis, generation of leukotri-enes and cytokines, and phagocytosis. Colchicine is also being investigated as an anticancer drug.However, the therapeutic value of colchicine against cancer is restrained by its low therapeutic index.Its toxicity includes dose-dependent gastrointestinal toxicity, neutropenia, bone marrow damage, andanemia. Colchicine myotoxicity is a rare but important adverse effect that typically affects men aged50–70 years with renal impairment from taking low-dose colchicine (1.2 mg/day). For further readings,see Dalbeth et al. (2014) and Slobodnick et al. (2015).

O

O

O

O

O

HN

O

Fig. 13 Colchicine


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StrychnineStrychnine (Fig. 14) is a highly toxic indole alkaloid; it is one of the most famous chemical compoundsknown to chemists and the public alike. It is the major alkaloid isolated from the seeds of the treesStrychnos nux-vomica and Strychnos ignatii Bergius (Saint Ignatius’s bean), which are broadly distributedin the Asian tropics. Strychnine was first isolated in pure form from Strychnos ignatii Bergius by Pelletierand Caventou in 1818 and was subsequently reported to have several benefits including increasingappetite, toning skeletal musculature, increasing memory, and curing snakebites. Strychnine was evenused as an aphrodisiac and to cause euphoria until the 1970s. Currently, it is only used in neurotransmis-sion studies in specialized laboratories due to its mechanism of action, which acts as an antagonist ofglycine and acetylcholine receptors, affecting the motor nerves in the spinal cord that control musclecontraction. Its ease of isolation led to strychnine being a widely used pest control agent in the eighteenthcentury for rodents; this use continues today in some countries, but is banished in most. For furtherreadings, see Overman (2012) and Van Heerden et al. (1993).

Conclusions and Future Directions

Among the plant secondary metabolites exhibiting evident toxicity in humans and animals, alkaloids,terpenes, steroids, and phenolic compounds have led to drugs and templates for drug design. Many ofthese molecules affect neural transmission or cell division processes, which gave rise to drugs for thetreatment of cancer and central nervous disorders. In addition to the importance of plant secondarymetabolites to the development of drugs, toxic plant proteins such as lectins have also emerged as tools fordisease diagnosis and as candidates to develop new anticancer drugs.

Natural compounds can be lead compounds, allowing the design and rational planning of new drugs,biomimetic synthesis development, and the discovery of new therapeutic properties not yet attributed toknown drugs. In this scenario, toxic or potentially toxic plants have made an enormous contribution tomodern therapeutics that is beyond the number of drugs approved. They have primarily impactedknowledge of the biological targets and discovery of new chemical structures with unique pharmacolog-ical profiles. In addition to being representative of the chemical sophistication of plants, drugs such asmorphine, paclitaxel, vincristine, and vinblastine are still irreplaceable in alleviating human suffering bytreating pain and cancer. Compounds such as physostigmine, colchicine, and phorbol esters are importanttools in pharmacological, physiological, and biochemical studies. Drugs such as cocaine and curare areprototypes of modern drugs used in surgery. Cardiac glycosides remain as the most representativeexample of the potential of highly toxic plant components in therapeutics and identification of biologicaltargets. Ergot alkaloids characterize toxic and therapeutic secondary metabolites produced by fungi asparasites of cereals (Claviceps species) and related grass endophytes (Epichloë sp., Neotyphodium sp.,and Balansia sp.).

N

O O

H

N

H

Fig. 14 Strychnine


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The use of plants by traditional communities was the starting point for developing the majority of thedrugs cited above, as well as others not mentioned in this chapter, such as quinine and artemisinin used totreat malaria. However, despite the important drugs that have come from terrestrial flora, it is estimatedthat only 6 % of the approximately 300,000 species (some estimates are as high as 500,000 species) ofhigher plants have been systematically investigated pharmacologically, and only 15 % have beeninvestigated phytochemically (Cragg and Newman 2013). Among the new promising bioactive agentsfrom higher plants, maytansinoids (Lambert 2013) and cucurbitacins (Chen et al. 2012) deserve furtherattention as antitumor agents, and immunostimulating saponins have proven valuable in vaccines (Garçonand Van Mechelen 2011).

