Cinchona Alkaloids: Structures and Stereochemistry

• Quinoline alkaloids come mainly from cinchona bark.
• Major members include quinine, quinidine, cinchonine, and cinchonidine.
• More than twenty-five alkaloids have been isolated from Yellow Cinchona (Cinchona calisaya and Cinchona ledgeriana) or Red Cinchona (Cinchona succirubra).
• These plants are from the Rubiaceae family.

Basic Structures of Cinchona Alkaloids

• Cinchona alkaloids have a quinoline ring (benzene + pyridine) and a bicyclic quinuclidine.
• Cinchona possesses the 9’-rubanol skeleton, derived from ruban.
• Ruban comes from a 4-methyl quinoline nucleus and a quinuclidine nucleus.
• Rabe suggested this nomenclature to simplify naming and indicate origin from Rubiaceae.
• Quinine and quinidine are stereoisomers.
• Cinchonine and cinchonidine are stereoisomers.
• Cinchonine & quinidine have C8= R , C9 = S configuration.
• Cinchonidine & quinine C8 = S , C9 = R configuration.
• Stereoisomers have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in space.

Biosynthetic pathway

• Studies show quinine comes from the monoterpenoid-tryptophan pathway.
• Dashed arrows indicate uncertain biosynthetic routes involving TDC (tryptophan decarboxylase), STR (strictosidine synthase), and SGD (strictosidine b-D-glucosidase).

Identification Tests of Quinine

• Fluorescence Test: Quinine produces a strong blue fluorescence with an oxygenated acid (acetic acid, sulfuric acid), even at low concentrations.
• Quinine hydrochloride and hydroiodide salts do not respond to this test.
• Thalleioquin Test: Adding bromine-water and strong ammonia to a weakly acidic quinine salt solution creates an emerald-green color.
• The colored product is thalleioquin, its chemical composition not yet established.
• This test can detect quinine at concentrations as low as 0.005%.
• Quinidine also gives a positive result, but cinchonine and cinchonidine do not.

Uses

• Cinchona and its alkaloids were used to treat malaria for years.
• Quinine sulfate is still used for malaria, as a tonic, analgesic, and for cold treatment.
• It poisons protozoa.
• Quinidine treats cardiac arrhythmias like arterial & ventricular tachycardia, atrial fibrillation & ventricular contraction.
• Quinidine is found as salts (sulfate & gluconate).
• It lowers myocardial excitability, conduction velocity & contractility.
• Totaquine is a mixture of total alkaloids, containing 7-12% anhydrous quinine and 70-80% total alkaloids.
• It is an antimalarial and cold remedy but not a cardiac depressant, usual dose 600mg.

Cinchonism or quinism

• Treatment with cinchona products may cause mild cinchonism.
• Symptoms include flushed and sweaty skin, tinnitus, blurred vision, impaired hearing, confusion, reversible high-frequency hearing loss, headache, abdominal pain, rashes, dysphoria, nausea, vomiting, and diarrhea.
• Ringing in the ears is a symptom of toxicity.

Isoquinoline alkaloids

• Isoquinoline is a heterocyclic aromatic organic compound and a structural isomer of quinoline.
• Isoquinoline and quinoline are benzo pyridines derivatives.

Types of isoquinoline alkaloids

• Benzylisoquinoline or BIQ alkaloids: About 4000 known.
• Many are important in medicine, some are toxic, and others are arrow poisons.
• Examples include papaverine and tubocurarine.
• Tetrahydrobenzylisoquinoline or THBIQ alkaloids: Nitrogen-containing ring is saturated.
• About 100 compounds known, found in almost all families that contain BIQ alkaloids.
• (+)-reticuline is the most important compound from a biosynthetic view.
• Phenanthrene alkaloids: Found mainly in the papaveraceae family as morphine & related alkaloids.
• Ipecac which contains emetine
• Hydrastis which contains hydrastine
• Curare which contains (+)-tubocurarine
• Berberis which contains berberine
• Opium which contains morphine & related alkaloids
• Sanguinaria which contains sanguinarine.

