General info
• Caesalpinia is a genus of flowering plants in the family Fabaceae. It includes 10 species.
• Taxonomy: Historically, inclusion in the genus has been highly variable. Some publications include anywhere from 75 to 165 species, depending on inclusion or inclusion of species listed under other genera such as Hoffmannseggia. (73)
• Caesalpinia sampan shares similarities with C. machinate, a species of Brazilian timber in the pea (Fabaceae) family. Portuguese explorers initially referred to the trees as pau-brasil - pau as Portuguese for "stick," metonymy for wood, and brasa for brasil, Portuguese for "ember" - for the deep red hue characteristic of the wood. Pau-brasil was also used to described the Asian sappanwood. And besides sharing in the common name brazilwood, C. machinate and C. sampan also share in some botanical features, chemical constituents, and functional uses of dye and wood.
• Etymology: The genus name Caesalpinia honors the botanist, physician, and philosopher Andrea Cesalpinio (1519-1603). (73)
- Originally known as Brazilwood, Sappanwood was considered one of the most important source of red dyestuffs for textiles from the middle ages to the end of the 19th century.

Botany
• Sapang is a small tree, 3 to 5 meters high, with scattered spines. Leaves are compound, up to 50 centimeters long. Pinnae are about 20, opposite, and 10 to 20 centimeters long. Leaflets are 20 to 30, obliquely oblong to oblong-rhomboid. Flowers are yellow, on terminal panicles, 2 to 2.5 centimeters in diameter with densely wooly filaments. Fruit is a hard, indehiscent, shiny pod, about 7 centimeters long, and 3.5 to 4 centimeters wide, with a hard recurved beak at the upper angle.

Distribution
- Introduced, and probably of prehistoric introduction.
- Locally abundant throughout the Philippines at low and medium altitudes in dry thickets, parang, etc.
- Native to Assam, Bangladesh, Cambodia, East Himalaya, Laos, Myanmar, Nepal, Sri Lanka, Thailand, Vietnam. (20)

Constituents
- Coloring matter of sampan wood appears to be identical to the brazilin obtained from brazilwood.
- Study yield a principle resembling haematein.
- Resinous extract yields a crystalline principle, which when fused with potash, yields resorcin.
- Besides brazilin, additional constituents include gallic and tannic acids.
- The coloring matter of sampan wood has been attributed to brazilin.
- Tannin is found in the leaves,19%, bark and fruit walls, 44%.
- Leaves yield volatile oil, 0.16 to 0.25%; d-a-phellandrene, terpene, and methyl alcohol.
- Pods contain 40% tannin.
- Seed on extraction with petroleum ether yield an orange colored fixed oil.
- Sapwood is white. Heartwood, 90% of the total volume, is yellow or deep orange when fresh, turning to dark red.
- Stem yields a gum.
- Bark, pods and roots yield dyes. Pods contain about 40% tannin. Roots yield a yellow dye.
- Study yielded isoflavonoids from the dried heartwood.
- Study isolated 21 compounds: Neocaesalpin A (1), Neocaesalpin B (2); three brazilin derivatives:Brazilein (3), Brazilin (4), brazilide A (5); two dibenzoxocins: Protosappanin A (6), Protosappanin C (7); two lignans: (±)-Lyoniresinol (8), (-)-Syringaresinol (9); two chalcones: 3-deoxysappanchalcone (10), Sappanchalcone (11); one homoisoflavonoid:3-deoxysappanone B (12); two flavonoids: Rhamnetin (13), 3,8-dihydroxy-4,10-dimethoxy-7-oxo-[2]benzopyrano[4,3-b]benzopyran(14); one stilbene: (E)-3,Y-dime-thoxy-4,4'-dihydroxystilbene (15); one chroman: 3,7-dihydroxy-chroman-4-one (16);three sterols: Stigrnasterol (17), β-sitosterol (18), Daucosterin (19); two fatty acid:Dimethyl adipate (20), Stearic (21).
- Studies have isolated various types of phenolic components including one xanthone, one coumarin, three chalcones, two flavones, three homoisoflavonoids, and brazilin. Brazilin [(6a S-cis)-7, 11b-dihydrobenz[b]indeno[1,2-d]pyran-3,6a,9,10(6H)- tetrol], is a major and active compound found in CS heartwood. (see study below) (23)
- Study of seeds isolated five new cassane diterpenoids, phanginins R-T (1-3) and caesalsappanins M and N (4 and 5), together with seven known compounds 6-12. (see study below) (41)
- Study yielded eight compounds identified as tectorigenin (1), sappanone A (2), 3-deoxysappanone B (3), sappanchalcone (4), 3-deoxysappanchalcone (5), protosappanin B (6), (-)-syringaresinol (7) and episappanol (8). (see study below) (44)
- Phytochemical screening yielded flavonoids, phenolic compounds, tannins, saponin, protein, oxalic acid, carbonate, oil and fat. (see study below) (46)
- Study of methanol extract of seeds yielded five cassane-type diterpenoids identified as phanginin (1), phanginin A (2), phanginin D (3), phanginin H (4), and phanginin J (5). (see study below) (62)
Study of C. sappan herartwood yielded four new phenolic compounds, caesalpiniaphenols A-D (1-4), together with eight known compounds. (see study below) (65)
- Study of methanol extract yielded six active compounds identified as sappanchalcone (2), 3-deoxy-4-O-methylsappanol (3), brazi9lein (4), brazilin (5), sappanol (6), and 4-O-methysappanol (7). Compound 1 was a new compound: (6aS,11bR)-7,11b-dihydro- 6H-indeno[2,1-c]chromene-3,6a,10,11-tetrol. (see study below) (66)
- Study of seeds isolated a new cassane-type diterpene, named Phangininoxy A (1) and one known Phanginin A (2). (69)
- Studies on sappan wood's chemical constituents have led to identification of many structural kinds of phenolic components, including brazilin, one xanthone, one coumarin, three chalcones, two flavones, and three homoisoflavonoids. (74)
- Study of 70% ethanol extract isolated 8 known compounds: 3R,4S)-3-(3′,4′-hydroxybenzyl)-3,4-dihydro-2″,3″-dimethyl-3H-[1,3]dioxolo [4,5-c]chromen-7-ol (1), brazilin (2), protosappanin A (3), protosappanin C (4), protosappanin B (5), caesalpin J (6), sappanone B (7), and sappanchalcone (8). (see study below) (86)

Properties
- Considered emmenagogue, astringent, sedative, stomachic, tonic, vulnerary.
