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Serratenediol

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Serratenediol
Names
IUPAC name
(3S,6R,8S,11R,12S,15S,16R,19S,21R)-3,7,7,11,16,20,20-heptamethylpentacyclo[13.8.0.03,12.06,11.016,21]tricos-1(23)-ene-8,19-diol
Other names
Pinusenediol[1]
Identifiers
3D model (JSmol)
  • InChI=1S/C30H50O2/c1-26(2)21-10-8-19-18-28(5)15-12-22-27(3,4)25(32)14-17-30(22,7)23(28)11-9-20(19)29(21,6)16-13-24(26)31/h8,20-25,31-32H,9-18H2,1-7H3/t20-,21-,22-,23-,24-,25-,28-,29+,30-/m0/s1 X markN
    Key: FMUNNDDBCLRMSL-PIGMOXAFSA-N
  • C[C@@]12CC[C@@H]3[C@@]([C@H]1CC[C@H]4C(=CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)O)C)C2)(CC[C@@H](C3(C)C)O)C
Properties
C30H50O2
Molar mass 442.728 g·mol−1
Appearance Powder[2]
poorly soluble
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Serratenediol, first discovered by Y. Inubushi, T. Sano, and Y. Tsuda in 1964[3], is a naturally occurring pentacyclic triterpenoid.[4] The compound has drawn interest for its distinctive carbon framework and potential biological activities. Serratenediol is characterized by a rare seven‑membered C-ring, a defining feature of the serratene class of triterpenoids,[5] which differentiates it from the more common lupane, oleanane, or ursane types.[6] Additionally unlike other typical triterpenes, which are characterized by eight methyl groups, serratenediol possesses only seven. Structurally, it is further distinguished by its characteristic hydroxyl groups located at the C-3 and C-21 positions.[7] The compound is also known as pinusenediol.[8]

Stereochemistry and conformation

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The conformational structure and stereochemistry of serratenediol have been thoroughly researched using a combination of various analytical techniques, including NMR spectroscopy, NMR solvent shift analysis, X-ray crystallography, optical rotary dispersion (ORD), and circular dichroism (CD). These methods confirmed the absolute configuration of the molecule's nine stereocenters across its characteristic 6-6-7-6-6 fused pentacyclic ring system. Additionally it has also been revealed that rings A, B, and C adopt stable chair conformations, while ring D assumes a half-chair conformation and ring E adopts a sofa conformation.[9]

Natural occurrence and isolation

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The compound is found primarily in plants of the Lycopodiaceae family, especially in the genus Lycopodium (now often segregated into genera like Huperzia and Phlegmariurus).[10][11][12] A standard isolation protocol for the molecule involves utilizing the aerial parts of the clubmoss Lycopodiastrum casuarinoides. The process begins with macerating air-dried plant matter followed by a triple extraction using a 75% ethanol solution. The crude extract undergoes liquid-liquid extraction utilizing ethyl acetate and a 3% tartaric acid solution, causing the target triterpenoid to accumulate in the organic ethyl acetate phase. Final purification is achieved via sequential silica gel column chromatography. Initial elution with a dichloromethane and methanol gradient separates the crude fractions. Subsequent fine purification using a petrolether and ethyl acetate gradient effectively isolates pure serratenediol serrat-en-3β,21α-diol from closely related side-component stereoisomers like serrat-en-3α,21β-diol and serrat-en-3α,21α-diol.[13]

Synthesis

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One of the first total syntheses of serratenediol was accomplished by Glenn D. Prestwich and Jeffrey N. Labovitz at Stanford University in 1974. The synthesis relies on biomimetic, non-enzymatic strategies in order to rapidly build the complex ring structure as the precursor of the reaction (3-(m-methoxyphenyl)propanal) is systematically extended branch by branch to reach the target molecule. Some of the commonly practiced organic chemical reactions used in this synthesis include Grignard additions, chloro-ketal Claisen rearrangements, dissolving metal reductions (including the Birch reduction), RuO4​ oxidations, Wittig olefinations, esterifications, Collins oxidations, orthoacetate Claisen rearrangements, and standard functional group protection and deprotection steps to manipulate the intermediates.[14]

One reaction step in particular provides the reaction's label namesake of biomimetic, namely the procedures of the polyene cyclization. This transformation follows the Stork-Eschenmoser postulate, which describes the stereospecific, concerted ring closure of a polyene chain into a polycyclic framework in a single step. The reaction is remarkably clean and efficient for this synthesis, as the stereochemistry of the starting material strictly dictates the outcome; the (E)-double bonds of the acyclic precursor invariably direct the formation of all-trans fused ring junctions.[15]

Biosynthesis

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The plant biosynthesis of serratenediol occurs via secondary metabolic pathways through downstream modifications of squalene. Research from Saga, et al.[16] on Lycopodium clavatum has brought to light that the carbon backbone preceding serratenediol is oxidized firstly through various oxidosqualene cyclases (OCSs) to 2,3,22,23-dioxidosqualene, which serves as the starting point for various cyclization reactions through the cyclases LCC, LCD, and LCE.

