476-28-8

Usage

Uses

Used in Pharmaceutical Industry:
Lycorine is used as an analgesic for its pain-relieving properties, which are more potent than aspirin. Its analgesic activity is attributed to its resemblance to the morphine and codeine skeletons.
Used in Cardiovascular Applications:
Lycorine is used as a hypotensive agent, helping to lower blood pressure. It also exhibits antiarrhythmic action and has a relaxant effect on an isolated epinephrine-precontracted pulmonary artery, while increasing contractility and the rate of an isolated perfused heart. These effects are mediated by stimulation of b-adrenergic receptors.
Used in Antimicrobial Applications:
Lycorine is used for its antifungal activity against Candida albicans and has a strong inhibitory effect on parasite (Encephalitozoon intestinalis) development.
Used in Other Therapeutic Applications:
Lycorine possesses antifeedant, antimalarial, emetic, anti-inflammatory, antiplatelet, and antifertility activities, making it a versatile compound for various therapeutic purposes.

History

In 1895, Morishima successfully extracted lycorine from the bulb of Lycoris radiata. However, its structure was unidentified until in 1935. In 1959, its stereochemical structure was dissected by monocrystal.The solvent extraction method, chromatographic separation, and resin absorption are commonly used for lycorine extraction. However, lycorine obtained from these techniques is not pure enough and often mixed with other alkaloids. The great differences in the efficacies of different alkaloids prevent such blending from being directly used. Furthermore, the separation and purification process so required has an adverse effect on and limits the development and utilization of the medicinal value of lycorine.

Indications

Injection: 25?mg/ml, for resistance to amebic protozoa and treatment of intraintestinal/extraintestinal amebiasis. Subcutaneous injection: 25–50? mg/injection and 50?mg/day.

Pharmacology

Great progress has been made in exploration of the pharmacological activities and mechanisms of lycorine and its derivatives in recent years.1. Effect on Central Nervous System Lycorine can accelerate the mice’s conditioned reflex of motor and defense nature. A mouse intraperitoneally injected with lycorine at 2?mg/kg and a rabbit intramuscularly injected with lycorine at 12 or 20?mg/kg are exposed to a good sedative effect. For a mouse and a rat injected with lycorine at 12?mg/kg and 15? mg/kg, respectively, the sleep time of hexobarbital sodium, pentobarbital sodium, and miltown is extended. According to the hot plate test, the analgesic actions of morphine and rhizoma corydalis are better in a mouse intraperitoneally injected with lycorine at 12?mg/kg.2. Effect on Cardiovascular System Intravenous injection of lycorine results in a slight antihypertensive effect in anesthetized dog, cat, and rabbit, while no inhibitory effect is observed in isolated heart of toad.3. Anti-inflammatory Effect The lycorine may stimulate the pituitary gland-adrenocortical function, which is possibly relevant to its anti-inflammatory action. Intravenous or subcutaneous injection of lycorine at 3? mg/kg significantly inhibits formaldehyde-induced (rabbit) and albumen-induced (rat) foot swelling. Its inhibitory effect on albumeninduced foot swelling in rat was abolished when adrenal gland was removed.4. Effect on Smooth Muscle Lycorine can excite the isolated uteri of guinea pig and rabbit, which is free from the counteraction by diphenhydramine. The isolated uterus of rat is excited by a small dose of lycorin but inhibited by a large dose. This effect is relevant to the inhibition by lycorine on cholinesterase.5. Emetic Effect Lycorine has a good emetic action. The incubation period for emesis is similar to that of ipecine and longer than that of apomorphine, with low toxicity reported. Therefore, it is sometimes used as the emetic for food poisoning.6. Antitumor Effect According to the in?vivo experiment, lycorine can inhibit the anaerobic glycolysis of the ascites tumor cells of mice but has no effect on their respiration and aerobic glycolysis. The in?vitro test indicates that, however, lycorine can lead to a significant inhibition on the aerobic glycolysis of tumor cells but little effect on their respiration and anaerobic glycolysis. Lycorine is capable of inhibiting adenosine triphosphatase, which is possibly relevant to its cytotoxicity.7. Antiparasitic and anti-malaria effect Dihydrolycorine is better than ipecine in terms of the counteraction against amebic dysentery, with lower toxicity. Thus, it has the potentiality to be a better drug against amebic dysentery. Not only that, dihydrolycorine can be used against paragonimiasis as well.8. Other Effects Upon the subcutaneous injection of a small amount of lycorine, the blood glucose is observed to be reduced slightly in the target rabbit or rat, with the epinephrine-induced hyperglycemia in the rat relieved. A large amount, however, can only result in a significant rise of blood. Lycorine, similar to SKF-525A, can inhibit drug metabolism to a weak extent. The amebic protozoa can be killed by lycorine. A rat intraperitoneally injected with lycorine at 6?mg/kg has more uric acid excreted.