At present, the development of powerful analytical tools based on genomics, proteomics,metabolomics, bioinformatics, and other twenty-first-century technologies are meaningfully acceleratingthe identification and characterization of natural products. The knowledge gained has allowed theidentification of new bioactive structures, which can be optimized by using combinatorial chemistry togenerate new drug candidates for many diseases. Several authors have considered the synergistic andreciprocal benefits of linking these technologies with reliable ethnobotanical and ethnomedical studies oftraditional medicines (Ngo et al. 2013). This approach might be fruitful because many bioactivecompounds are failing due to lack of efficacy in the clinic, which means that the links between drugdiscovery screenings and the actual disease are not strong enough. Given that several new toxins havebeen identified due to their interactions with specific proteins, there is a natural tendency for toxin-baseddrug discovery to be built on the expectation that the toxin’s target protein is critical for the expression of aparticular disease. In fact, current high-throughput screening techniques consider single molecular targetsas the basis for the screening assay. Target-based drug discovery assumes that modulating a singlemolecular target will affect the course of the disease, but this is not often the case in practice. Despiteadvances in genomics and other modern techniques, the high rate of clinical failures implies that the targetvalidation is still uncertain or that the intermediate step of functional testing in animal models relies onnon-predictive surrogates for the human disease. Better biology that is more relevant to human diseaseand appropriate for drug discovery is greatly needed to inform decision-making. Systems biologyapproaches are emerging as a promise to accelerate hypothesis-driven biology by modeling specificphysiological problems in target validation or clinical physiology and by rapid characterizing andinterpreting disease-relevant cell and cell system level responses.

To conclude, alongside plant toxins and terrestrial animal venoms, advances in diving techniques in the1970s opened the seas as a promising source of drugs (e.g., ziconotide, a nonnarcotic analgesic isolatedfrom the venom of the cone snail, Conus spp.). Furthermore, several important medicines have arisenfrom microbial sources (e.g., penicillins and daunomycin-antitumor related agents). The introduction ofgenetic techniques that allow the isolation/expression of biosynthetic cassettes frommicrobes may signifya new frontier in natural products-driven discovery, and plant endophytes offer an exciting new resource.

Cross-References

▶ Plant AB Toxins with Lectin Domains▶ Plant Alkaloids: Main Features, Toxicity, and Mechanisms of Action▶ Plant and Fungal Toxins as Sources for Drugs of Abuse


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http://link.springer.com/SpringerLink:ChapterTarget



References

Alañón F, Alañón MA, Jiménez JA, Calero B, Noriega B, Plaza B. Comparison between topicalanesthesia with cocaine versus lidocaine plus adrenaline for outpatient laser dacryocystorhinostomy.Arch Soc Esp Oftalmol. 2014;89(2):53–7.

Canel C, Moraes RM, Dayan FE, Ferreira D. Podophyllotoxin. Phytochemistry. 2000;54(2):115–20.Chen X, Bao J, Guo J, Ding Q, Lu J, Huang M, Wang Y. Biological activities and potential molecular

targets of cucurbitacins: a focus on cancer. Anticancer Drugs. 2012;23(8):777–87.Čolović MB, Krstić DZ, Lazarević-Pašti TD, Bondžić AM, Vasić VM. Acetylcholinesterase inhibitors:

pharmacology and toxicology. Current Neuropharmacol. 2013;11(3):315–35.Cragg GM, Newman DJ. Natural products: a continuing source of novel drug leads. Biochim Biophys

Acta. 2013;1830(6):3670–95.Czarnowski C, Bailey J, Bal S. Curare and a Canadian connection. Can Fam Phisician.

2007;53(9):1531–2.Dalbeth N, Lauterio TJ, Wolfe HR. Mechanism of action of colchicine in the treatment of gout. Clin Ther.

