Bitter Principles - Lecture Notes PDF

Bitter Principles Asmaa Mahana, Ph.D. Department of Pharmacognosy Alexandria University Office Hours: Thursday 9 a.m.- 12 p.m.  Lecture Outline Introduction on Bitter Principles ▪ Definition. ▪ General Characters. ▪ Classification. Terpenoid Bitters Non-Terpenoid Bitters  Bitt...

Bitter Principles Asmaa Mahana, Ph.D. Department of Pharmacognosy Alexandria University Office Hours: Thursday 9 a.m.- 12 p.m.  Lecture Outline Introduction on Bitter Principles ▪ Definition. ▪ General Characters. ▪ Classification. Terpenoid Bitters Non-Terpenoid Bitters  Bitter Principles-Definition ❑ A group of natural products which are non-homogenous from the chemical point of view, they have in common a characteristic bitter taste and are neither alkaloids nor glycosides. Bitter Principles-General Characters ❑ Bitter principles are mainly of vegetative origin, rarely of animal origin. ❑ They essentially comprise of C, H, and O, but free from or rarely have N. ❑ They are abundant in certain plant families especially Compositae, Labiatae and Umbellifereae. Bitter Principles-General Characters ❑ Bitter principles or Bitters have an intensely bitter taste. ❑ They were traditionally used in liquid medicaments to stimulate appetite. ❑ Many of these bitters and drugs containing them are still included in tonic formulations and are usually administered before meals.  Bitter Principles-General Characters ❑ It has been proposed that bitter principles stimulate the taste buds, thus producing reflex secretion of gastric juices. ❑ Extracts of bitter principle containing drugs have been originally used as bitter stomachic. ❑ Many of these drugs are now mainly used for other pharmacological activities. Cinchona Gentian Hops Quassia Calumba Bitter Principles-Classification Monoterpenoids Sesquiterpenoids Terpenoid bitters Diterpenoids Triterpenoids Bitter Principles Phenolic Chromone Non-Terpenoid Coumarin bitters Coumarone Anhydride  Bitter Principles-Terpenoid Bitters ❑ These bitters are built up of different number of isoprene units (isoprenoids) (C5H8). Two isoprene units Monoterpenoids (C10H16) Three isoprene units Sesquiterpenoids (C15H24) Terpenoid bitters Four isoprene units Diterpenoids (C20H32) Six isoprene units Triterpenoids (C30H48) Bitter Principles-Terpenoid Bitters Sesquiterpene Lactones ❑ They are C-15 lactone derivatives. ❑ Characteristic of family Compositae. ❑ Generally, they can be classified according to their carbocyclic skeletons. Bitter Principles-Terpenoid Bitters Sesquiterpene Lactones ❑ The α,β-unsaturated Iactone with an exocyclic methylene functionality appears to be essential for the biological activities of this class. ❑ These functional groups represent reactive receptor sites for biological nucleophiles such as thiol and amino groups of enzymes.  Bitter Principles-Terpenoid Bitters Sesquiterpene Lactones ❑ The α,β-unsaturated Iactone with an exocyclic methylene functionality appears to be essential for the biological activities of this class. ❑ Therefore, sesquiterpene lactones have a wide spectrum of biological activities including antitumor, antileukemic, antimalarial and antimicrobial activities.  Terpenoid Bitters-Sesquiterpene Lactones Parthenolide Biological Source: ❑ Fever few flowers, which is the dried flower-heads of Chrysanthemum parthenium, Family Compositae.  Terpenoid Bitters-Sesquiterpene Lactones Parthenolide Actions and Uses: ❑ Treatment and prophylaxis of migraine.  Terpenoid Bitters-Sesquiterpene Lactones Parthenolide Actions and Uses: ❑ Treatment and prophylaxis of migraine. ❑ Treatment of rheumatoid arthritis & menstrual problems. ❑ Recently, it has been shown to have anticancer activity.  