- Studies have suggested anti-anaphylactic, antibacterial, anticoagulant, anticomplementary, antifungal, anti-inflammatory, antitumor, antiviral, cytotoxic, immunostimulant, sleep-inducing, antiacne, lipase inhibitory, antioxidant, termiticidal, cognitive enhancing, antipyretic, analgesic, cardioprotective, tyrosinase inhibitory, antiaging properties.

Parts utilized
Bark, wood, heartwood, and seeds.

Uses
Edibility
- In Yogyakarta, Indonesia, the wood is used as natural coloring agent of traditional refreshment or drink.
Folkloric
- Decoction of wood and bark used for tuberculosis, atonic diarrhea, dysentery, postpartum tonic, skin infections, wounds, ulcers, and anemia.
- Seeds used for stomach aches and nervous disorders.
- Decoction of wood used by women as tonic after confinement; also used as emmenagogue and and for vomiting of blood.
- Dried heartwood used against inflammation.
- Decoction is used as diuretic.
- Roots, stems and seeds used as sedative and vulnerary.
- In Indo-China, seeds used as stomachic. Wood decoction used as emmenagogue.
- In Thailand, used for arthritis, cancer, and inflammatory complaints.
- In Ayurveda, useful in vitiated conditions of Pitta, burning sensations, wounds, ulcers, leprosy, skin diseases, diarrhea, dysentery, and diabetes.
- In Unani medicine, used to stop bleeding from chest and lung, for wound healing, to treat rheumatism, and to improve the complexion.
- In India, use to stop bleeding in gums, treatment of aphthous ulcers, stomatitis, and gum erosions.
- In Kerala, decoction of heartwood used for blood purifying, antithirst, and anti-diabetic properties.
- In Indonesia, the plant is used for treatment of dysentery, hemoptysis, and ophthalmic disorders and as a depurative. The Buginese tribe add it to daily drinking water to prevent and treat osteoporosis. (87)
Others
- Dye: Heartwood yields a valuable red crystalline dye, brazilin. Chiefly used as a dyewood, popular for coloring cotton, silk, and wool fabrics. Elsewhere, used for coloring leather, silk, batik, calico printing, furniture and handicrafts. Also used for coloring wines and meats. Considered safe for coloring food products and pharmaceuticals.
- Lambanog: In some parts of the Quezon province, a popular colorant for the coconut liquer, lambanog. Also, strip of sappan wood used to test for purity of lambanog, imparting a yellow coloration.
- Wood: (1) Firewood: has an energy value of 25,000 kj/kg. (2) Source of commercial redwood or Brazilwood. (3) Carpentry. Used for inlaying work, cabinetry, and with its straight grains, of great value in making violin bows and walking sticks. (•) (4) Wood is a component of Vicco Vajradanti, a famous toothpaste and tooth powder in India.
- Gum/resin: Stem produces a gum. (9)
- Agroforestry: Due to economic and cultural significance, sappan wood has been extensively harvested in many parts of Southeast Asia, causing concerns on its sustainability. The tree is harvested every 6-8 years, cut about 1 m above ground to allow sprouts to grow from the stump. Average yield of inner pulp is about 80 kg/tree. Seeds are harvested on the second year; the heartwood ready after 6-12 years. A yield of 2000-2500 kg of pods may be obtained, which may yield 200-250 kg of seeds per hectare. Wood dye yield varies with varietal and cultural factors. (74)
- Tannins: The fruits, like most Caesalpinia species, are rich in tannins and may be used for the treatment of leather. (76)

The Sapan Wood Test

In the Quezon area, rather than medicinal, sapang finds greater use as a test for the purity of lambanog. Sappan wood is known to produce a red dye. Studies have identified brazilin as the wood constituent responsible for the color.

The Traditional Rural Lithmus Test: In rural Quezon, the sapan wood has long been used for testing the purity of lambanog. A strip of sappan wood swirled in unadulterated lambanog will impart a yellow color. Above: (1) Gin, bright pink. (2) Vodka, reddish-brown. (3) Bating, the initial distillate in the lambanog process gives a reddish-orange color. (4) Coconut lambanog with the typical "true" unadulterated yellow coloration (5) Nipa or sasa lambanog with a lighter yellow, probably due to a lower "proof."

Studies
• Antimicrobial: Aqueous extract study showed antimicrobial activity against methicillin-sensitive S aureus (MSSA) as well MRSA and suggests a potential to restore the effectiveness of B-lactam antibiotics against MRSA. (1) Study evaluated the antimicrobial activity of various extract of C. sappan against various microorganisms viz., E. coli, B. cereus, E. faecalis, Bacillus subtilis, K. pneumonia. Methanol, ethanol, and acetone extracts showed effective antimicrobial activity against the bacterial.
• Immunosuppressive component: Brazilein, an important immunosuppressive component of CS showed inhibition of T cell proliferation and suppress mice humoral immune response. (2)
• Antioxidant / Heartwood: Study evaluated the antioxidant activity of CS heartwood in both in vitro and in vivo models. EA, methanol, and water extracts showed strong antioxidant activity in both DPPH and nitric oxide models. (3)
• Antioxidant: Ethanol extract showed strong superoxide anion radical and nitric oxide scavenging activity. Phenolic compounds were the major constituents for the antioxidant activity. Results suggest CS extract may be proposed as a dietary supplement for the prevention of oxidative damage or DNA damage by hydroxyl radicals.
• Anticonvulsant:Study of aqueous MeOH extracts isolated pure compounds sappanchalcone and brazilin which showed remarkable anticonvulsant activity. (4)
• Xanthine Oxidase Inhibitors / Protosappanins: Study of MeOH extract of Vietnamese CS isolated neoprotosappanin and protosappanin A dimethyl acetal which showed xanthine oxidase inhibitory activity comparable to allopurinol. (5) Protosappanin A isolated from the heartwood shown to have a mild sedative effect.
