Carpaine: Difference between revisions

| Verifiedfields = changed

| verifiedrevid = 399708506

| Name = Carpaine

| Reference =<ref>''Merck Index'', 11th Edition, '''1866'''.</ref>

| ImageFile = Carpaine.png

| ImageAlt = Skeletal formula of carpaine

| ImageFile1 = Carpaine 3D ball.png

| ImageAlt1 = Ball-and-stick model of the carpaine molecule

| IUPACName =<small>(''1S,11R,13S,14S,24R,26S'')-13,26-Dimethyl-2,15-dioxa-<wbr />12,25-diazatricyclo[22.2.2.211,14]triacontane-3,16-dione</small>

| OtherNames = (+)-Carpaine

|Section1={{Chembox Identifiers

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 3433

| CASNo_Ref = {{cascite|correct|??}}

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = VLR223H4QP

| SMILES = O=C3O[C@H]1CC[C@H](N[C@H]1C)CCCCCCCC(=O)O[C@@H]2[C@@H](N[C@@H](CC2)CCCCCCC3)C

|Section2={{Chembox Properties

| Formula = C₂₈H₅₀N₂O₄

| MolarMass = 478.70 g/mol

| MeltingPt = 121 °C

'''Carpaine''' is one of the major [[alkaloid]] components of [[papaya]] leaves which has been studied for its [[cardiovascular]] effects.<ref name = "NICE">{{cite journal |last1=Burdick |first1=Everette M. |title=Carpaine: An alkaloid of Carica papaya—its chemistry and pharmacology |journal=Economic Botany |date=December 1971 |volume=25 |issue=4 |pages=363–365 |doi=10.1007/BF02985202}}</ref> Carpaine extracted from Carica papaya trees has been reported to have diverse biological properties, such as [[anti-malarial]], [[anti-inflammatory]], [[anti-oxidant]], and [[vasodilatory]] effects.<ref>{{cite journal |last1=Sudi |first1=Suhaini |last2=Chin |first2=Yee-Zheng |last3=Wasli |first3=Nur Syafinaz |last4=Fong |first4=Siat-Yee |last5=Shimmi |first5=Sadia Choudhury |last6=How |first6=Siew-Eng |last7=Sunggip |first7=Caroline |title=Carpaine Promotes Proliferation and Repair of H9c2 Cardiomyocytes after Oxidative Insults |journal=Pharmaceuticals |date=15 February 2022 |volume=15 |issue=2 |pages=230 |doi=10.3390/ph15020230|doi-access=free |pmid=35215343 |pmc=8880139 }}{{Creative Commons text attribution notice|cc=by4|from this source=yes}}</ref> Especially, Carpaine possessed significant anti-[[plasmodium|plasmodial]] activity ''in vitro'' (IC₅₀ of 0.2 μM) and high selectivity towards the parasites.<ref>{{cite journal |last1=Julianti |first1=Tasqiah |last2=Oufir |first2=Mouhssin |last3=Hamburger |first3=Matthias |title=Quantification of the Antiplasmodial Alkaloid Carpaine in Papaya (Carica papaya) Leaves |journal=Planta Medica |date=25 August 2014 |volume=80 |issue=13 |pages=1138–1142 |doi=10.1055/s-0034-1382948|pmid=25153096 }}</ref>

Circulatory effects of carpaine were studied in Wistar male rats weighing 314 +/- 13 g, under [[pentobarbital]] (30&nbsp;mg/kg) anesthesia.<ref>Hornick, C. A.; Sanders, L. I.; Lin, Y. C. "Effect of carpaine, a papaya alkaloid, on the circulatory function in the rat." ''Research Communications in Chemical Pathology and Pharmacology'' (1978), 22(2), 277-289.</ref> Increasing dosages of carpaine from 0.5&nbsp;mg/kg to 2.0&nbsp;mg/kg resulted in progressive decrease in [[Systole|systolic]], [[diastolic]], and mean arterial blood pressure. Selective autonomic nervous blockade with [[atropine]] sulfate (1&nbsp;mg/kg) or [[propranolol]] hydrochloride (8&nbsp;mg/kg) did not alter the circulatory response to carpaine. Carpaine, 2&nbsp;mg/kg, reduced cardiac output, 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 [[macrocycle|macrocyclic]] [[lactone|dilactone]] structure, a possible [[cation]] [[chelation|chelating]] structure.

