Carpaine
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Carpaine is the major
piperidine alkaloid Piperidine alkaloids are naturally occurring chemical compounds from the group of alkaloids, which are chemically derived from piperidine. Alkaloids with a piperidine building block are widespread and are usually further subdivided according to ...
component of
papaya The papaya (, ), papaw, () or pawpaw () is the plant species ''Carica papaya'', one of the 21 accepted species in the genus '' Carica'' of the family Caricaceae, and also the name of its fruit. It was first domesticated in Mesoamerica, within ...
leaves which has been studied for potential medicinal effects. Carpaine extracted from Carica papaya trees has been reported to have diverse biological properties, such as
anti-malarial Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young c ...
,
anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation, fever or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs reduce pain by inhibiting mechan ...
,
anti-oxidant Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants are frequently added to industrial products, s ...
, and
vasodilatory Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel wal ...
effects. Especially, Carpaine possessed significant anti-
plasmodial A plasmodium is a living structure of cytoplasm that contains many nuclei, rather than being divided into individual cells each with a single nucleus. Plasmodia are best known from slime molds, but are also found in parasitic Myxosporea, and so ...
activity ''in vitro'' (IC50 of 0.2 μM) and high selectivity towards the parasites. Circulatory effects of carpaine were studied in Wistar male rats weighing 314 +/- 13 g, under
pentobarbital Pentobarbital (US) or pentobarbitone (British and Australian) is a short-acting barbiturate typically used as a sedative, a preanesthetic, and to control convulsions in emergencies. It can also be used for short-term treatment of insomnia but ...
(30 mg/kg) anesthesia. Increasing dosages of carpaine from 0.5 mg/kg to 2.0 mg/kg resulted in progressive decrease in
systolic Systolic is an adjective describing something pertaining to a systole, part of the cardiac cycle. Systolic may also refer to: Physiology and medical *Systolic hypertension *Systolic heart murmur Mathematics *Systolic geometry Technology *Systoli ...
,
diastolic Diastole ( ) is the relaxed phase of the cardiac cycle when the chambers of the heart are refilling with blood. The contrasting phase is systole when the heart chambers are contracting. Atrial diastole is the relaxing of the atria, and ventricul ...
, and mean arterial blood pressure. Selective autonomic nervous blockade with
atropine Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. It is typically give ...
sulfate (1 mg/kg) or
propranolol Propranolol is a medication of the beta blocker class. It is used to treat hypertension, high blood pressure, some types of cardiac dysrhythmia, irregular heart rate, thyrotoxicosis, capillary hemangiomas, akathisia, performance anxiety, and ...
hydrochloride (8 mg/kg) did not alter the circulatory response to carpaine. Carpaine, 2 mg/kg, reduced
cardiac output In cardiac physiology, cardiac output (CO), also known as heart output and often denoted by the symbols Q, \dot Q, or \dot Q_ , edited by Catherine E. Williamson, Phillip Bennett is the volumetric flow rate of the heart's pumping output: tha ...
, stroke volume, stroke work, and cardiac power, but the calculated total peripheral resistance remained unchanged. It is concluded from these results that carpaine affects the myocardium directly. The effects of carpaine may be related to its
macrocyclic Macrocycles are often described as molecules and ions containing a ring of twelve or more atoms. Classical examples include the crown ethers, calixarenes, porphyrins, and cyclodextrins. Macrocycles describe a large, mature area of chemistry. ...
dilactone Lactones are cyclic carboxylic esters. They are derived from the corresponding hydroxycarboxylic acids by esterification. They can be saturated or unsaturated. Lactones are formed by lactonization, the intramolecular esterification of the corresp ...
structure, a possible
cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
chelating Chelation () is a type of bonding of ions and their molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These l ...
structure.