• Anti-allergic: Study of extracts of CS showed potent inhibitory activity against B-hexosaminidase release as marker of degranulation in rat basophilic leukemic cells. Among the compounds tested, sappanchalcone showed the most potent anti-allergic effect. (6)
• Hypolipidemic: A methanolic extract showed significant anti-hypercholesterolemic activity.
• Cardioactive effects of Brazilein: Brazilein, a molecule with a non-steroidal skeleton, obtained from CS ethanol extracts showed a positive inotropic action with little effect on heart rate and coronary perfusion, an effect achieved through inhibition of Na-K-ATPase system. (7)
• Hypoglycemic / Brazilin: Brazilin (7,11b-dihydrobenz[b]indeno-[1,2-d]pyran-3,6a,9,10(6H)-tetrol), the principle component of C. sappan, has been found to exhibit hypoglycemic properties and to increase glucose metabolism in diabetic rats.
• Nephroprotective: Study of an ethanolic extract of CS in male albino rats showed nephroprotective and antioxidant activities by histopathological and biochemical observations against acetaminophen-induced renal damage in rats. (10)
• Ovarian Cancer Growth Inhibition: Study showed C. sappan aqueous extract inhibited growth of human ovarian cancer cell line and induce apoptosis by increasing expression of Caspase-3, Caspase-9, and decrease expression of surviving. (11)
• Constituents / Anti-Tumor Activities: Study isolated 21 compounds (see constituents). Neocaesalpin A, brazilein, brazilin, and sappanchalcone exhibited moderate cytotoxicity against seven tumor cell. lines. A stilbene, (E)-3,Y-dime-thoxy-4,4'-dihydroxystilbene, exhibited hepatoprotective activity against D-GaIN-induced toxicity in WB-F344 cells. (13)
• Hepatoprotective / CCl4 Hepatotoxicity: Study of methanol and aqueous extracts of the heartwood of CS in CCl4-induced hepatotoxicty showed potent hepatoprotective activity comparable to standard silymarin. (14)
• Neuraminidase Inhibitory Activity / Anti-Influenza Virus: Study of yielded six constituents with neuraminidase inhibitory activity: Brazilein, brazilin, protosappanin A, 3-deoxysappanchalcone,
sappanchalcone and rhamnetin. Of these, 3-deoxysappanchalcone and sappanchalcone showed the highest activity against influenza virus (H3N2). (15)
• Anti-Arthritic: Study showed CS significantly attenuates CIA in rats by decreasing the levels of IL-1b, IL-6, TNF-α and PGE2 in serum and the expression of COX-2 and transcription factor NF-kB in paw cartilage. (17)
• Antihelmintic / Bark: Study evaluating the ethanol and aqueous extracts of CS bark against Pheritima posthuma showed anthelmintic activity with paralysis and death of worms compared to standard reference Albendazole. (18)
• Brasilin / Antibacterial: Study isolated an active antibacterial principle from CS, brasilin, which showed potent activity against antibiotic-resistance bacteria, notably methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, multi-drug resistant Burkholderia capacia. Results showed brasilin is bactericidal against MRSA. (19)
• Anti-Inflammatory: Study evaluated the effects of an ethanolic extract on human chondrocytes and macrophages. Results demonstrated an anti-inflammatory effect in an in vitro cell model of joint inflammation. Blockade of IL-1ß-induced NF-kB signaling and downstream pro-inflammatory targets may be beneficial for reducing cartilage breakdown in arthritis. (21)
• Antibacterial: Study evaluated the antimicrobial activity of C. sappan and Mimosa pudica against S. aureus, B. subtilis, P. aeruginosa, E. coli, K. pneumonia, P. vulgaris, C. albicans and A. niger. Extracts of C. sappan showed broad spectrum activity against both gram-positive and gram-negative bacteria and fungi attributed to the identified alkaloids and tannins. (22)
• Brazilin: Brazilin [(6a S-cis)-7, 11b-dihydrobenz[b]indeno[1,2-d]pyran-3,6a,9,10(6H)- tetrol], is a major and active compound found in CS heartwood. It has been reported to possess antibacterial, anti-inflammatory, anti-photoaging, hypoglycemic, vasorelaxant, anti-allergic, anti-acne, anti-oxidant properties. CS heartwood extract is safe and did not produce toxicity in both male and female rats. It is considered to be a safe natural compound with the potential as medicinal compound, as well as applications in food, beverage, cosmetics, and pharmaceutical industries. (Review) (24)
• Anti-HIV-1 Integrase Activity: Study evaluated an EtOH extract of C. sappan and its isolated compounds for anti-HIV-1 IN effect. Extraction from heartwood and roots isolated nine compounds. Compound 2, sappanchalcone exhibited the strongest anti-HIV-1 IN effect with an IC50 value of 2.3 µM. (25)
• Anti-Tumor Mechanisms / Review: Article reviews the studies done on the mechanisms on Caesalpinia sappan effects on tumors, including areas of cytotoxicity, tumor cell apoptosis, antimultidrug resistance, inhibition of tumor metastases, enhancement of chemotherapeutic effects, etc. (26)
• Wound Healing / Brazilin: Study evaluated the wound healing effect of standardized brazilin rich extract (BRE) from C. sappan heartwood. Results showed brazilin and BRE showed similar antioxidant and antibacterial activity (P>0.05). Cytotoxicity study showed brazilin and BRE was nontoxic up to 500 µg/mL concentrations. Results suggest BRE could be used as a potential herbal compound for the treatment of wound healing and can be a replacement for brazilin due to its similar biological activities and low cost production. (27)
• Anti-Cancer / Apoptosis Induction / HeLa Cell Line / Heartwood: Study evaluated the cytotoxicity activity of extracts from C. sappan heartwood against multiple cancer cell lines. Cell death through induction of apoptosis was evidenced by DNA fragmentation and caspase-3 enzyme activation. (29)
• Antioxidant : Study of 85% ethanol extract from C. sappan heartwood yielded protosappanin A, protosappanin B and brazelein. All showed in vitro antioxidant activity. The ECS, protosappanin A and protosappanin B showed more inhibition of MDA and scavenging of H2O2, while brazilein showed more scavenging of hydroxyl radicals. (30)
• Silver Nanoparticles / Potential Nanoantibiotic: Study reports on the synthesis of AgNPs using Caesalpinia sappan extract as a reducing agent to convert Ag+ to AgNPs. Results showed a source of potential novel nanoantibiotics against MRSA (methicillin resistant Staphylococcus aureus). (31)