== History ==

After the first isolation of Carpaine by Greshoff in 1890, [[Merck & Co.|Merck & Company]] assigned the [[empirical formula]] {{chem2|C14H27NO2}} to it, which was soon corrected to {{chem2|C14H25NO2}} by van Rijn.<ref name = "NICE"/> In 1930s, Barger and his collogues investigated various degradation products of Carpaine and was able to obtain a series of chemical structures of Carpaine.<ref>{{cite journal |last1=Barger |first1=G. |last2=Robinson |first2=Robert |last3=Urushibara |first3=Y. |title=141. Synthetical experiments relating to carpaine. Part I. Synthesis of a basic long-chain lactone |journal=Journal of the Chemical Society (Resumed) |date=1937 |pages=714 |doi=10.1039/JR9370000714}}</ref>

[[File:Structures of Carpaine over the years.png|thumb|The development of Carpaine structures over the years|380px|left]]

Then in 1953, Rapoport and his collogues at the [[University of California]] obtained a new form of Carpaine chemical structure which they found the nitrogen-containing ring had a [[piperidine]] structure instead of the [[pyrrolidine]] as previously thought; they also located the position of the [[lactone]] 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.<ref name = "NICE"/>

However, Spiteller-Friedmann and Spiteller used [[Mass Spectrometry]] to discover that the molecular weight of Carpaine is closer to 478 g/mol, which is represented by twice of the original empirical formula.<ref name = "NICE" /> The new finding proved that Carpaine consists of two identical halves, which form a 26-membered cyclic [[diester]], or [[dilactone]], with an empirical formula of {{chem2|C28H50N2O4}}, and the configuration was finally determined by Coke and Rice in 1965.<ref name = "NICE"/>

== 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.<ref name = "NICE" />

One possible extraction rout 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/{{chem2|[[HCl]]}} for 24 hrs at room temperature. Then the extract was dissolved in water/{{chem2|HCl}} mixture, filtered, and extracted with [[petroleum ether]] to remove fat materials. The acid fraction was adjusted to pH 8.0 ~ 9.0 using {{chem2|[[NH4OH]]}} solution and extracted with [[chloroform]]. Finally, the chloroform fractions were pooled and evaporated and the whole operation was repeated again so the crude alkaloid Carpaine was obtained.<ref>{{cite journal|journal=International Journal of Food Properties|title=Isolation and Identification Carpaine in Carica papaya L. Leaf by HPLC-UV Method|date=2015 |doi=10.1080/10942912.2014.900785 |url=https://www.tandfonline.com/doi/full/10.1080/10942912.2014.900785 |last1=Wang |first1=Xiuyi |last2=Hu |first2=Changying |last3=Ai |first3=Qian |last4=Chen |first4=Yanfen |last5=Wang |first5=Zhiwei |last6=Ou |first6=Shiyi |volume=18 |issue=7 |pages=1505–1512 }}</ref>

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]] and [[LC-MS]].<ref name = "YES">{{cite journal |last1=Yap |first1=Jing Ying |last2=Hii |first2=Ching Lik |last3=Ong |first3=Sze Pheng |last4=Lim |first4=Kuan Hon |last5=Abas |first5=Faridah |last6=Pin |first6=Kar Yong |title=Quantification of Carpaine and Antioxidant Properties of Extracts from Carica Papaya Plant Leaves and Stalks |journal=Journal of Bioresources and Bioproducts |date=November 2021 |volume=6 |issue=4 |pages=350–358 |doi=10.1016/j.jobab.2021.03.002|doi-access=free }}</ref>

== 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]] 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]] levels.<ref name = "YES"/>

===Cardioprotective Effects===

In the setting of [[ischemia-reperfusion injury]] (IRI), studies have shown Carpaine provided significant protection to recover the wounded area affected by the [[hydrogen peroxide]] 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]] and reducing the overproduction of reactive oxygen species.<ref>{{cite journal |last1=Sudi |first1=Suhaini |last2=Chin |first2=Yee-Zheng |last3=Wasli |first3=Nur Syafinaz |last4=Fong |first4=Siat-Yee |last5=Shimmi |first5=Sadia Choudhury |last6=How |first6=Siew-Eng |last7=Sunggip |first7=Caroline |title=Carpaine Promotes Proliferation and Repair of H9c2 Cardiomyocytes after Oxidative Insults |journal=Pharmaceuticals |date=15 February 2022 |volume=15 |issue=2 |pages=230 |doi=10.3390/ph15020230|doi-access=free |pmid=35215343 |pmc=8880139 }}</ref>

===Anti-inflammatory Properties===

Studies have shown Carpaine’s ability to modulate the body’s inflammatory response by inhibiting the production of pro-inflammatory [[cytokines]], such as tumor [[necrosis]] factor-alpha (TNF-α) and [[interleukin-6]] (IL-6), which would be beneficial in treating chronic disease, including [[rheumatoid arthritis]], [[asthma]], etc.<ref>{{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 }}</ref>

===Anti-oxidant Properties===

The enhanced anti-oxidant activity in papaya leaves demonstrated in studies is due to the high concentration of [[polyphenols]], which are known for their strong anti-oxidant properties for combatting [[oxidative stress]] in the body, that can lead to cellular damage and various chronic diseases. The anti-oxidant capacity was measured using the [[DPPH]] (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 (pharmacology)|potency]] than old leaves (IC₅₀ = 382 μg/mL per 100 mg). <ref name ="YES" />

== References ==

[[Category:Piperidine alkaloids]]