ETHNO PHARMACOLOGICAL AND PHYTO PHARMACOLOGICAL PERCEPTION ON KALANCHOE (CRASSULACEAE) – A COMPREHENSIVE REVIEW

ETHNO PHARMACOLOGICAL AND PHYTO PHARMACOLOGICAL PERCEPTION ON KALANCHOE (CRASSULACEAE) - A COMPREHENSIVE REVIEW

Selvakumari *, R. Muthukumaran, S. Atchaya, S. Kowsalya and N. Elavarasan

Department of Pharmacognosy, College of Pharmacy, Mother Theresa Post Graduate & Research Institute of Health Sciences, Indira Nagar, Gorimedu, Priyadarshini Nagar, Puducherry, India.

ABSTRACT: Natural molecules from plants are vital sources to explore potent lead molecules in the drug discovery process. Plants as A source of medicine is an ancient practice in India. The Indian subcontinent is a wide repository of medicinal plants that are being used in the traditional system of medicines. Kalanchoe is one of the medicinal plants; the succulent leaf juice is prepared by grinding the leaves mechanically and is a Tyler-made medicine being prescribed by traditional practitioners to combat various diseases and disorders. Various species of Kalanchoe find an important place in traditional medicine across the globe. This review article is a systematic compilation of recent updates on the worldwide ethnopharmacological uses and phytomolecules as therapeutic markers, pharmacological profiles, pharmacokinetic studies and SAR of bufadienolides from varied species of Kalanchoe. The systematic compilation of review articles will direct the scientific community to focus their research by doing further molecular and targeted throughput screening of the lead molecules from Kalanchoe, results in drug discovery from the potent herbal plant Kalanchoe. In addition, the unveiled tylor made medicine from ethnic herb Kalanchoe is substantiated by the scientific studies gives the scientific validation of folklore claims of Kalanchoe.

Keywords: Kalanchoe, Ethnopharmacological uses, Phytomolecules, Therapuetic markers, Pharmacokinetic studies, SAR of Bufadienolides

INTRODUCTION: Indian subcontinent is a wide repository of medicinal plants that are used in the traditional system of medicines. Plants as a source of medicine is an ancient practice in India. About 70 percent of the rural population in India depends on native medicinal plants ¹. Exploring the potential traditional herbs is the need of the hour for modern drug discovery.

Using the strategies in Reverse pharmacognosy to focus on molecular targets and genomic approaches could give potential leads from herbal medicines. A remarkable example of one such medicinal herb is Taxus baccata and its pharmaceutical phytomolecule Taxol, an antimicrotubule, an antineoplastic or cytotoxic chemotherapy drug in modern medicine.

The site of administration is into the veins as an injection or infusion. Hence exploring the potential lead molecules from the herbs would facilitate the discovery of novel leads from the asset of Indian medicinal plants. One such potential Indian medicinal plant is Kalanchoe belong to the family Crassulaceae. It is need of the hour to compile the updated global ethnopharmacological uses, phytopharmacological studies, including the therapeutic markers, pharmacokinetic studies, and SAR of bufadienolides from Kalanchoe.

In addition, this review article will direct the scientific community to focus their research by doing further.

Molecular and targeted throughput screening of the lead molecules from Kalanchoe results in drug discovery from Indian medicinal plants against various diseases and disorders ².

Taxonomy of Kalanchoe: Crassulaceae comprises approximately 35 genera and 1500 species, and the majority is succulents. It consists of diversified morphology, cytology, and habbit ³. The taxonomical hierarchy of Kalanchoe is as follows, a kingdom: Plantae (Plants), subkingdom: Tracheobionta (Vascular Plants), super division: Spermatophyta (Seed plants), division: Magnoliophyta (flowering plants), class: Magnoliopsida (dicotyledonous), subclass: Roxidae, order: Saxifragales, family: Crassulaceae, genus: Kalanchoe ^{4, 5}.