• Toxicity Evaluation: Study evaluated acute and subacute toxicities of sappan wood extracts in rats. For acute toxicity, a single oral dose of 5000 mg/kg of sappan wood was given to rats. Subacute study involved a daily oral administration at various doses up to 1000 mg/kbw for 30 days. Results showed the extract did not produce any acute or subacute toxicity in both female and male rats. (33)
• Cytotoxic and Apoptotic Potential: Study evaluated the anti-cancer potential of heartwood of C. sappan. In vivo study in albino mice using Ehrlich ascites carcinoma model resulted in increase life span. Analysis of apoptotic potential of water extract on HeLa cells showed a cell cycle analysis that was apoptotic in nature. Results showed the water extract from the heartwood of C. sappan showed promising cytotoxic and apoptotic potential. In vivo anti-cancer and anti-inflammatory activities were also promising. (34)
• Hahnemannian Clinical Verification: In a study of only acute cases, conducted to elicit the proving of C. sappan in Hahnemannian method and to introduce the medicine in Homeopathy, results suggest great potential in the treatment of vertigo. It can also be used in the treatment of headache, dysuria, eye pain, loss of appetite. (35)
• Anthelmintic / Antioxidant / Leaves: Study evaluated the phytochemistry, antioxidant, and anthelmintic activities of C. sappan leaves. Results showed C. sappan leaves methanolic extract has significant antioxidant potential compared with standard vitamin C. The methanol extract also exhibited potent anthelmintic activity against earthworm Eisenia fetida. (36)
• Hepatoprotective / Antioxidant / Acetaminophen Induced Hepatotoxicity: Study evaluated the antioxidant and hepatoprotective activities of an ethanol extract of C. sappan on acetaminophen (APAP) induced rat hepatic injury. C. sappan significantly (p<0.01) decreased hepatic parameters towards normalization in a dose dependent manner. It also increased the levels of SOD and CAT, GPX, GST, and reduced glutathione. Histological analysis showed attenuation of necro-inflammatory changes in the liver. Results suggest significant antioxidant property and protection of the liver from APAP induced oxidative injury and liver damage. (37)
• Inhibition of IL1ß-Mediated Overexpression of MMP in Human Chondrocytes: Exacerbated production of matrix metalloproteinases (MMP) is a key even in the progression of osteoarthritis. Study evaluated the MMP-inhibitory activity of ethanolic extract of CS extract in human OA chondrocytes. Results showed the MMP-inhibitory potential of the extract on human OA chondrocytes. In part, the mechanism might involved the targeting of NF-kB mediated promoter activation. (38)
• Antidiabetic: Study evaluated a chloroform extract of C. sappan used at two doses, 200 and 400 mg/kbw, administered orally for 21 days to alloxan-induced diabetic rats. Results showed significant (p<0.001) reduction of blood glucose, total cholesterol and triglyceride levels when compared to standard Glibenclamide. (39)
• Induction of Cell Death in Head and Neck Cancer Cells: Study evaluated the effects of a chloroform extract of C. sappan on cell death in head and neck cancer cells. Results showed noticeable decrease in viability of HNSCC4 and HNSCC31 cells (head and neck cancer cell lines) compared to that of HaCaT (control group) cells. The increase in cell death may be linked to increased cellular levels of p53 and p21.
(40)
• Cassane Diterpenoids / Anti-Cancer / Cytotoxic and Pro-Apoptotic Effect / Seeds: Study of seeds isolated five new cassane diterpenoids, phanginins R-T (1-3) and caesalsappanins M and N (4 and 5), together with seven known compounds 6-12. All were tested against 4 cancer cells lines: ovarian cancer A278) and HEY, gastric cancer AGS, and non-small cell lung cancer A549. Compound 1 showed significant toxicity against the four cancer cell lines with IC50 of 9.9 ± 1.6 µM, 12.2 ± 6.5 µm, 5.3 ± 1.9 µM, and 12.3 ± 3.1 µm, respectively. Compound 1 also dose-dependently induced A2780 cells apoptosis and promoted the expression of tumor suppressor p53 protein. Results suggest the cassane diterpenoids might have potential as anti-cancer agent. (41)
• Immunomodulatory Effects: Study evaluated the effects of various extracts of C. sappan on phagocytic function of macrophages. In vivo effect was evaluated by oral administration of the extracts on Swiss albino mice. In vitro potential was studied using peritoneal macrophages from Swiss albino mice. All extracts showed phagocytic modulation in vivo. An ethanol extract showed significant (p<0.05) increase in phagocytic activity. Increased phagocytic response was noted in murine peritoneal macrophages after extract treatment. The phagocytosis suggest an immunomodulatory effect through a nonspecific immune mechanism. (42)
• Natural Dyeing: A previous study reported on the effect of aluminum hydroxide on the mordanting of C. sappan dyeing. The study evaluated the inherent dyeing properties by analysis of color difference, air permeability, and characteristics developed by pre-mordanting, post-mordanting, or simultaneous modanting methods. (43)
• Attenuation of H2O2 Induced Endothelial Cell Damage: Study isolated eight compounds. Tectorigenin (compound 1) and sappanone A (2), 3-deoxysappanone B (3) and sappanchalcone (4) can significantly attenuate endothelial cell damage induced by H2O2. (see constituents above) (44)
• Sappanone A / Melanogenesis Inhibition: Study of C. sappan isolated homisoflavanone, sappanone A. It showed dose-dependent inhibition of both melanogenesis and cellular tyrosinase activity via repression of tyrosinase gene expression in mouse B16 melanoma cells. (45)
• Analgesic / Heartwood: Study of ethanol extract of heartwood of C. sappan and its three different crude fractions showed significant peripheral analgesic activity (p<0.001) in acetic acid induced writhing in albino mice. (46)
• No Mutagenic Activity / Cytotoxicity: Study evaluated the mutagenic activity of water extract of sappan heartwood. It showed no mutagenic activity at tested doses assayed by Ames test using S. typhimurium TA98 and TA100.. On genotoxicity assay, the extract showed cytotoxic effect to V79 cell line, without any toxic DNA effect at concentration between 5 and 200 µg/ml. (47)