The symmetrical 2,3,22,23-dioxidosqualene precursor is first processed by the enzyme LCC, which catalyzes an epoxide-initiated cationic polycyclization cascade. This enzymatic cascade builds the first two rings of the framework and terminates via deprotonation to yield the stable bicyclic intermediate pre-α-onocerin.[16]

This intermediate is subsequently processed by LCD and LCE, which open the remaining terminal epoxide ring to form two additional rings, resulting in a key carbocation intermediate. From this point, the biosynthesis diverges into two pathways:[16]

  • Under the catalysis of LCD, the intermediate undergoes elimination to form α-onocerin. Subsequent protonation of its exocyclic methylene group drives a final cyclization cascade that rearranges the skeleton into the classic serratane framework, yielding serratenediol after a final elimination.
  • Alternatively LCE directly converts the intermediate into a pentacyclic carbocation. The primary outcome is the nucleophilic addition of water to yield tohogenol as the major product. Alternatively, a less thermodynamically favored elimination reaction can occur without water addition, yielding serratenediol as a minor byproduct of this pathway.

Physical properties

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The compound forms powder. It is poorly soluble in water, but soluble in chloroform, dichloromethane, ethyl acetate, DMSO, acetone, etc.[17]

Uses

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Scientific studies have investigated serratenediol for several potential therapeutic applications: anti-inflammatory effects, antiviral activity (it has demonstrated strong inhibitory effects on the activation of the Epstein–Barr virus), and bone health studies.[18][19] Beyond these areas, its role in cancer research has garnered particular attention. Notably, a 2012 study conducted by the Jeju Biodiversity Research Institute of the Republic of Korea revealed that the compound is highly capable of influencing human tumor cells.[20] The basis of this discovery is built upon the presence of various Lycopodium species used in certain traditional Chinese and Korean medicine as a form of cancer therapy. Building also on earlier animal models demonstrating that these triterpenes inhibit tumor progression[21], these researchers evaluated the specific effects of serratenediol on human leukemia (HL-60) cells. The compound demonstrated a powerful, dose-dependent growth inhibition on the cancer cells, achieving a 50% reduction in tumor cell growth at a concentration of just 12.5 µM, which increased to over 80% inhibition at 50 µM. This antiproliferative effect is driven by the induction of programmed cell death (apoptosis); serratenediol actively decreases the expression of anti-apoptotic proteins like Bcl-xL while simultaneously increasing pro-apoptotic proteins like Bax. Crucially, parallel testing on normal, healthy body cells (RAW264.7) showed that serratenediol maintains high selectivity for cancer tissue, as healthy cell viability remained safely above 90% even at the maximum tested concentrations.[20]