FIG. 1: HABITAT OF K. GASTONNIS-BONNIERI           

FIG. 2: POTTED K. GASTONNIS-BONNIERI

TABLE 1:  ETHNOMEDICAL USES OF KALANCHOE GLOBALLY

 Ethnomedical Uses of Kalanchoe: In the southern part of India the leaf of Kalanchoe gastonis-bonnieri Fig. 1 & 2, is being consumed in an empty stomach and after half an hour interval, one and half litres of water is to be taken for three days in early morning, results in the expulsion of kidney stone from the urinary tract.  Traditional physicians are practicing this one of the potential traditional medicine to overcome renal calculi and avoid surgery or lithotripsy along with analgesics, which is the only method of choice to combat kidney stones in modern medicine. In addition, the succulent leaf juice is prepared by grinding the leaves mechanically, is a Tyler-made herbal medicine being prescribed by traditional practitioners to combat urolithiasis. Various species of Kalanchoe find an important place in ethnic medicine across the globe ⁶. The worldwide ethnomedical use of Kalanchoe is tabulated in Table 1.

Phytomolecules as Chemotaxonomic Markers of Kalanchoe: Secondary metabolites in plants are predominantly synthesized for defense mechanism. They exhibit specific pharmacological and toxicological effects on animals and humans. At a low dose they possess therapeutic action. The plants synthesizing such potential molecules as its defense mechanisms and exploring the synthesized potential molecules is the basic step of the drug discovery process. The medicinal herbs are used by native or ethnic peoples or in traditional medicine are the reservoir of lead molecules.

In this perspective the reservoir of leads synthesized in the genus Kalanchoe is been collated in this review.

Bufadienolides - Chemotaxonomic marker of Kalanchoe: Kalanchoe reported the presence of varied, complex bufadienolides and flavonoids as the major active constituents ¹³. Bufadienolides are the characteristics chemotaxonomic marker of Kalanchoe as well as Crassulaceae subfamily Kalanchooideae as a whole. Bufadienolides are reported as neurotoxins and acts in defense mechanisms against predators ¹⁴.  The varied, complex structure of bufadienolides reported in Kalanchoe is tabulated in Table 2. Bryophyllin A, B & C, Kalanchoside A, B, C, Kalanhybrin A, B, C, Bersaldeginin 1,3,5- orthoacetate, Bersaldeginin 3- orthoacetate, Bersaldeginin 1 - orthoacetate, Daigremontianin, Methyl daigremonate, Daigredorigenin 3-acetate, Hellibrigenin 3-acetate, 3-0-acetyldaigredorigenin, Lanceotoxin A & B, Kalanchoside, Bryotoxin A, B & C are reported in the species of Kalanchoe viz., K. lanceolata, K. diagremonitana, K. tubiflora, K. diagremonitana x tubiflora, K. pinnata, K. gracilis, K. hybrida, K. lanceolata, K. tomentosa, K. tubiflorum, and Bryophyllum pinnata.

TABLE 2: BUFADIENOLIDES - CHEMOTAXONOMIC MARKER FROM THE GENUS KALANCHOE

S. no.

Constituents

Species & Parts

Chemical Structure

References

1

Hellibrigenin-3- acetate

k. lanceolata - Leaves

15 & 16

2

Bersaldegenin 1,3 5- orthoacetate       Daigremontianin

k. daigremonitana k. tubiflora Leaves k.daigremonitana k. tubiflora k. Daigremontianax tubiflora Leaves

15, 17, 19, 20 & 23

3

Bryophyllin A & C

K. pinnata K. daigremontiana Leaves k. Daigremontianax tubiflora

Bryophyllin A, R= CHO Bryophyllin C, R = CH2OH

19, 23 & 15       20

4

Bryophyllin B

Bryophyllumpinnata Leaves

18

5

Methyl daigremonate               Bersaldegenin-3-orthoacetate Bersaldegenin-1-orthoacetate

K. daigremontiana x tubiflora Leaves

Bersaldegenin-3– acetate, R1 = Ac; R2= H Bersaldegenin-1– acetate, R1 = H; R2= Ac

19 & 15

6

Kalanchoside A, B, C

K. gracilis Aerial parts

15 & 22

R

R1

H

H

H

R2

CH2 Kalanchoside A

CH2 Kalanchoside B

O Kalanchoside C

7

Kalanhybrin A, B, C

K. hybrida Whole plant

21

Kalanhybrin A Kalanhybrin B Kalanhybrin C

R1 H Ac H

R2 Ac H Ac

R3 CHO CHO CH3

8

Daigredorigenin-3-acetate

K. hybrida Whole plant

21

9

3-O-Acetyldaigredorigenin

K. daigremontiana

23

10.