• Cytotoxicity Against A-549 Lung Cancer Cell Line / Heartwood: Study evaluated the in vitro cytotoxic activity of heartwood of Caesalpinia sappan and roots of Anona squamosa. C. sappan showed potent cytotoxic activity with cytotoxicity inhibition percentage of C. sappan was 87% at 1000 µg/mL with IC50 value of 49 ± 0.03 µg/ml. (48)
• Brazilin Against A-549 Lung Cancer Cell Line / Heartwood: Study examined the protective effect of C. sappan and its major component, brazilin, against t-BHP (tert-butylhydroperoxide)- induced cell death. The inductive effect of brazilin was more potent than the extract. Results showed the extract of C. sappan and brazilin induce expression of HO-1 and the enzyme diminishes t-BHP-induced cell death in HEI-OC1 cells. (49)
• Brazilin / A Novel Collagen Receptor Agonist in Human Platelets: Study examined the effects of brazilin on platelet activation ex vivo. Results showed relatively low concentrations of brazilin (1 to 10 µM) potentiated platelet aggregation induced by collagen in washed human platelets. Results suggest brazilin acts as a novel collagen receptor agonist, and may offer a potential as anti-thrombotic agent targeting collagen receptors. (50)
• Hepatoprotective / Antifibrotic Effects / Thioacetamide-Induced Liver Fibrosis in Rats: Study evaluated the antifibrotic effects of C. sappan extract on rats with liver fibrosis induced by thioacetamide (TAA) and the expression of transforming growth factor ß1 (TGF-ß1), α-smooth muscle actin (α-SMA), and proliferating cell nuclear antigen (PCNA). CS treatment significantly increased hepatic antioxidant enzymes in TAA-treated rats, with alleviation of liver fibrosis, and normalized the expression of TGF-β1, αSMA, PCNA, MMPs, and TIMP1 proteins. (51)
• Anti-Inflammatory / Analgesic / Antioxidant / Seeds: Study evaluated a seed extract for antioxidant, analgesic, and anti-inflammatory activities. The extract showed potent antioxidant activity by DPPH and H2O2 method, 73.9 and 77.7% at 300 µg mL, respectively, as compared to standard ascorbic acid. Extract showed maximum inhibition of 74.2% at 300 mg/kg by carrageenan induced paw edema method as compared to diclofenac. It showed potent analgesic activity at 71% at 300 µg/ml by writhing reflexes in mice. (52)
• Anti-Breast Cancer / Migration Inhibition Activity: C. sappan contains brazilin and brazilein compounds proven to have cytotoxic activity on breast cancer cells. Study evaluated the effect of CS extract on breast cancer cells migration inhibition using 4T1 breast cancer cells as model of metastatic breast cancer. Cytotoxic assay was done by MTT and anti-metastatic effect effect by scratch wound healing assay. (53)
• Proliferative Inhibition and Apoptosis of Human Gastric Cancer Cells: Study evaluated extracts of C. sappan on its effects on growth inhibition and cell apoptosis in human gastric (SGC-7901) cells. Growth curve of cell line showed inhibitory effects of CS extracts on cell proliferation. Dose dependent changes in morphology typical of apoptosis were seen 48 hours following CSE treatment. (54)
• Antitumor Effects of Purified Protosappanin B: Study assessed the antitumor effects of protosappanin B extracted from Lignum Sappan. Protosappanin B reduced the viability of human bladder cancer T24 cells and mouse bladder cancer BTT cells in a time-dependent manner (p<0.05 and significantly inhibited the growth of human colon cancer cell lines HCT-116 and SW-480, with IC50 values of 21.32 µg/ml (SW-480), 26.73 µg/ml (HCT-116) and 76.53 µg/ml (BTT) cells. Protosappanin B also significantly increased the survival of BTT tumor-bearing mice. (55)
• Sappanone A / Protection Against Cisplatin-Induced Renal Injury: Cisplatin, an anticancer drug, can cause nephrotoxicity due to enhanced inflammatory response and oxidative stress. Sappanone A (SA) is a homoisoflavanone isolated from the heartwood of C. sappan. Study showed SA inhibited cisplatin-induced kidney injury by activating Nrf2 and inhibiting NF-kB activation. Results suggest a therapeutic potential for SA in the treatment of CP-induced kidney injury. (56)
• Cassane Diterpenoids / Cytotoxicity Against HepG2 Cell Line / Seeds: Study of seeds of CS yielded four cassane diterpenoids viz., phanginin L (1), phanginin M (2), phanginin I (3), phanginin G (4). Phanginin (compound 1) showed moderate cytotoxicity against HepG2 cell line with IC 50 of 9.13 μg·mL. (57)
• Protosappanin A / Graft Survival and Attenuation of Acute Rejection: Study investigated the potency of protosappanin A in rat heart transplantation. Results showed protosappanin A or cyclosporine significantly prolonged heart allograft survival (p<0.01), alleviated myocardial pathologic damages (p<0.01) and decreased CD4/CD8 ratio (p<0.05) and inhibited perforin and granzyme B mRNA expressions in graft (p<0.05). Findings suggest protosappanin A prolonged heart allograft survival by significantly attenuating acute rejection. (58)
• Protosappanin A / Immunosuppression in Organ Transplantation: Protosappanin A from C. sappan has exhibited anti-rejection activity in heart transplanted rat. In the study, protosappanin A exhibited inhibitory effect on cell proliferation. It may act on T cells through inhibition of NF-kB activation and downstream gene expressions in IFN-r and IP10, while reducing T cell proliferation to induce an immunosuppressive effect. Results suggest potential therapeutic evaluation of protosappanin A for clinical organ transplantation or other T cell-mediated immune disorders. (59)
• No Wound Healing Effect on Excision Wound Model: Study evaluated the wound healing activity of sappanwood extract in an excisional wound of Balb/c mice. Results showed administration of C. sappan extract gels topically had no healing effect on skin excisional wound. (60)
• Termiticidal / Seed: Coptotermes formosanus is known as a household destructive insect in rural and urban areas. Study evaluated the termiticidal activity and the concentration of seed ethanol extract that will kill termites. Results showed Sappan seeds ethanol extract has significant potential in the control of termites specifically at 30% concentration. (61)