Clinical Use

Dihydrolycorine, generated through the hydrogenation of lycorine, has been used clinically due to its better resistance against amebic dysentery and lower toxicity. The amine salt made of lycorine has an antitumor effect in animals.Lycorine exposure may cause skin irritation (red and swollen) and itching. Nosebleed may be induced in case of inhalation. In case of overdose, it may cause salivation, emesis, diarrhea, bradycardia, cold hands/feet, or even death due to respiratory center paralysis. The major studies of clinical application are focused on (1) antitumor effect, (2) effect on the central nervous system, (3) effect on the cardiovascular system, (4) anti-inflammatory effect, (5) effect on smooth muscle, and (6) emetic effect.

Purification Methods

It crystallises as orange crystals from MeOH (m 281-283o), CHCl3/EtOH (m 272-274o), pyridine or from EtOH (m 277o, dec). It has been distilled under high vacuum. The hydrochloride has m 288o (from MeOH/HCl), and the picrate has m 196-197o(from EtOH), [Cook et al. J Chem Soc 4176 1954, Martin & Tu J Org Chem 46 3763 1981, Beilstein 27 II 547, 27 III/IV 6463.]

InChI:InChI=1/C16H17NO4/c18-11-3-8-1-2-17-6-9-4-12-13(21-7-20-12)5-10(9)14(15(8)17)16(11)19/h3-5,11,14-16,18-19H,1-2,6-7H2/t11-,14-,15+,16+/m0/s1

Upstream product

• 7344-73-2 1-O-acetyllycorine 
• 2188-68-3 (1S,2S,12bS,12cS)-1,2-diol-2,4,5,7,12b,12c-hexahydro-1H-[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridine hydrochloride 
• 7154-01-0 3-(3,4-methylenedioxyphenyl)-1,2-propanediol 
• 94-59-7 1-allyl-3,4-methylenedioxybenzene 
• 70175-74-5 2,2-dimethyl-4-(3,4-methylenedioxybenzyl)dioxolane 
• 57134-53-9 3,4-methylenedioxyphenylethyne 
• 1618099-57-2 (E)-2-(2-(benzo[d][1,3]dioxol-5-yl)vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 
• 2373-80-0 3,4-methylenedioxy-trans-cinnamic acid 
• 136612-46-9 (4aR*,8R*,8aR*)-8-(3',4'-methylenedioxyphenyl)-3,4,4a,7,8a-hexahydroisocoumarin 
• 136612-44-7 (3aS*,4R*,5R*,6S*,7S*,7aS*)-5,6-dihydroxy-7-(3',4'-methylenedioxyphenyl)-4-phenylselanyl-3a,4,5,6,7,7a-hexahydroindolin-2-one 

Downstream Products

• 97438-92-1 ungeremine 
• 98604-27-4 1-hydroxy-4,5-dihydro-[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridinylium; chloride 
• 2121-16-6 ungeremine hydrochloride 
• 477-12-3 2-deoxylycorine 
• 481-58-3 (12bS,12cS)-2,4,5,7,12b,12c-hexahydro-1H-[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridine 
• 15324-61-5 (1aR,2a¹S,11bS,11cS)-2a¹,3,4,6,11b,11c-hexahydro-1aH-[1,3]dioxolo[4,5-j]oxireno[2,3-a]pyrrolo-[3,2,1-de]phenanthridine 
• 641-89-4 anhydrolycorine 
• 40360-71-2 anhydrolycorine-7-one 
• 74555-92-3 (1S,2S,12bS,12cS)-1-Ol-2-chloro-2,4,5,7,12b,12c-hexahydro-1H-[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridine 
• 2030-55-9 dihydrolycorine 
• 1308667-09-5 (1S,2S,3a⁽¹⁾S,12bS)-1-hydroxy-2,3a⁽¹⁾,4,5,7,12b-hexahydro-1H-[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridine-1,2-diyl bis(2,3-dimethylbenzoate) 
• 1308667-12-0 (1S,2S,3a⁽¹⁾S,12bS)-1-hydroxy-2,3a⁽¹⁾,4,5,7,12b-hexahydro-1H-[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridine-1,2-diyl bis(3-chlorobenzoate) 
• 1308667-11-9 (1S,2S,3a⁽¹⁾S,12bS)-1-hydroxy-2,3a⁽¹⁾,4,5,7,12b-hexahydro-1H-[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridine-1,2-diyl bis(2-chlorobenzoate) 
• 1308667-08-4 (1S,2S,3a⁽¹⁾S,12bS)-1-hydroxy-2,3a⁽¹⁾,4,5,7,12b-hexahydro-1H-[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridine-1,2-diyl bis(2-methylbenzoate) 

Relevant academic research and scientific papers

Preparation of Structurally Diverse Compounds from the Natural Product Lycorine

The synthesis of a 52-member compound collection from the natural product lycorine is reported, highlighted by divergent cross-coupling and substitution strategies and an unusual ring rearrangement induced by reaction with aryne intermediates.