Lanceotoxin A Lanceotoxin B

K. lanceolata

23

R2 Lanceotoxin     Lanceotoxin B

11

Kalanchoside

K. tomentosa

23

12

Bryotoxin A, B & C

K. tubiflorum

Bryotoxin A

23

R1

R2

Bryotoxin B

CH2OH

O

Bryotoxin C

CHO

H2

Flavonoids - Chemotaxonomic Marker of Kalanchoe: Flavonoids are polyphenolic compounds have 15 carbon skeleton contains two phenyl ring (ring A & B) and heterocyclic ring (ring C containing oxygen). Chemically they are C6-C3-C6. Flavonoids are widely distributed in plants. They are plant pigments that attract pollinator animals. Pharmacologically they are well-known free radical scavengers. Kalanchoe reported for the presence of flavonols and flavone as chemotaxonomic markers in the form of flavonoid glycosides. Rhamnoside or Rhamnopyranoside is the sugar molecule as chemotaxonomic markers in the place of primary metabolites attached in the glycone part. Flavonoids glycosides reported in Kalanchoe species are K. spathulata, K. gracilis, K. brasiliensis, K. laciniata, K. pinnata, K. gastonis-bonnieri, K. streptantha, Bryophyllum pinnatum and K. marmorata. Flavonols reported in the above species are Patulein, Quercetin, Quercetin, and flavone molecules reported are Kaempferol, Eupafolin, Luteolin, Kapinnatoside (Kaempferol diglycoside), Afzelin, Rhamnoisorobin, Isorhamnetin, and Kaempferitrin Table 3.

TABLE 3: FLAVONOIDAL MARKER COMPOUNDS FROM THE GENUS KALANCHOE

Pharmacological Studies on Kalanchoe: Various species of Kalanchoe is referenced in folklore and traditional medicine worldwide. Updated pharmacological studies of Kalanchoe using In-vitro & In-vivo screening methods with species names is tabulated in Table 4. Kalanchoe exhibits diversified pharmacological action due to the presence of multifaceted, complex phytomolecules. Kalanchoe exerts action on various non-communicable diseases as well as communicable diseases, based on the scientific studies so far and showed neuropharmacological activity, CNS depressant activity, sedative activity, anticonvulsant activity, cardiovascular activity, cytotoxic and antitumor activity, anti-inflammatory activity, analgesic, wound healing, hepatoprotective activity, immunomodulatory activity, diuretic & urolithiatic activity, antihypertensive activity, antidiabetic activity, muscle relaxant, and uterine relaxant activity, antiallergic activity, acetylcholine esterase inhibitory activity, thyroid peroxidise. Inhibition activity, inhibition of lymphocyte proliferation activity as a pharmacological action on non-communicable diseases and antiviral, antifungal, antibacterial, antileishmanial activity as pharmacological action on communicable diseases including insecticidal activity.

TABLE 4: PHARMACOLOGICAL ACTIVITY OF KALANCHOE

Phytomarkers as Therapeutic Potential of Kalanchoe: Natural bioactive phytomolecules is the important source of drug discovery. Exploring the phytoleads will hit the therapeutic targets against various human diseases and disorders. The pharmacological action is scientifically validated by various in-vitro and in-vivo screening for the lead molecules from Kalanchoe. The phytoleads, along with pharmacological studies, is tabulated in Table 5.

Bufadienolides: Daigremontianin, Bersaldegenin- 1,3,5- orthoacetate (K. daigremontiana x K. tubiflora) exerts sedative and cytotoxic action, Bryophyllin A (IC⁵⁰ = 0.4 mM) more potent, Bryophyllin C, Bersaldegenin-3 acetate (K. pinnata) showed antitumor activity, 3β-Acetate Hellebrigenin, Bufotalinin, 19-Oxo-bufalin, Hellebrigenin, Monohydroxy-bufotalin, 19-oxo-desacetylcinobufagin, 1βHidroxybufalin, Bufalin, and 3-Dehydroxy cinobufagin (K. mortagei) showed cytotoxic and apoptotic activity. Bryophyllin B (K. brasiliensis) showed Cytotoxic activity.

