Siphonols A–E: Novel nitric oxide inhibitors from Orthosiphon stamineus of Indonesia

doi:10.1016/S0960-894X(02)00854-5

Bioorganic & Medicinal Chemistry Letters

Volume 13, Issue 1, January 2003, Pages 31-35

https://doi.org/10.1016/S0960-894X(02)00854-5 Get rights and content

Abstract

From the methanolic extract of Orthosiphon stamineus, four novel highly oxygenated isopimarane-type diterpenes named siphonols A–D (1–4) and a novel biogenetically interesting norisopimarane-type diterpene named siphonol E (5) were isolated. The new compounds 1–3 and 5 showed more potent inhibitory effects on the nitric oxide (NO) production in lipopolysaccharide (LPS)-activated macrophage-like J774.1 cells than a positive control N^G-monomethyl-l-arginine (l-NMMA). Siphonols A–E (1–5) represent the first examples of isopimaranes oxygenated at C-20.

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Acknowledgments

This work was supported in part by a Grant-in-Aid for International Scientific Research (No. 13576027) from The Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Clerodendranthus spicatus (Thunb.) C. Y. Wu possesses a definite curative effect in treating acute and chronic kidney diseases, gout, and urinary system diseases, and has been used as a national medicine for thousands of years. Meanwhile, as its toxic side effects are minimal, C. spicatus has been widely used as a healthy tea-"kidney tea" to improve kidney function. As the specific and main secondary metabolites of C. spicatus, the highly oxygenated diterpenoids exhibit various pharmacological effects such as anti-inflammation, anti-tumor, inhibition of renal fibrosis, treatment of gout, and anti-diabetes. The detailed phytochemistry, plant origin, bioactivity, and structure-activity relationships of them were surveyed here firstly to lay a foundation for the further development of the plant.
Antidiabetic Properties and Mechanism of Action of Orthosiphon stamineus Benth Bioactive Sub-fraction in Streptozotocin-induced Diabetic Rats
2013, JAMS Journal of Acupuncture and Meridian Studies
Citation Excerpt :
Orthosiphon stamineus Benth [syn: Orthosiphon aristatus (B1) Miq., Orthosiphon grandiflorus Bold., Orthosiphon spicatus (Thumb.) Bak.; Lamiaceae] [1] is one of the popular traditional folk medicines extensively used in Southeast Asia for the treatment of a wide range of diseases. It is used: (1) in Indonesia for rheumatism, diabetes, hypertension, tonsillitis, epilepsy, menstrual disorder, gonorrhea, syphilis, renal calculus, and gallstones [2], (2) in Vietnam for urinary lithiasis, edema, eruptive fever, influenza, hepatitis, jaundice, and biliary lithiasis [3], and (3) in Myanmar to alleviate diabetes, and urinary tract and renal diseases [4,5].
Orthosiphon stamineus is a popular folk medicine widely used to treat many diseases including diabetes. Previous studies have shown that the sub-fraction of chloroform extract was able to inhibit the rise of blood glucose levels in a glucose tolerance test. This study was carried out to evaluate the chronic effect and possible mechanism of action of the bioactive chloroform sub-fraction of O. stamineus using streptozotocin-induced diabetic rats and in vitro methods. Administration of the chloroform extract sub-fraction 2 (Cƒ2-b) at a dose of 1 g/kg twice daily on diabetic rats for 14 days showed a significant lowering (p < 0.05) of the final blood glucose level compared to the pretreatment level. However, there were no significant differences in the plasma insulin levels post-treatment compared to the pretreatment levels for all doses of Cƒ2-b. Conversely, Cƒ2-b at a concentration of 2 mg/mL significantly increased (p < 0.001) the glucose uptake by the rat diaphragm muscle. The increase in glucose uptake was also shown when the muscle was incubated in a solution containing 1 IU/mL of insulin or 1 mg/mL of metformin. Furthermore, the effect of this sub-fraction on glucose absorption in the everted rat jejunum showed that Cƒ2-b at concentrations of 0.5 mg/mL, 1 mg/mL and, 2 mg/mL significantly reduced the glucose absorption of the jejunum (p < 0.05–0.001). Similarly, the absorption of glucose was also inhibited by 1 mg/mL and 2 mg/mL of metformin (p < 0.001). These results suggest that the effect of Cƒ2-b may be due to extra-pancreatic mechanisms. There was no evidence that the plant extract stimulated the release of insulin in order to lower the blood glucose level.
A novel allelopathic substance, 13-epi-orthosiphol N, in Orthosiphon stamineus
2013, Journal of Plant Physiology
Citation Excerpt :
Several biologically active compounds, including terpenes, have already been isolated from O. stamineus. These compounds exhibited anti-inflammatory (Masuda et al., 1992) and anti-proliferate activities (Awale et al., 2002; Sahib et al., 2009), cytotoxicity (Tezuka et al., 2000; Holla et al., 2011) and nitric-oxide inhibition (Awale et al., 2003) in animal cells. However, no allelopathic substance has been reported in O. stamineus.