Total synthesis of (±)-Lycorine from the endo -cycloadduct of 3,5-dibromo-2-pyrone and (E)-β-borylstyrene

A new synthetic route to (±)-lycorine, starting from the endo-cycloadduct of 3,5-dibromo-2-pyrone and (E)-β-borylstyrene, is reported. Boronate oxidation and a set of reactions including face-selective epoxidation provided the pivotal C1-OH group and C3/C3a double bond.

Potential intermediate, (±)-di-o-acetyl-3α-phenylselanyl-3,3a-dihydro-B-nor-6,7a- secolycorin-5-one for synthesis of the Amaryllidaceae alkaloid lycorine: Formal and total syntheses of (±)-lycorine

Formal and total syntheses of the Amaryllidaceae alkaloid, (±)-lycorine 1, were achieved by new synthetic routes via (±)-di-o-acetyl-3α-phenylselanyl-3,3a-dihydro-B-nor-6,7a- secolycorin-5-one 32. Namely, stereoselective intramolecular Diels-Alder reaction of triene ester 5 afforded, in good yield, the cis-lactone 6, which was converted into β(stereochemical)-hydroxy-γ-lactam 23. Oxidation of silyl ether 24 with m-chloroperbenzoic acid gave only β-(tert-butyldimethylsiloxy)-α-epoxide 25, the stereostructure of which was determined by its X-ray crystallographic analysis. Payne rearrangement of compound 25 and successive acetylation furnished α(stereochemical)-acetoxy-β(stereochemical)-epoxy γ-lactam 29, which was transformed into (±)-lycorine 1 by construction of the B ring. Formal total synthesis of (±)-lycorine 1 is also described.

A New and Stereoselective Synthetic Route to an Amaryllidaceae Alkaloid, (+/-)-Lycorine

Formal and total syntheses of an Amaryllidaceae alkaloid, (+/-)-lycorine, were achieved by a new synthetic route via (+/-)-3-(phenylseleno)-seco-dihydro-B-norlycorin-5-one.

Phosphatidylpyrrolophenanthridine Alkaloids from Zephyranthes Flava

Four new alkaloidal phospholipids, 2-O-glycerophosphoryllycorine, phosphatidyllycorines, phosphatidylpseudolycorines and phosphatidyllycorinium methocation, were isolated from the flowers of Zephyranthes flava.The structures of these compounds were established by comprehensive spectral analyses, chemical transformations and synthesis, where possible.The biological profile of this novel group of alkaloidal conjugates is appraised.Key Word Index - Zephyranthes flava; Amaryllidaceae; flowers; phosphatidylpyrrolophenanthridines; 2-O-glycerophosphoryllycorine, phosphatidyllycorines, phosphatidylpseudolycorines, phosphatidyllycorinium methocation; biological activity.

Stereoselective Transformation of the Alkaloid Lycorine to O-Demethylungiminorine and Ungiminorine

Diacetyllycorine, an Amaryllidaceae alkaloid, was transformed stereoselectively to the more heavily oxygenated congener, O-demethylungiminorine, by a route similar to that suggested for the biosynthesis of narcissidine.Similarly, acetylhippamine was converted to ungiminorine.A method of high yield conversion of lycorine to hippamine is also described. - The above transformations constitute a formal total synthesis of ungiminorine.Keywords--- Amaryllidaceae alkaloid; lycorine; hippamine; ungiminorine; O-demethylungiminorine; lycorine-chlorohydrin; permanganate oxidation; phosphoryl chloride; stereoselective hydroxylation; distorted boat conformation

A MODIFIED TOTAL SYNTHESIS OF (+/-)-LYCORINE

A modified total synthesis of lycorine was accomplished starting from the lactam-ester (5).Selective reduction of the lactam carbonyl of 5, followed by cyclization gave 5-oxolycorene (4).Epoxidation of 4 gave stereoselectively the α-epoxide (9).Repeated application of Sharpless method to convert epoxide into allylic alkohol and acetylation of the product gave diacetyl 5-oxolycorine (19).Lithium aluminium hydride reduction of 19 gave (+/-)-lycorine.