Ipecac

• Dried rhizomes & roots of Cephaelis ipecacuanha (Brazilian ipecac) or Cephaelis acuminate (Nicaragua or Panama ipecac).
• Family: Rubiaceae.
• Yields not less than 2% of ether-soluble alkaloids.
• Contains five alkaloids, including emetine, cephailine, & psychotrine.
• Syrup form treats drug overdose and certain poisoning by emetic effect.
• Emetine stimulates gastric mucous membranes and the central medullary chemoreceptor trigger zone.
• Cephaeline has stronger emetic activity and higher toxicity than emetine.
• Emetine is used as hydrochloride as a specific medicine for amoebic dysentery, it kills protozoa at 0.5-1.0 mg/mL.
• Emetine or methylcephaeline.

Hydrastis or golden seal

• Consists of the dried rhizomes & roots of Hydrastis canadensis
• Family: Runuculaceae.
• Three alkaloids isolated: hydrastine, berberine, & canadine.
• Hydrastine (1.5-4%) is the most important.
• Yields not less than 2.5% of anhydrous ether-soluble alkaloids.
• Hydrastine & berberine are astringents and anti-inflammatory for mucous membrane inflammation (intestinal, vaginal, eye, urinary tract infections).
• Used for uterine hemorrhage, diarrhea and acne.

Curare

• South American arrow poison: dried extract from bark & stems of Strychnos castelnaei or S. crevauxii
• Family: Loganiaceae.
• Contains alkaloids & quaternary compounds, including (+)-tubocurarine, a bis-benzyl isoquinoline structure.
• Exhibits a paralyzing effect on voluntary muscles (curariform effect) by blocking nerve impulses to skeletal muscles.
• Toxic to blood vessels.
• Tubocurarine is used as a skeletal muscle relaxant in surgical procedures without deep anesthesia.
• Also used to control convulsions of strychnine poisoning & tetanus.
• Adjunct therapy in neuro psychiatry & diagnostic aid in myasthenia gravis.
• Rarely used now as adjunct for clinical anesthesia due to available alternatives like cisatracurium and rocuronium.

Berberis (barberry)

• Sixteen isoquinoline alkaloids isolated from Berberis vulgaris.
• Contains quaternary proto berberines and bisbenzyl isoquinolines, including (-)-tejedine.
• Antibacterial, anti-inflammatory, hemostatic, diuretic and vasodilator.
• Berberine acts as a remedy against bacterial, viral, fungal and parasitic infections.

Opium

• Gum opium, is the air-dried milky exudates obtained by incising the unripe capsules of Papaver somniferum
• Family: Papaveraceae.
• Opium is Greek for poppy juice, papaver is Latin for poppy, somniferum is Latin and means to produce sleep.
• Cultivation is controlled internationally by the International Narcotic Control Board of the United Nations.
• Grown in Turkey, India, Russia, Romania, Australia, France, China & Spain.

Cultivation

• Planted in October.
• Reaches 15cm height in spring, then the fruit appears.
• In June/July when fully grown & unripe, each plant has 5-8 poppy (fruit), superficially cut to obtain a milky juice, left one day & collected on the second.
• Contains 30 different alkaloids: morphine (4-21%), codeine (0.8-2.5%), noscapine (narcotine) (4-8%), papaverine (0.5-2.5%), thebaine (0.5-2%).
• Other alkaloids: narceine, protopine, laudanine, codamine, cryptopine.
• Contains 3-5% meconic acid, free or combined with morphine, codeine & other alkaloids.
• Meconic acid gives a red color in ferric chloride solution.
• The color is not altered when dilute HCl is added.
• Meconic acid is only found in opium, so this test detects opium.

Classification of opium alkaloids

• Opium alkaloids are in 3 main groups:
• Phenanthrene alkaloids: act on the CNS to produce depressant effect & they stimulate the contraction of the smooth muscles (morphine, codeine, thebaine).
• Benzylisoquinoline alkaloids: little action on CNS but mainly antispasmodic because of smooth muscles relaxant (papaverine & noscapine).
• Phenylethylamine alkaloids: narceine.
• Phanathrene derivatives contain a benzene ring, phenolic OH, N-CH3 (tertiary amine), and ether linkage.
• Changing OH to OCH3 at position-3 give codeine, & if the other OH is changed to OCH3 with changing of the double bonds we end up with thebaine
• Codeine & its salts are narcotic analgesics & antitussive.
• Less toxic and less habit forming than morphine.
• Thebaine is a phenanthrene derivative and a CNS stimulant.