• Cytotoxic Constituents / Phanginin / Seeds: Study identified cytotoxic constituents from the methanol extract of seeds of C. sappan. Five cassane-type diterpenoids were identified as phanginin (1), phanginin A (2), phanginin D (3), phanginin H (4), and phanginin J (5). Compounds 1-4 showed effective inhibition against HL-60 cells with IC50 values of 16.4±1.5, 19,2±2.0, 11,7±1.6 and 22.5±5.1 µM. Treatment of HL-60 cells with various concentrations of compound 3 (0-30µM) resulted in growth inhibition and induction of apoptosis. Compounds 1-3 exhibited cytotoxic activity against HeLa cells. Results suggest compound 3 (phanginin D) is one of the main active constituents of sappan seed contributing to apoptotic cell death via activation of caspases. (62)
• Antitubercular / 2-Deoxysappanchalcone / Heartwood: In a screening study about 500 species of medicinal plant methanol extracts and solvent partitioned fractions, the ethyl acetate solvent partitioned fraction from the heartwood of C. sappan exhibited strong antitubercular activity. The new active compound was identified as 3-deoxysappanchalcone. It showed activity against both drug susceptible and drug resistant strains of M. tuberculosis at MIC50s of 3.125-12.5 µg/mL in culture broth and MIC50s of 6.25=12.5 µg/mL inside macrophages and pneumocytes. It also exhibited partial synergy with streptomycin/ethambutol against MTb H37Rv. It showed no cytotoxicity against A549 cell line up to a concentration of 100 µg/mL. (63)
• Synergistic Cytotoxic Effect / C. sappan Wood, Ficus septica Leaves and Doxorubicin on MCF-7 Cells: Study evaluated the cytotoxic effect of sappan wood (ECS) and awar-awar (EFS) leaves, and its combination with doxorubicin on MCF-7 cells focusing on cell cycle progression and apoptosis induction. The combination of ECS with EFS and doxorubicin showed synergistic cytotoxic effect. The synergistic cytotoxic effect of the combination was through G2/M phase accumulation and apoptosis induction. Results suggest a potential for the development of co-chemotherapeutic agent. (64)
• Phenolic Compounds / Anti-Inflammatory Activity / Heartwood: Study of C. sappan heartwood yielded four new phenolic compounds, caesalpiniaphenols A-D (1-4), together with eight known compounds. Compounds 4, 5, and 7 showed weak inhibitory activity against LPS-induced NO production in macrophage RAW 264.7 cells with IC50 values of 12.2, 3.5 and 5.7 µM. respectively. (65)
• Suppression of Melanin Synthesis by Phenolic Constituents: A methanol extract of sappan wood was found to inhibit melanin synthesis in cultured human melanoma HMV-II cells stimulated with forskolin. Six active compounds were isolated (1-5 and 7) along with a non-active compound (6). The compounds were identified as sappanchalcone (2), 3-deoxy-4-O-methylsappanol (3), brazi9lein (4), brazilin (5), sappanol (6), and 4-O-methysappanol (7). Compound 1 was a new compound: (6aS,11bR)-7,11b-dihydro- 6H-indeno[2,1-c]chromene-3,6a,10,11-tetrol . Compounds 5 and 7 showed strong suppression of melanin synthesis in HMV-II cells. Results suggest Brazilin (5) is a new class of melanin inhibitor and that sappanwood can be used as a cosmetic material. (66)
• Stimulation of Osteoblastic Cells: On previous study, an ethanol extract of heartwood exhibited a proliferation stimulating activity against primary osteoblastic cells. This study evaluated extracts and isolated active constituents for their stimulating activity on osteoblastic cells. A new biphenyl dimer, caesappanin C (1), along with two known compounds, protosappanin A (2) and sappanchalcone (3) were isolated from an active fraction. Compound 1 exhibited strongest activity and significantly increased the cell viability up to 276±5%. The other two compounds also stimulated cell proliferation and increased cell viability up to 133±8% and 187±4%, respectively. (67)
• Enhancement of Peripheral Nerve Regeneration after Sciatic Nerve Injury: Study evaluated the effect of C. sappan ethanol extract (Su Mu ethanol extract: SME) on immune function, and its suppression of autoimmune response to the promotion of nerve regeneration in Balb/c mice. Results showed SME may significantly inhibit immune function of Balb/c mice, inhibit lymphocyte proliferation transformation, reduce the degree of cell-mediated immunity and humoral immunity, The intervention of SME after sciatic nerve injury may reduce the secondary nerve damage caused by autoimmune response after Waller degeneration and the degree of demyelination, and contribute to damage nerve regeneration and functional recovery. (68)
• Depigmentation Activity / Inhibition of Tyrosinase Activity: Excessive exposure to UV light increase melanin synthesis and cause hyperpigmentation of the skin. The pharmacologic activity of C. sappan with brazilein and brazilin as antioxidants have potency as free radical scavengers and directly inhibit tyrosinase activity in the process of melanogenesis. This study evaluated the inhibitory ability of C. sappan ethanolic extract on tyrosinase enzymes in vitro and examined the affinity of brazilein and brazilin as skin depigmentation agent against melanogenesis target protein in silico. Results showed the brazilein and brazilin in the ethanol extract have stronger affinity compared to kojic acid and ascorbic acid. Study suggests further fractionation and invitro testing for inhibition of tyrosinase related protein 1 enzyme and D-dopachrome tautomerase. (70)
• Ameliorating Effect in Lead-Induced Oxidative Stress: Study evaluated the ameliorating effect of C. sappan in lead toxicity in male Wistar rats. Lead induces biological damages to liver, kidney, and heart tissues and cause oxidative stress. C. sappan showed an ameliorating effect attributed to its antioxidant activity. However, it failed to reduce to lead content of the tissues completely. (71)
• Brazilin / Inhibition of Rheumatoid Arthritis Activity in Collagen-Induced Arthritis: Study evaluated the anti-rheumatoid activity of brazilin isolated from an ethyl acetate extract of C. sappan in mice with type-II collagen-induced arthritis. The brazilin markedly attenuated mouse CIA and reduced the serum levels of inflammatory cytokines including TNF-a, IL-1ß, and IL-6. The brazilin purified from C. sappan exhibited protective efficacy in collagen-induced arthritis in a mouse model of RA. (72)