TABLE 5: PHYTOMARKERS OF KALANCHOE AND ITS THERAPEUTIC POTENTIAL

FIG. 3: PDB ID 4RES- STRUCTURE OF NA+/K+-ATPASE

Flavonoids ⁵⁴: Patuletin acetyl rhamnoside (K. brasiliensis) showed inhibiton of lymphocytes proliferation activity, Quercetin, Quercitrin (Potent compound with low toxicity profiles), Afzelin, Quercetin 3-0-α-L- rabinopyranosyl, α-l-rhamnaopyranoside, Quercetin-3-o-α-L- rhamnopyranoside (K. pinnata) showed antileishmanial activity, Quercitrin(K. pinnata) showed antiallergic activity.

Amino Acid Salt: Kalanchosine dimaleate (K. brasiliensis) showed anti-inflammatory activity.

Alkene Compound & Steroid Compound: 1-(3-oxo-olean-12-ene) & β-sitosterol (K. thrysiflora) showed Cytotoxic activity.

Pharmacokinetic and Efficacy Studies:

Metabolism of Quercetin Glycosides From K. Pinnata Against Cutaneous Leishmaniasis: Three flavonoid glycosides present in the aqueous extract (320 mg/kg b/w) of K. pinnata Quercetin 3-O- α-L-arabinopyranosyl (1→2)- α-L-rhamnopyranoside, Quercetin 3-O-α-L-rhamnopyranoside and Quercetin (16 mg/kg body weight/oral daily) significantly reduces the parasite load and controls lesion growth caused by Leishmania amazonensis. The plasma of the treated mice showed quercetin and quercetin glucuronides are the metabolites of flavonoid glycosides from K. pinnata. The pharmacological activity is due to the presence of quercetin glycosides ⁵³.

SAR of Bufadienolides AS Na+/K+-Atpase Inhibitor as an Anticancer Agent – In-silico Studies ⁵⁵: The protein target used for the study is Na+/K+-ATPase originated from Sus scrofa (PDB 1D 4RES).

The binding pose of bufadienolides- Bryophyllin A (1), Bryophyllin C (2), Bersaldegenin-3-acetate (3) from Kalanchoe pinnata on the protein target, is virtually screened and the functional group of the compounds 1-3 responsible for better binding is investigated computationally using Auto Dock 4.2. The steric hindrance of Glu117 to the 1, 3, 5-orthoacetate moiety is removed.

TABLE 6: COMPUTIONAL STUDY OF BUFADIENOLIDES WITH NA+/K+-ATPASE

Hydrogen bond energy, electrostatic interaction, and ligand efficiency is also investigated.

The docking studies showed that 1,3,5-orthoacetate moiety, 10-CHO, 11-OH, and 14-OH is responsible for the increased activity of compound 1 Bryophyllin A other than compound 2 & 3. 11-OH group appeared to decrease the toxicity of bufadienolide ⁵⁵.

CONCLUSION: The species of Kalanchoe (Crassulaceae) has diversified morphology, cytology and habit. The current updates on ethnopharmacological, phytochemical and pharmacological studies on Kalanchoe are collated in this review article. Bufadienolides and flavonoids are the chemotaxonomic markers of Kalanchoe. Bufadienolides are investigated as a toxic substance; research work has to be focused on identifying the therapeutic dose; hence it may have a narrow therapeutic window similar to cardiac glycosides, digoxin. In addition, due to the diversified chemical structure of phytometabolites, Kalanchoe exerts varied pharmacological action. The metabolic study of quercetin glycoside and SAR of bufadienolides are scientifically noticeable; hence pharmacokinetic studies and SAR of the phytomolecules is the need of the hour to identify lead molecules in the drug discovery process. The unveiled tylor made medicine from ethnic herb Kalanchoe is substantiated by the scientific studies gives the scientific validation of folklore claims of Kalanchoe.

ACKNOWLEDGEMENT: Sincere thanks to Miss. R. Harini, Ph.D. Scholar, Department of Pharmacognosy, College of Pharmacy, Mother Theresa Post Graduate & Research Institute of Health Sciences, Puducherry, for drawing the chemical structures

CONFLICTS OF INTEREST: Nil

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    How to cite this article:

    Selvakumari E, Muthukumaran R, Atchaya S, Kowsalya S and Elavarasan N: Ethno pharmacological and phyto pharmacological perception on kalanchoe (crassulaceae) - a comprehensive review. Int J Pharm Sci & Res 2022; 13(4):1428-40. doi: 10.13040/IJPSR.0975-8232.13(4).1428-40.

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