Terpenoid Bitters-Sesquiterpene Lactones Artemisinin Biological Source: ❑ The Chinese herb Qing Hao, which is the leaves and the closed, unexpanded flower heads of Artemisia annua, Family Compositae. Endoperoxide moiety Terpenoid Bitters-Sesquiterpene Lactones Artemisinin: A Drug Discovery Story Artemisinin was isolated and identified in 1972 Terpenoid Bitters-Sesquiterpene Lactones Artemisinin: A Drug Discovery Story  Terpenoid Bitters-Sesquiterpene Lactones Artemisinin Actions and Uses: ❑ Treatment of malaria; it has been shown to be valuable and effective against resistant strains of Plasmodium falciparum. ❑ Endoperoxide moiety is essential for antimalarial activity. ❑ The high lipid solubility ensures rapid penetration into CNS so useful for the treatment of cerebral malaria, which is otherwise fatal.  Terpenoid Bitters-Sesquiterpene Lactones Artemisinin Why Artemisinin is an excellent antimalarial agent? ❑ Approximately equal in potency to chloroquine. ❑ Active against chloroquine resistant strains of Plasmodium falciparum. ❑ The high lipid solubility ensures rapid penetration into CNS; so it’s a first-line drug for the treatment of cerebral malaria caused by P. falciparum, which is otherwise fatal.  Terpenoid Bitters-Sesquiterpene Lactones Artemisinin Dosing: ❑ Artemisinin and derivatives have t1/2 on the order of an hour. ❑ Therefore, they require at least daily dosing over several days. ❑ For example, the WHO-approved adult dose of co-artemether is four tablets at 0, 8, 24, 36, 48, and 60 hours (six doses).  Terpenoid Bitters-Sesquiterpene Lactones Artemisinin Combination Therapy (ACT) ❑ Recently, WHO has recommended ACT as the first-line therapy for P. falciparum malaria worldwide. Artemisinin Partner drug Kills the majority of A slowly eliminated drug parasites at the start of with long t1/2 to clear the treatment. remaining parasites. Terpenoid Bitters-Sesquiterpene Lactones Artemisinin Derivatives Why Semisynthetic Derivatives of Artemisinin are made? ❑ Semisynthesis enabled studying structure- activity relationships (SAR). ❑ Semisynthesis improved the poor water and even oil solubility which is important to diversify routes of administration.  Terpenoid Bitters-Sesquiterpene Lactones Semisynthetic Derivatives Artemisinin  Terpenoid Bitters-Sesquiterpene Lactones Mechanism of Action Artemisinin  Terpenoid Bitters-Triterpenoids ❑ These bitters are built up of six isoprene units (isoprenoids) (C5H8). C30 Compounds Quassinoids Tetracyclic Limonoids Triterpenoids Pentacyclic Cucurbitacins (Saponins)  Terpenoid Bitters-Triterpenoids Bruceolides ❑ They are an important group of quassinoids. Biological Source: ❑ Brucea javanica, Family Simarubaceae.  Terpenoid Bitters-Triterpenoids Bruceolides ❑ They are an important group of quassinoids. ❑ Bruceolides have a C-8 hydroxy methyl engaged in an ether function with C-13. ❑ Class I are esters of the parent alcohol bruceolide at C-15 position. Class I Terpenoid Bitters-Triterpenoids Bruceolides  Terpenoid Bitters-Triterpenoids Bruceolides ❑ Class I Bruceolides reached the level of clinical trials as anticancer agents. Class I SAR ❑ Diosphenol group at C2- C3. ❑ An ester at C-15 with α,β- unsaturated group at C2’- C3’. ❑ A lactone at C-16.  Terpenoid Bitters-Triterpenoids Class I Bruceolides Mechanism of Anticancer Action Carrier  Terpenoid Bitters-Triterpenoids Class II Bruceolides ❑ Similar to class I, they have a C-8 hydroxy methyl engaged in an ether function with C-13. ❑ Class II Bruceolides lack ester group at C-15 position. ❑ Class II have significant antimalarial activity but no anticancer activity.  Bitter Principles-Non-Terpenoid Bitters ❑ Non-terpenoid bitters are classified according to their chemical structure & functional groups present. Phenolic Chromone Non-Terpenoid Coumarin bitters Coumarone Anhydride Coumarone (Benzofuran) Non-Terpenoid Class-Phenolic Bitters Biological Source: Cynarin ❑ It is obtained from Leaves of artichoke, Cynara scolymus, Family Compositae. ❑ Cynarin is a Caffeic acid derivative. ❑ It is a 1,3-dicaffeoylquinic acid (It is a diester). Non-Terpenoid Class-Phenolic Bitters Actions and Uses: Cynarin ❑ Artichoke Leaf extract has the property of liver protection, also has a choleretic activity. ❑ Cynarin and leaf extract are used in jaundice. ❑ Several pharmaceutical preparations are available including