Alkaloids of opium: Morphine

• Most important of the opium alkaloids.
• Morphine & related alkaloids are derivatives of phenanthrene.
• Morphine & its salts are narcotic analgesics; they are strong hypnotics & narcotics.
• Induce nausea, vomiting, constipation, & habit forming.

Ethyl morphine (dionine)

• Used less than codeine.
• Formed by ethylation of phenolic OH of morphine and also used in ophthalmology as analgesic.
• Diacetyl morphine (heroin)
• Formed by acetylation of morphine.
• Very toxic & expensive.
• 100 times stronger than morphine.
• A drug of addiction.
• Available in free base form, a matte-white powder and smokable.
• Hydromorphone, also known as dihydromorphinone
• Is semi‐synthetic, created from the natural opiates
• Prepare by reducing morphine in HCL solution (one of OH group replaced by ketone group and adjacent double bond is removed).
• It is a powerful narcotic analgesic & tends to strongly depress the respiratory mechanism.
• Hydrocodone, also known as dihydrocodone: bears the same relation to codeine as hydromorphone dose to morphine, used mainly as a cough suppressant agent.

Apomorphine

• Prepared by heating morphine in a sealed tube with HCl.
• Used as emetic & valuable in cases of poisoning.

Papaverine

• Derivative of benzylisoquinoline and a smooth muscle relaxant.

Noscapine

• Commonly called narcotine.
• Derivative of benzyl isoquinoline.
• Has no narcotic properties so called anarcotine.
• Used as anti-tussive.

Pantopon

• Preparation of the total alkaloids of opium deprived or excluded from any other non alkaloidal material.
• Alkaloids are in the same proportion as inside opium drug.
• Contains about 50% morphine.
• More preferable than morphine alone due to synergistic effect.
• Opioid is used for compounds which inhibit the pain reaction within the CNS.
• Opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract.
• The receptors in these organ systems mediate both the beneficial effects and the side effects of opioids.
• Analgesic effects of opioids are due to decreased perception of pain, decreased reaction to pain and increased pain tolerance.
• Side effects of opioids include sedation, respiratory depression, constipation, and euphoria.
• Opioid refers to the synthetic morphine like compounds.
• Many offer the same narcotic & pain-relieving properties as morphine, but they are not as habit-forming.
• Others possess cough relieving activity of codeine but are not addictive, examples morphinan opioids, methadone & meperidine.
• Opioids bind to specific opioid receptors in the central nervous system and other tissues.
• There are three principal classes of opioid receptors, μ, κ, δ (mu, kappa, and delta).

Classification of opioids

• Natural opiates: morphine, codeine, and thebaine.
• Semi-synthetic opioids: created from the natural opiates or morphine esters, such as hydromorphone.
• Fully synthetic opioids: such as pethidine, tramadol
• Opiate is limited to natural alkaloids in the resin of the opium poppy (Papaver somniferum).
• Opioid refers to both opiates and synthetic substances, as well as opioid peptides.

Sanguinaria (blood root)

• Consists of the dried rhizomes & roots of Sanguinaria canadensis
• Family: Papaveraceae.
• Contains benzyl phenanthridine alkaloids sanguinarine, chelerythrine, protopine.
• Sanguinarine & chelerythrine form red & yellow salts, respectively.
• Also contains red resin & starch.
• Mainly used as ingredient of compound white pine syrup.
• Sanguinarine, like colchicine, causes doubling of the chromosomes in the cell.

Biosynthesis Of Isoquinoline Alkaloids

• Result from the condensation of a phenylethylamine derivative with a phenylacetaldehyde derivative.
• Both moieties are derived from phenylalanine or tyrosine.
• Biosynthesis of morphine.
• Morphine is formed from two molecules of tyrosine.
• Derived from a benzylisoquinoline metabolite.
• The enzymatically controlled methylation pattern which gives rise to reticuline.
• Stepwise demethylation of the therapeutically unimportant thebaine leads first to the relatively mild analgesic codeine and then to the potent narcotic morphine.
• P. somniferum has a highly evolved and useful secondary metabolism ending in morphine.
• P. bracteatum, a thebaine-producing poppy, lacks significant demethylation capability.
• Thebaine can be converted to codeine semisynthetically, thus assuring a source of the latter alkaloid without making morphine.