History

After the first isolation of Carpaine by Greshoff in 1890,
Merck & Company Merck & Co., Inc. is an American multinational pharmaceutical company headquartered in Rahway, New Jersey. The company does business as Merck Sharp & Dohme or MSD outside the United States and Canada. It is one of the largest pharmaceutical com ...
assigned the
empirical formula In chemistry, the empirical formula of a chemical compound is the simplest whole number ratio of atoms present in a compound. A simple example of this concept is that the empirical formula of sulfur monoxide, or SO, is simply SO, as is the empir ...
to it, which was soon corrected to by van Rijn. In 1930s, Barger and his collogues investigated various degradation products of Carpaine and was able to obtain a series of chemical structures of Carpaine. Then in 1953, Rapoport and his collogues at the
University of California The University of California (UC) is a public university, public Land-grant university, land-grant research university, research university system in the U.S. state of California. Headquartered in Oakland, California, Oakland, the system is co ...
obtained a new form of Carpaine chemical structure which they found the nitrogen-containing ring had a
piperidine Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless liquid with an odor de ...
structure instead of the
pyrrolidine Pyrrolidine, also known as tetrahydropyrrole, is an organic compound with the molecular formula (CH2)4NH. It is a cyclic secondary amine, also classified as a saturated heterocycle. It is a colourless liquid that is miscible with water and most ...
as previously thought; they also located the position of the
lactone Lactones are cyclic carboxylic esters. They are derived from the corresponding hydroxycarboxylic acids by esterification. They can be saturated or unsaturated. Lactones are formed by lactonization, the intramolecular esterification of the corresp ...
ring between atoms numbered 3 and 6 on the piperidine nucleus. Later work from Govindachari & Narasimhan and Tichy and Sicher further confirmed this
structural formula The structural formula of a chemical compound is a graphic representation of the molecular structure (determined by structural chemistry methods), showing how the atoms are connected to one another. The chemical bonding within the molecule is al ...
. However, Spiteller-Friedmann and Spiteller used
Mass Spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is used ...
to discover that the molecular weight of Carpaine is closer to 478 g/mol, which is represented by twice of the original empirical formula. The new finding proved that Carpaine consists of two identical halves, which form a 26-membered cyclic
diester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distinc ...
, or
dilactone Lactones are cyclic carboxylic esters. They are derived from the corresponding hydroxycarboxylic acids by esterification. They can be saturated or unsaturated. Lactones are formed by lactonization, the intramolecular esterification of the corresp ...
, with an empirical formula of , and the configuration was finally determined by Coke and Rice in 1965.


Isolation of Carpaine

Carpaine occurs in papaya leaves in concentrations as high as 0.4%, which is enough to make it available commercially at very reasonable costs. One possible extraction route was accomplished first drying the leaves in an electric blast drying oven and milled to fine powder. The powdered plant material were macerated with a mixed solution of ethanol/water/ for 24 hrs at room temperature. Then the extract was dissolved in water/ mixture, filtered, and extracted with
petroleum ether Petroleum ether is the petroleum fraction consisting of aliphatic hydrocarbons and boiling in the range 35–60 °C, and commonly used as a laboratory solvent. Despite the name, petroleum ether is not an ether; the term is used only figurativ ...
to remove fat materials. The acid fraction was adjusted to pH 8.0 ~ 9.0 using solution and extracted with
chloroform Chloroform, or trichloromethane (often abbreviated as TCM), is an organochloride with the formula and a common solvent. It is a volatile, colorless, sweet-smelling, dense liquid produced on a large scale as a precursor to refrigerants and po ...
. Finally, the chloroform fractions were pooled and evaporated and the whole operation was repeated again so the crude alkaloid Carpaine was obtained. Another extraction route reported that mechanical blending of the leaves prior to extraction significantly enhances the yield of Carpaine. After blending the leaves with water and freeze-dried, the samples were soaked in ethanol. This mixture was then concentrated and purified using an acid-base method followed by chloroform extraction to isolate the Carpaine. Finally, the purity and structure were analyzed using
NMR Nuclear magnetic resonance (NMR) is a physical phenomenon in which atomic nucleus, nuclei in a strong constant magnetic field are disturbed by a weak oscillating magnetic field (in the near and far field, near field) and respond by producing ...
and LC-MS.