Cholicynar®, lipocholine®, and Chophytol®. Non-Terpenoid Class-Phenolic Bitters Actions and Uses: Cynarin ❑ Artichoke Leaf extract has the property of liver protection, also has a choleretic activity. ❑ Cynarin and leaf extract are used in jaundice. ❑ Several pharmaceutical preparations are available including Cholicynar®, lipocholine®, and Chophytol®. Non-Terpenoid Class-Phenolic Bitters Mechanism of action: Cynarin ❑ Cynarin increases the secretion of bile, which is thought to be responsible for the described cholertic and cholagogic activity. ❑ The liver protective effect of cynarin was mediated through maintaining the level of GSH and ROS scavenging ability. Cynarin effectively acts against hepatotoxicity Non-Terpenoid Class-Phenolic Bitters Biological Source: Silymarin ❑ It is obtained from fruits & seeds of Milk Thistle or Silybum marianum, Family Compositae. ❑ Silymarin is a Flavono-lignans. ❑ It is formed in plants through oxidative coupling of a flavonoid molecule (Taxifolin) with a hemi-lignan molecule (C6-C3) (Coniferyl alcohol). Non-Terpenoid Class-Phenolic Bitters Actions and Uses: Silymarin ❑ A very effective hepatoprotective therapy. ❑ Employed in many liver tonic preparation. ❑ It is currently marketed in Europe particularly in Germany as the most effective liver remedy (hepatoprotective drug) particularly in those forms of hepatitis affecting the liver parenchyma. ❑ Several pharmaceutical preparations are available in the market; e.g. Legalon® tablets and Silymarin® tablets and sachets.  Bitter Principles-Non-Terpenoid Bitters ❑ Non-terpenoid bitters are classified according to their chemical structure & functional groups present. Phenolic Chromone Non-Terpenoid γ Coumarin α bitters Coumarone Benzo-α-pyrone Benzo-γ-pyrone Anhydride Coumarone (Benzofuran)  Non-Terpenoid Class-Chromone Bitters Furanochromones Khellin Biological Source: ❑ Fruits of Ammi visnaga, Family Umbelliferae. ❑ The fruit contains about 1% of khellin beside two other crystalline compounds, visnagin (0.1%) and khellolglycoside (0.3 %).  Non-Terpenoid Class-Chromone Bitters Khellin Tests for Identification: KOH Pellets ❑ Khellin Rose-red color. ❑ Khellin Decolorizes KMnO4 solution. Khellin  Non-Terpenoid Class-Chromone Bitters Actions: Smooth muscle relaxant. Khellin Uses: ❑ Khellin can be used as antispasmodic agent to treat renal colics and uretheral spasms. ❑ Renal colics are mostly due to kidney stone formation. Khellin has been suggested to relieve renal colics by relaxing the ureter and acting as a diuretic.  Non-Terpenoid Class-Chromone Bitters Actions: Khellin ❑ Potent selective coronary vasodilator & bronchodilator. Uses: ❑ It is mainly used in angina pectoris & Coronary insufficiency. ❑ It was also used in bronchial asthma.  Non-Terpenoid Class-Chromone Bitters Actions: Khellin ❑ It has photochemotherapy activity. Uses: ❑ Khellin can be used in photochemotherapeutic treatment of Vitiligo (3x/Week) for a period of 12-18 months. ❑ Vitiligo is a disease which causes loss of pigmentation in different portions of skin.  Non-Terpenoid Class-Chromone Bitters Uses: Khellin can be used for Vitiligo (3x/Week). Khellin Mechanism of action ❑ When khellin is applied topically in combination with narrow band UVB light (310-315 nm), it is able to stimulate melanocytes (cells that produce melanin) in hair follicles to restore pigmentation. However, relapse is common.  Non-Terpenoid Class-Chromone Bitters Actions: Khellin ❑ Smooth muscle relaxant. ❑ Selective coronary vasodilator & bronchodilator. ❑ Photochemotherapeutic activity. Uses: ❑ Antispasmodic agent to treat renal colics. ❑ It is used in angina pectoris, severe chest pain due to lack of blood, thus a lack of oxygen supply of the heart muscle, due to obstruction or spasm of the coronary arteries. ❑ It is used for treatment of vitiligo.  