• Heartwood and Seeds / Sources of Bioactive Compounds: The heartwood is the plant's richest source of bioactive compounds. Heartwood phytochemicals are primarily homoisoflavonoids, while the seeds generally yield diterpenoids. While sappanin is a common homoisoflavonoid in related species, the rarer brazilin is the key compound of interest in C. sappan. Twenty carbon diterpenoids from the seed formed four isoprene units. Interest in diterpenoids in diterpenoids surged after the approval of the diterpenoid taxane drug, Taxol (from Taxus brevifolia), as a first-line treatment for cancer. Discovery of diterpenoids' significant biologic activity in cancer therapy made C. sappan a subject of growing pharmacological interest. The unique combination of bioactive compounds from both heartwood and seeds underlines C. sappan's versatility and potential for the development of novel therapeutic agents. The toxicity prediction for C. sappan indicates a toxicity class between 4 and 5, with emphasis on Sappanone A with a predicted LD50 of 3,800 mg/kg, and lowest predicted toxicity. (75)
• Sleep-Inducing Activity / Heartwood: Study evaluated a crude ethanolic extract of Sappanwood heartwood for toxicity and sleep-inducing activity in Swiss mice using doses of 250, 500, 1000, and 5000 mg/kg in Swiss mice. Toxicity study showed safety up to a dose of 5000 mg/kg. The extract exhibited sleep-inducing activity but with a significant difference to Zoletil. (77)
• Brazilin / Anti-Acne Activity-Inducing Activity / Antioxidant / Lipase Inhibitory / Wood: In screening studies for antiacne activity, methanolic and 50% ethanolic extracts of C. sappan wood showed potent activity out of 28 species of plants extracts. Extracts showed inhibition of Propionibacterium acnes growth, lipase inhibitory activity, and antioxidant activity. Brazilin, protosappanin A, and sappanone B were isolated from methanolic extracts. Brazilin showed better antibacterial activity (MIC=MBC 0.50 mg/ml) than protosappanin A 1.00 mg/ml) and sappanone B (>2.00 mg/ml). The IC50 for lipase inhibition was lowest for Brazilin (6 µM), which showed strong inhibition compared to protosappanin A (100 µM) and chloramphenicol (677 µM, positive control). Antioxidant activity of brazilin (IC50 8.8 µM) was not significantly different from protosappanin A (9.1 µM), both higher than sappanone B (IC50 14.5 µM). Study suggests Brazilin has sufficient potency for use as antiacne agent. (78)
• Toxicological Study on Wood-Derived Dye: Natural dyes from tree bark of C. sappan has been used in many consumer products. Study evaluated the toxicity effect of aqueous extract of C. sappan dye on Wister albino rats. Acute oral toxicity testing showed no clinical signs of toxicity and no mortality up to dose level of 100-2000 mg/kg for 14 days; no deaths up to dose level of 5000 mg/kbw. Organ-body weight ratio of kidney liver, and abdomen did not change when compared to control. (79)
• Anticancer Against Mutant EGFR in Lung Squamous Cell Carcinoma / Wood: Lung squamous cell carcinoma (LUSC), a subtype of non-small cell lung cancer (NSCLC), frequently harbors mutations in the epidermal growth factor receptor (EGFR), which regulates cell proliferation and survival and makes EGFR an attractive therapeutic target for LUSC. Study evaluated the anticancer potential of C. sappan phytochemicals against mutant EGFR through computational approach, including molecular docking and biologic activity prediction. Study identified several phytochemicals with potential to inhibit mutant EGFR in LUSC. Exclusion of BBB-permanent compounds enhances the clinical relevance by minimizing CNS-related side effects. Results underscore the potential of natural compounds as alternative therapeutic agents for targeting EGFR in LUSC, and suggests further in vitro and in vivo validation. (80)
• Natural Phosphodiesterase-1 Inhibitor / Cognitive Enhancing / Wood: A decrease in cAMP and cGMP in the brain is linked to human cognitive problems. Its degradation is attributed to phosphodiesterases (PDEs), and inhibition of PDE1 is a potential mechanism to increase cAMP and cGMP. Study evaluated the potential of CS wood as PDE1 inhibitor. Results showed the ethanol extract and ethyl acetate fraction effectively inhibited the activity. Brazilin, the major compound in CS wood, also exhibited potent inhibitory effect on PDE1. In silico assay showed interaction between tetraacetylbrazilin and brazilin with the PDE1B active site involved hydrogen bonding and π–π interactions. Results suggest potential for development as natural cognitive enhancers. (81)
• Antipyretic / Anti-Inflammatory / Antioxidant / Review: Literature review shows the antioxidant and anti-inflammatory properties of C. sappan are linked to fever as a sign of illness. Sappan wood has been shown to have antioxidant effect by lowering reactive oxygen species via SOD, GPx, or CAT markers. It inhibits inflammatory cytokines IL-1, IL-6, TNF-α and INF produced during fever. It has anti-inflammatory effect by inhibiting PGE2 production in fever. Review supports the use of C. sappan for treatment of fever. along with its potential as component in traditional health beverages. (82)
• Analgesic / Antipyretic / Leaves: Study evaluated the analgesic and antipyretic activity of ethanolic extract of sapan wood leaves in Webster mice. Phytochemical screening revealed alkaloids, flavonoids, saponins, monoterpenoids, and sesquiterpenoids. Analgesic activity was evaluated using acetic acid induced writhing method in mice with mefanamic acid as control. Antipyretic activity was evaluated in yeast-induced mice with paracetamol as positive control. The ethanolic extract of leaves showed analgesic and antipyretic activities, with optimum dose of 6.3 mg and 84 mg/20 g BW, respectively. (83)
• Enhanced Quality / Sappan Supplementation of Sugarcane Vinegar / Functional Beverage: Study evaluated the innovative combination of C. sappan extract with sugarcane juice for functional vinegar production. Sampan-supplemented vinegars exhibited significantly enhanced quality parameters, such as increased total acidity and total phenolic content (TPC), with improvement directly proportional to the concentration of the extract used. GC-MS studies revealed unique volatile organic compounds (VOCs) present in the supplemented vinegars. Extract supplementation of 2 and 4 g/L substantially enhanced both antioxidant capacity and antimicrobial activity of the resulting vinegars. Results highlight the synergistic potential in developing novel functional vinegar beverages with enhanced bioactive properties and additional health benefits beyond conventional vinegars. (84)