Orthosiphon stamineus (Java tea) has been widely used as traditional herb and several bioactive compounds against animal cells have been isolated. However, no bioactive compound against plants has been reported. Therefore, we investigated possible allelopathic properties and substances in O. stamineus. Aqueous methanol extracts of O. stamineus inhibited root and hypocotyl growth of cress (Lepidium sativum) and lettuce (Lactuca sativa) seedlings. Increasing the extract concentration increased the inhibition, which suggests that O. stamineus may have allelopathic properties. When the extract was divided into an ethyl acetate and an aqueous fraction, the ethyl acetate fraction showed the stronger inhibitory effect. Thus, the ethyl acetate phase was further purified, and the main allelopathic substance was isolated and identified as 13-epi-orthosiphol N, a novel compound, by spectral data. 13-epi-Orthosiphol N inhibited root and hypocotyl growth of cress and lettuce at concentrations greater than 10 μmol/L. The concentrations required for 50% inhibition ranged from 41 to 102 μmol/L. These results suggest that 13-epi-orthosiphol N may be an allelochemical and main contributor to the growth inhibitory effect of O. stamineus and may have potential as a template for the development of new plant control substances.
Diuretic properties of Orthosiphon stamineus Benth
2009, Journal of Ethnopharmacology
Citation Excerpt :
This plant has been used in traditional medicine for centuries to improve general health, treatment of kidney diseases, bladder inflammation, gout and diabetes (Wagner, 1982; Akowuah et al., 2005). O. Stamineus is also being used to treat rheumatism, tonsillitis and menstrual disorder (Awale et al., 2003). Phenolic compounds such as lipophilic flavones, caffeic acid derivatives (rosmarinic acid and 2,3-dicaffeoyltartaric acid) (Sumaryono et al., 1991; Akowuah et al., 2004), sinensetin and methoxy flavones (Pietta et al., 1991), diterpenes, betulinic acid, oleanolic acid and sitosterol (Tezuka et al., 2000) have been isolated from O. stamineus.
Orthosiphon stamineus has been used in traditional medicine for centuries especially to treat diseases of the urinary system.
To investigate the diuretic activity, to elucidate its possible mechanism and to evaluate the renal effects of Orthosiphon stamineus extract.
Water extracts were administered orally at doses of 5 and 10 mg/kg to Sprague–Dawley rats and the control groups were given commercial diuretic drugs either furosemide or hydrochlorthiazide at 10 mg/kg. Urine volume, urine pH, urine density and urine electrolytes were determined every hour for 4 h. Blood was assayed for glucose, albumin, blood urea nitrogen (BUN) and creatinine.
O. stamineus extract exhibited dose-dependent diuretic activity. However, excretion of Na⁺ and Cl⁻ was not markedly elevated, but urinary excretion of K⁺ was significantly increased. O. stamineus extracts slightly increased the serum BUN, creatinine and blood glucose level. Although these levels were statistically significant when compared to control, these levels were still within normal range.
O. stamineus exhibited diuretic activity, but was less potent than furosemide and hydrochlorothiazide. Care should be taken when consuming this herb as slight increase of kidney function enzymes was recorded.
Studies on diuretic and hypouricemic effects of Orthosiphon stamineus methanol extracts in rats
2008, Journal of Ethnopharmacology
Orthosiphon stamineus (Labiatae) is a traditional folk medicine widely used in Southeast Asia for the treatment of several kidney disorders, gout and as a diuretic. This study was conducted to examine the diuretic and hypouricemic effects of Orthosiphon stamineus leaf extracts.
The diuretic effect of different methanol extracts was examined by treating different groups of Sprague–Dawley rats with single (2 g/kg) oral doses of methanol and methanol:water (1:1) extracts. Hydrochlorothiazide (10 mg/kg) was used as positive control in acute study. Methanol and methanol water (1:1) extracts at 0.5 g/kg were administered for a period of 7 consecutive days. Cumulative urine volume and electrolytes (Na⁺ and K⁺) concentrations at different time intervals were measured. On the other hand, hypouricemic activity of methanol:water extract (1:1) was experimented using different oral single doses (0.25, 0.5, 1 and 2 g/kg). Allopurinol was used as positive control. Uric acid concentration in serum was analyzed by using RP-HPLC at 280 nm.
Sodium and potassium excretion increased significantly (p < 0.05 and <0.01) in the first 8 h of treatment with a single dose (2 g/kg) of the extracts in a pattern comparable to that of the known diuretic hydrochlorothiazide. Meanwhile, repeated administration of 0.5 g/kg methanol:water (1:1) extract showed a significant increase in urine volume (from day 3 to day 7) (p < 0.01) and electrolytes excretion (Na⁺ and K⁺) from day 2 to day 7 (p < 0.05 and <0.01). On the other hand, 0.5, 1 and 2 g/kg of methanol:water (1:1) extract and the standard allopurinol reduced the serum urate level in hyperuricemic rats at hour 6.
These results provided an evidence of the high tendency of methanol:water (1:1) extract of Orthosiphon stamineus towards diuretic and hypouricemic effects in rats.
Asymmetric synthesis of the fully functionalized six-membered A-ring of siphonol A
2024, Organic and Biomolecular Chemistry

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Siphonols A–E: Novel nitric oxide inhibitors from Orthosiphon stamineus of Indonesia

Abstract

Section snippets

Acknowledgments

Tetrahedron

Tetrahedron

Ann. Surg.

Am. J. Respir. Crit. Care. Med.

Chem. Pharm. Bull.

J. Nat. Prod.