Non-Terpenoid Class-Chromone Bitters Khellin Derivatives Why Semisynthetic Derivatives of Khellin are made? ❑ Semisynthesis enabled studying structure- activity relationships (SAR). ❑ Semisynthesis improved the potency and selectivity profiles of khellin and reduced its side effects. Acute Liver Failure Dizziness Reversible Jaundice Elevated Liver Enzymes  Non-Terpenoid Class-Chromone Bitters Khellin Derivatives ❑ Extensive SAR studies of Khellin revealed that: ✓ Chromone nucleus is responsible for bronchodilator effect. ✓ Benzofuran nucleus is responsible for coronary vasodilator effect. Coronary Vasodilatation Bronchodilatation  Non-Terpenoid Class-Chromone Bitters Khellin Derivatives ❑ Chromone is responsible for bronchodilator effect. ❑ Cromolyn Sodium (Sodium Cromoglicate) emerged to become a first line prophylactic treatment for bronchial asthma. ❑ Unlike khellin, It has no muscle relaxant properties, but it is effective in preventing antigen induced bronchospasms.  Non-Terpenoid Class-Chromone Bitters Khellin Derivatives ❑ Benzofuran is responsible for coronary vasodilator effect. ❑ Amiodarone is a potent dilator for treating angina. ❑ It is established for prophylactic control of supraventricular & ventricular arrhythmias.  Bitter Principles-Non-Terpenoid Bitters ❑ Non-terpenoid bitters are classified according to their chemical structure & functional groups present. Phenolic Chromone Non-Terpenoid β Coumarin α bitters Coumarone Benzo-α-pyrone Benzo-γ-pyrone Anhydride Coumarone (Benzofuran) Non-Terpenoid Bitters-Coumarin Bitters Furanocoumarins (Psoralens) ❑ They are heterocyclic aromatic compounds derived from linear condensation of a coumarin nucleus (benzo-α-pyrone) with a furan ring. ❑ They are produced by some plants as phytoalexins after infection with fungi. α Non-Terpenoid Bitters-Coumarin Bitters Biological Source: Furanocoumarins (Psoralens) ❑ Fruits of Ammi majus, Family Umbelliferae. ❑ Bergapten was first isolated from the oil of bergamot from Citrus bergamia, Family Rutaceae. Name R R1 Psoralen H H Xanthotoxin H OCH3 Imperatorin H OCH2-CH=C(CH3)2 Bergapten OCH3 H  Non-Terpenoid Class-Coumarin Bitters Actions: Photochemotherapeutic activity. Psoralens Uses: Treatment of psoriasis & eczema. ❑ Psoriasis is a chronic autoimmune condition that causes hyper proliferation of outer skin layer. skin redness and irritation Thick skin with flaky, silver-white patchy scales  Non-Terpenoid Class-Coumarin Bitters Actions: Photochemotherapeutic activity. Psoralens Uses: Treatment of psoriasis & eczema.  Non-Terpenoid Class-Coumarin Bitters Actions: Photochemotherapeutic activity. Psoralens Uses: Treatment of vitiligo. ❑ Psoralens are used in in conjunction with exposing the skin to UVB light from lamps or sunlight. Dosing: ❑ The dosage comes in 10 mg tablets, which are taken in the amount of 30 mg, 75 minutes before a PUVB (psoralen + UVB) light treatment.  Non-Terpenoid Class-Coumarin Bitters Uses: Treatment of vitiligo. Psoralens Mechanism of action: (Two possible mechanisms) ❑ The exact topical mechanism of action is unknown. Psoralens given orally are preferentially taken up by epidermal cells. ❑ Psoralens sensitize the skin to the ultraviolet rays which act on the melanocytes in the normal pigmented skin and around the vitiligo patches and stimulate the melanin pigment to seep into the epidermal cells.  Non-Terpenoid Class-Coumarin Bitters Mechanism of action: Psoralens ❑ It has been suggested that melanocytes in the hair follicles are stimulated by psoralens to move up the follicle and to repopulate the epidermis. Second possible mechanism similar to khellin  Non-Terpenoid Class-Coumarin Bitters Contraindications: Psoralens ❑ Patients with high blood pressure or a history of liver problems are at risk of inflammation and irreparable damage to both liver and skin. ❑ The eyes must be protected from UVB radiation.  Non-Terpenoid Class-Coumarin Bitters Side effects: Psoralens ❑ Nausea. ❑ Headaches. ❑ Dizziness. ❑ Insomnia (in rare cases). ❑ Skin burning. ❑ Increased risk of squamous cell carcinoma. A prospective study of 1380 patients over 5 years revealed an approximately nine-fold increase in risks of squamous cell carcinoma among PUVA treated patients. 61