2014;36(10):1465–79.Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, Katz R, Independent Consultant, Di

Marzo V, Jutras-Aswad D, Notcutt WG, Martinez-Orgado J, Robson PJ, Rohrback BG, Thiele E,Whalley B, Friedman D. Cannabidiol: pharmacology and potential therapeutic role in epilepsy andother neuropsychiatric disorders. Epilepsia. 2014;55(6):791–802.

Di Marzo V. A brief history of cannabinoid and endocannabinoid pharmacology as inspired by the workof British scientists. Trends Pharmacol Sci. 2006;27(3):134–40.

Di Marzo V, Stella N, Zimmer A. Endocannabinoid signalling and the deteriorating brain. Nat RevNeurosci. 2015;16(1):30–42.

Everett G, Gabbra N. The pharmacology of medieval sedatives: the “GreatRest” of the AntidotariumNicolai. J Ethnopharmacol. 2014;155(1):443–9.

Garçon N, VanMechelen M. Recent clinical experience with vaccines using MPL- and QS-21-containingadjuvant systems. Expert Rev Vaccines. 2011;10(4):471–86.

Gerhards N, Neubauer L, Tudzynski P, Li SM. Biosynthetic pathways of ergot alkaloids. Toxins.2014;6:3281–95.

Goel G, Makkar HPS, Francis G, Becker K. Phorbol esters: structure, biological activity, and toxicity inanimals. Int J Toxicol. 2007;26(4):279–88.

Gordaliza M, Garcia PA, Miguel del Corral JM, Castro MA, Gomez-Zurita MA. Podophyllotoxin:distribution, sources, applications and new cytotoxic derivatives. Toxicon. 2004;44(4):41–459.

Grotenhermen F, M€uller-Vahl K. The therapeutic potential of Cannabis and cannabinoids. Dtsch ArzteblInt. 2012;109(29–30):495–501.

Grynkiewicz G, Gadzikowska M. Tropane alkaloids as medicinally useful natural products and theirsynthetic derivatives as new drugs. Pharmacol Rep. 2008;60(4):439–63.

Heydari M, Hashempur MH, Zargaran A. Medicinal aspects of opium as described in Avicenna’s Canonof medicine. Acta Med Hist Adriat. 2013;11(1):101–12.

Ibanez S, Gallet C, Després L. Plant insecticidal toxins in ecological networks. Toxins. 2012;4(4):228–43.Jiang QL, Zhang S, Tian M, Zhang SY, Xie T, Chen DY, Chen YJ, He J, Liu J, Ouyang L, Jiang X. Plant

lectins, from ancient sugar-binding proteins to emerging anti-cancer drugs in apoptosis and autophagy.Cell Prolif. 2015;48(1):17–28.


Page 19 of 21

Keck TM, John WS, Czoty PW, Nader MA, Newman AH. Identifying medication targets forpsychostimulant addiction: unraveling the dopamine D3 receptor hypothesis. J Med Chem. 2015; inpress. doi: 10.1021/jm501512b.

Kirilmaz B, Saygi S, Gungor H, Onsel Turk U, Alioğlu E, Akyuz S, Asgun F, Tengiz I, Ercan E. Digoxinintoxication: an old enemy in modern era. J Geriatr Cardiol. 2012;9(3):237–42.

Lambert JM. Drug-conjugated antibodies for the treatment of cancer. Br J Clin Pharmacol.2013;76(2):248–62.

Leonov A, Arlia-Ciommo A, Piano A, Svistkova V, Lutchman V, Medkour Y, Titorenko VI. Longevityextension by phytochemicals. Molecules. 2015;20(4):6544–72.

Magge RS, De Angelis LM. The double-edged sword: neurotoxicity of chemotherapy. Blood Rev.2015;29(2):93–100.

Menger L, Vacchelli E, Kepp O, Eggermont A, Tartour E, Zitvogel L, Kroemer G, Galluzzi L. Trial watch:cardiac glycosides and cancer therapy. Oncoimmunology. 2013;2(2):e23082.