Potential Medical Uses


Dengue Fever Treatment

Recent research highlights the possible efficacy of Carpaine in managing the symptoms and severe complications associated with dengue fever. Carpaine in papaya leaves extract is the major active compounds that contributes to the anti-
thrombocytopenic In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets (also known as thrombocytes) in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coa ...
activity (raising the platelet counts in patient's blood). For example, a treatment used for a 45-year-old male patient in Pakistan diagonosed with dengue fever involved administering 25mL of the extracted Carpaine twice daily for five consecutive days. The treatment showed significant improvement in hematological parameters, a substantial increase in platelet and blood cell counts and
neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...
levels.


Cardioprotective Effects

In the setting of
ischemia-reperfusion injury Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is the tissue damage caused when blood supply returns to tissue ('' re-'' + ''perfusion'') after a period of ischemia or lack of oxygen (anoxia or hy ...
(IRI), studies have shown Carpaine provided significant protection to recover the wounded area affected by the
hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscosity, viscous than Properties of water, water. It is used as an oxidizer, bleaching agent, and antiseptic, usua ...
treatment by activating key pathway that promotes cell cycle progression and prevents cell death during stressful condition. Furthermore, Carpaine treatment further demonstrates its cardioprotective effects by improving mitochondrial
membrane potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. It equals the interior potential minus the exterior potential. This is th ...
and reducing the overproduction of
reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
.


Anti-inflammatory Properties

Studies have shown Carpaine’s ability to modulate the body’s inflammatory response by inhibiting the production of pro-inflammatory
cytokines Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
, such as tumor
necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologist Rudolf Virchow, who i ...
factor-alpha (TNF-α) and
interleukin-6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smoo ...
(IL-6), which would be beneficial in treating chronic disease, including
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...
,
asthma Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...
, etc.{{cite journal , last1=Sharma , first1=Anshu , last2=Sharma , first2=Ruchi , last3=Sharma , first3=Munisha , last4=Kumar , first4=Manoj , last5=Barbhai , first5=Mrunal Deepak , last6=Lorenzo , first6=José M. , last7=Sharma , first7=Somesh , last8=Samota , first8=Mahesh Kumar , last9=Atanassova , first9=Maria , last10=Caruso , first10=Gianluca , last11=Naushad , first11=Mo. , last12=Chandran , first12=Deepak , last13=Prakash , first13=Pramod , last14=Hasan , first14=Muzaffar , last15=Rais , first15=Nadeem , last16=Dey , first16=Abhijit , last17=Mahato , first17=Dipendra Kumar , last18=Dhumal , first18=Sangram , last19=Singh , first19=Surinder , last20=Senapathy , first20=Marisennayya , last21=Rajalingam , first21=Sureshkumar , last22=Visvanathan , first22=Marthandan , last23=Saleena , first23=Lejaniya Abdul Kalam , last24=Mekhemar , first24=Mohamed , title=Carica papaya L. Leaves: Deciphering Its Antioxidant Bioactives, Biological Activities, Innovative Products, and Safety Aspects , journal=Oxidative Medicine and Cellular Longevity , date=9 June 2022 , volume=2022 , pages=1–20 , doi=10.1155/2022/2451733, doi-access=free , pmid=35720184 , pmc=9203216


Anti-oxidant Properties

The enhanced anti-oxidant activity in papaya leaves demonstrated in studies is due to the high concentration of
polyphenols Polyphenols () are a large family of naturally occurring phenols. They are abundant in plants and structurally diverse. Polyphenols include phenolic acids, flavonoids, tannic acid, and ellagitannin, some of which have been used historically as ...
, which are known for their strong anti-oxidant properties for combatting
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
in the body, that can lead to cellular damage and various chronic diseases. The anti-oxidant capacity was measured using the
DPPH DPPH is a common abbreviation for the organic chemical compound 2,2-diphenyl-1-picrylhydrazyl. It is a dark-colored crystalline powder composed of stable Radical (chemistry), free radical molecules. DPPH has two major applications, both in laborat ...
(1,1-diphenyl-2-picrylhydrazyl) assay, where blended young papaya leaves exhibited significantly lower IC50 values (IC50 = 293 μg/mL per 100 mg) with a stronger anti-oxidant
potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of ho ...
than old leaves (IC50 = 382 μg/mL per 100 mg).


References

Lactones Piperidine alkaloids Macrocycles Heterocyclic compounds with 3 rings Nitrogen heterocycles Oxygen heterocycles