• Cardioprotective / Review: Review provides updates on recent developments on C. sappan studies related to protective effects of the bioactive compounds that reduce cardiac damage and enhance vasorelaxation. Brazilin and sappanone A effects molecular and cellular changes in cardiovascular disease pathogenesis by modulating oxidative, inflammatory, and apoptotic signaling pathways. The bioactive compounds have potential as therapeutic agents to combat myocardial infarction and vascular disease. (85)
• Effect on Supplementation of Pasteurized Milk: Study evaluated the microbiological and physiochemical qualities of pasteurized milk supplemented with 0, 2, 4, 6 and 8% (w/v) sappan wood extract. Preliminary analysis of wood extract revealed 44.66 mg/100 g phenol, 0.18 mg/100 mg flavonoids, 46.42 mg/100g tannins, and antioxidant activity at 85.82%. Addition of wood extract significantly increase antioxidant activity (p<0.05) of pasteurized milk during storage. Supplemented pasteurized milk showed lower bacterial count (p<0.05) and showed strong antibacterial activities against Escherichia coli, Shigella flexneri, Salmonella typhimurium, Staphylococcus aureus, and Listeria monocytogenes. Addition of sappan wood slightly increased protein content with no effect of pH and viscosity. Results showed increased microbiological quality, maintained physiochemical quality of the pasteurized milk, and extended product shelf-life. (86)
• Tyrosinase Inhibitory: C. sappan has been used as herbal medicine facial cleanser to treat skin damage. Study of 70% ethanol extract isolated 8 known compounds: 3R,4S)-3-(3′,4′-hydroxybenzyl)-3,4-dihydro-2″,3″-dimethyl-3H-[1,3]dioxolo [4,5-c]chromen-7-ol (1), brazilin (2), protosappanin A (3), protosappanin C (4), protosappanin B (5), caesalpin J (6), sappanone B (7), and sappanchalcone (8). Compounds were evaluated for invivo and invitro tyrosinase effects. Compounds 1, 2, 4, and 7 showed activating effects on tyrosinase. Compounds 3 showed competitive inhibitory effect on tyrosinase. Compound 6 showed anticompetitive inhibition, suggesting the enzyme inhibitors only bind to enzyme-substrate complex. The 70% EE of CS could inhibit formation of melanin in vivo. Compounds 2, 3, 5, and 6 promoted formation of tyrosinase in rat serum, while compound 7 inhibited synthesis of tyrosinase. (87)
• Antiosteoporotic / Heartwood: Study evaluated the anti-osteoporosis activity of C. sappan heartwood extracts via ability to stimulate the proliferation of osteoblasts isolated from neonatal mouse calvaria and to inhibit the formation of osteoclast-like cells responsible for bone absorption and resorption. All extracts increased proliferation of osteoblasts and inhibited formation of osteoclast-like cells. Among the extracts, the ethanol extract most robustly stimulated the osteoblasts and inhibited the formation of osteoclast-like cells, suggesting potential as anti-osteoporosis agent. (88)
• Antidiabetic / Heartwood / Review: Review evaluated the existing literature from 2000-2020 on the potency of CS heartwood as an antidiabetic agent. Although the numbers are limited, some invitro and invivo studies have shown that CS heartwood extract can reduce blood glucose levels. Review provides evidence for potential of CS heartwood to be developed as an antidiabetic agent. (89)
• Decoction Supplementation of OHAs / Decrease Blood Glucose / Heartwood: C. sappan wood has antioxidant and antihyperglycemic substances that can be used as supplemental therapy in stabilizing blood glucose levels. In 32 subjects, decoction of C. sappan wood as support of OHAs (oral hypoglycemic agents) gave significant effect of 54,51% compared to control (p=0.010). C. sappan has a brazilin content as a transporter that helps pancreas work in insulin secretion. (90)
• Natural Red Colorant / Brazilin / Heartwood: CS heartwood is used as a natural red colorant in several Asian ethnic traditional drinks as sole ingredient or mixed with other herbs. However, the pigment is unstable and easily degraded during storage. Study evaluated the effect of various blanching and drying methods on color stability, brazilin content, and antioxidant activity of CS heartwood drinks. Results showed blanching and drying methods affected the color intensity. For pure CS heartwood herbal drink, sample prepared with water blanching and cabinet drying (BCD) showed highest red value, leading to a 48% improvement compared to control. Sample BCD showed highest brazilin content, which was 376% higher than control. The BCD sample also showed highest antioxidant activity and total phenolic content, with IC50s of 98.99 ppm and 213.12 mg GAE/g respectively. Brazilin may act as antioxidant. Results suggest the combination of water blanching and cabinet drying (BCD) was the best method to improve the quality of the CS heartwood drink in both pure and mixed herbal drinks as a functional drink. (91)
• Nanoemulgel / Antiaging: Study evaluated the activity of C. sappan nanoemulgel as antiaging agent against target protein, matrix metalloproteinases (MMPs) by in silico assay and in vivo assay through MMP-1 and collagen expression parameter. Results showed C. sappan nanoemulgel has potential activity as an antiaging agent by repressing MMP-1 expression and dermal collagen degradation. Brazilin and brazilein from C. sappan inhibit the MMP-1, MMP-3, and MMP-9 by in silico assay. A 25% nanoemulgel formulation showed best antiaging result. (92)
• Anti-SARS CoV-2 Constituents: In silico study evaluated a few promising phytoconstituents of C. sappan for effects against disease-causing protein receptors of SARS CoV-2. Phytoconstituents of Caesalpin J, Deoxysappanone B, Methylepisappanol, Methylsappanol, Quercetin) showed superior or equivalent binding affinity against the three chosen receptors of SARS CoV-2 viz., spike glycoprotein, main protease, and RNA dependent RNA polymerase. In vivo studies are suggested to evaluate the antiviral properties of C. sappan against SARS CoV-2. (93)

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