Moore PW, Rasimas JJ, Donovan JW. Physostigmine is the antidote for anticholinergic syndrome. J MedToxicol. 2015;11(1):159–60.

Moudi M, Go R, Yien CYS, Nazre M. Vinca alkaloids. Int J Prev Med. 2013;4(11):1231–5.Ngo LT, Okogun JI, FolkWR. 21st century natural product research and drug development and traditional

medicines. Nat Prod Rep. 2013;30(4):584–92.Opie LH. Digitalis, yesterday and today, but not forever. Circ Cardiovasc Qual Outcomes.

2013;6(5):511–3.Overman LE. Is there no end to the total syntheses of strychnine? Lessons learned in strategy and tactics in

total synthesis. Angew Chem Int Ed Engl. 2012;51(18):4288–311.Raghavendra T. Neuromuscular blocking drugs: discovery and development. J R Soc Med.

2002;95(7):363–7.Rates SMK. Plants as source of drugs. Toxicon. 2001;39(5):603–13.Renner UD, Oertel R, Kirch W. Pharmacokinetics and pharmacodynamics in clinical use of scopolamine.

Ther Drug Monit. 2005;27(5):655–65.Rinner U, Hudlicky T. Synthesis of morphine alkaloids and derivatives. Top Curr Chem.

2012;309:33–66.Ron D, Kazanietz MG. New insights into the regulation of protein kinase C and novel phorbol ester

receptors. J Federation Am Soc Exp Biol. 1999;13(13):1658–76.Rossignol DA, Frye RE. The use of medications approved for Alzheimer’s disease in autism spectrum

disorder: a systematic review. Front Pediatr. 2014;2(87):1–8.Sipahi A, Satilmis T, Basa S. Comparative study in patients with symptomatic internal derangements of

the temporomandibular joint: analgesic outcomes of arthrocentesis with or without intra-articularmorphine and tramadol. Br J Oral Maxillofac Surg. 2015;53(4):316–20.

Slobodnick A, Shah B, Pillinger MH, Krasnokutsky S. Colchicine: old and New. Am J Med.2015;128(5):461–70.

Tepper SJ. Orally inhaled dihydroergotamine: a review. Headache. 2013;53(2):43–53.Van Heerden PV, Edibam C, Augustson B, Thompson WR, Power BM. Strychnine poisoning – alive and

well in Australia. Anaesth Intensive Care. 1993;21(6):876–7.Wang S, Qiu J, Shi Z, Wang Y, Chen M. Nanoscale drug delivery for taxanes based on the mechanism of

multidrug resistance of cancer. Biotechnol Adv. 2015;33(1):224–41.


Page 20 of 21

Watkins JW, Schwarz ES, Arroyo-Plasencia AM,Mullins ME. The use of physostigmine by toxicologistsin anticholinergic toxicity. [Internet]. 16 Dec 2014; Available from: http://www.ncbi.nlm.nih.gov/pubmed/25510306. doi:10.1007/s13181-014-0452-x

Wu W, Sun R. Toxicological studies on plant proteins: a review. J Appl Toxicol. 2012;32(3):377–86.Yared J, Tkaczuk KHR. Update on taxane development: new analogs and new formulations. Drug Des

Devel Ther. 2012;6:371–84.Zarogoulidis P, Tsakiridis K, Karapantzou C, Lampaki S, Kioumis I, Pitsiou G, Papaiwannou A,

Hohenforst-Schmidt W, Huang H, Kesisis G, Karapantzos I, Chlapoutakis S, Korantzis I, Mpakas A,Karavasilis V, Mpoukovinas I, Li Q, Zarogoulidis K. Use of proteins as biomarkers and their role incarcinogenesis. J Cancer. 2015;6(1):9–18.


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Plant Toxins as Sources of Drugs - rd.springer.com · areorganiccompoundsthatarenotdirectlyinvolvedinthenormalgrowth,development,orreproduction of plants. These compounds are also