References

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  1. ↑ Dev, Sukh (1 February 2018). Handbook of Terpenoids: Volume II. CRC Press. p. 2056. ISBN 978-1-351-08966-1. Retrieved 3 January 2026.
  2. ↑ "CAS NO. 2239-24-9 | Serratenediol | Catalog BBP00103 | Arctom | Products". arctomsci.com. Retrieved 3 January 2026.
  3. ↑ Inubushi, Y.; Sano, T.; Tsuda, Y. (1964). "Serratenediol: A new skeletal triterpenoid containing a seven membered ring". Tetrahedron Letters. 5 (21): 1303–1310. doi:10.1016/S0040-4039(00)90472-6.
  4. ↑ Devon, T. K. (2 December 2012). Handbook of Naturally Occurring Compounds V2. Elsevier. p. 341. ISBN 978-0-323-14510-7. Retrieved 2 January 2026.
  5. ↑ Sjostrom, Eero (22 October 2013). Wood Chemistry: Fundamentals and Applications. Elsevier. p. 101. ISBN 978-0-08-092589-9. Retrieved 3 January 2026.
  6. ↑ ApSimon, John (22 September 2009). The Total Synthesis of Natural Products, Volume 6. John Wiley & Sons. p. 132. ISBN 978-0-470-12957-9. Retrieved 2 January 2026.
  7. ↑ Inubushi, Yasuo; Tsuda, Yoshisuke; Sano, Takehiro; Konita, Takeshi; Suzuki, Sachiko; Ageta, Hiroyuki; Otake, Yoshiyuki (1967). "The Structure of Serratenediol". Chemical and Pharmaceutical Bulletin. 15 (8): 1153–1168. doi:10.1248/cpb.15.1153. ISSN 0009-2363.
  8. ↑ Handbook of Natural Products Data: Pentacyclic triterpenoids. Elsevier. 1990. p. 1518. ISBN 978-0-444-88173-1. Retrieved 3 January 2026.
  9. ↑ Allen, F. H.; Trotter, James (1970). "Crystal and molecular structure of the bromoindole derivative of 3β-methoxy-21-keto-Δ 13 -serratene". J. Chem. Soc. B. 0 (0): 721–727. doi:10.1039/J29700000721. ISSN 0045-6470.
  10. ↑ Inubushi, Y.; Sano, T.; Tsuda, Y. (1 January 1964). "Serratenediol: A new skeletal triterpenoid containing a seven membered ring". Tetrahedron Letters. 5 (21): 1303–1310. doi:10.1016/S0040-4039(00)90472-6. ISSN 0040-4039.
  11. ↑ Zhou, Jiaju; Xie, Guirong; Yan, Xinjian (21 February 2011). Encyclopedia of Traditional Chinese Medicines - Molecular Structures, Pharmacological Activities, Natural Sources and Applications: Vol. 4: Isolated Compounds N-S. Springer Science & Business Media. p. 537. ISBN 978-3-642-16779-9. Retrieved 2 January 2026.
  12. ↑ Orito, K.; Manske, R. H.; Rodrigo, R. (15 October 1972). "The Triterpenes of Lycopodiumlucidulum Michx". Canadian Journal of Chemistry. 50 (20): 3280–3282. doi:10.1139/v72-525. ISSN 0008-4042.
  13. ↑ Liu, Yang; Li, Jing; Li, Dan; Li, Xiao-Min; Li, Dai; Zhou, Gan; Xu, Kang-Ping; Kang, Feng-Hua; Zou, Zhen-Xing; Xu, Ping-Sheng; Tan, Gui-Shan (2019). "Anti-cholinesterase activities of constituents isolated from Lycopodiastrum casuarinoides". Fitoterapia. 139 104366. doi:10.1016/j.fitote.2019.104366.
  14. ↑ Prestwich, Glenn D.; Labovitz, Jeffrey N. (October 1974). "Application of nonenzymic biogenetic-like olefinic cyclizations to the total synthesis of dl-serratenediol". Journal of the American Chemical Society. 96 (22): 7103–7105. doi:10.1021/ja00829a050. ISSN 0002-7863.
  15. ↑ Trost, Barry M., ed. (1991). Comprehensive organic synthesis: selectivity, strategy & efficiency in modern organic chemistry. Oxford: Pergamon Press. pp. 341–378. ISBN 978-0-08-035929-8.{{cite book}}: CS1 maint: date and year (link)
  16. 1 2 3 Saga, Yusuke; Araki, Takeshi; Araya, Hiroshi; Saito, Kazuki; Yamazaki, Mami; Suzuki, Hideyuki; Kushiro, Tetsuo (2017-02-03). "Identification of Serratane Synthase Gene from the Fern Lycopodium clavatum". Organic Letters. 19 (3): 496–499. doi:10.1021/acs.orglett.6b03659. ISSN 1523-7060.
  17. ↑ "Serratenediol | CAS:2239-24-9 | Triterpenoids | High Purity | Manufacturer BioCrick". biocrick.com. Retrieved 3 January 2026.
  18. ↑ "Serratenediol | BCL | Caspase | PARP | TargetMol". TargetMol.com. Retrieved 3 January 2026.
  19. ↑ Tanaka, Reiko; Minami, Toshifumi; Ishikawa, Yohei; Matsunaga, Shunyo; Tokuda, Harukuni; Nishino, Hoyoku (10 July 2003). "Cancer chemopreventive activity of serratane-type triterpenoids on two-stage mouse skin carcinogenesis". Cancer Letters. 196 (2): 121–126. doi:10.1016/s0304-3835(03)00214-3. ISSN 0304-3835.
  20. 1 2 Ham, Young-Min; Yoon, Weon-Jong; Park, Soo-Yeong; Jung, Yong-Hwan; Kim, Daekyung; Jeon, You-Jin; Wijesinghe, W.A.J.P.; Kang, Sung-Myung; Kim, Kil-Nam (August 2012). "Investigation of the component of Lycopodium serratum extract that inhibits proliferation and mediates apoptosis of human HL-60 leukemia cells". Food and Chemical Toxicology. 50 (8): 2629–2634. doi:10.1016/j.fct.2012.05.019.
  21. ↑ Yamaguchi, Chiharu; Wanibuchi, Hideki; Kakehashi, Anna; Tanaka, Reiko; Fukushima, Shoji (2008-06-01). "Chemopreventive effects of a serratane-type triterpenoid, 3α-methoxyserrat-14-en-21β-ol (PJ-1), against rat lung carcinogenesis". Food and Chemical Toxicology. 46 (6): 1882–1888. doi:10.1016/j.fct.2007.12.018. ISSN 0278-6915.
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