Clavukellines A-N: dolabellane diterpenes from the soft coral Clavularia koellikeri

Abstract

Chemical investigation of the soft coral Clavularia koellikeri led to the isolation of fourteen new diterpenoid derivatives clavukellines A-N (1-14) featuring the dolabellane-type skeleton. Structural characterization of these compounds was accomplished through an integrated analytical strategy combining NMR spectroscopy and HR-ESI-MS. Absolute configurations were unambiguously assigned using ECD spectral simulation and DP4 + probability analysis. Preliminary pharmacological evaluation indicated that compounds 8 and 13 exhibited anti-inflammatory activity, while compounds 1-14 showed antithrombotic activity. This study reveals promising anti-inflammatory and antithrombotic potentials that warrant further investigation.

Keywords

Clavularia koellikeri / Dolabellane diterpenes Absolute configurations / Anti-inflammatory activity / Antithrombotic activity

Funding

This work was supported by the National Key R&D Program of China (No. 2024YFC2815900), China Postdoctoral Science Foundation (No. 2024M763097), Shandong Postdoctoral Science Foundation (No. SDCX-ZG-202400077), and Qingdao Postdoctoral Science Foundation (No. QDBSH20240102034).

Declaration of competing interests

These authors have no conflict of interest to declare.

Data availability

This work was supported by the National Natural Science Foundation of China (Nos. 82274510, 82474454, 82405070, 82360918), the Natural Science Foundation of Guangdong Province, China (No. 2024A1515012173), and the Jiangxi Provincial Administration of Traditional Chinese Medicine Science and Technology Plan (No. 2023B0597).

References

[1] Zhu SH, Gong Q, Li SW, et al. Uncommon 4-methylpregnane and anti-inflammatory 5α8α-epidioxysterols from the South China Sea soft coral Sarcophyton sp. Phytochemistry. 2025; 239:114586. https://doi.org/10.1016/j.phytochem.2025.114586.

[2] Zong Y, Yang JJ, Zhang HM, et al. Eleven undescribed sesquiterpenoids with multiple skeleton types and cytotoxicity from the South China Sea soft coral Lemnalia sp. Phytochemistry. 2025; 238:11457. https://doi.org/10.1016/j.phytochem.2025.114576.

[3] Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades from 01/ 1981 to 09/2019. J Nat Prod. 2020; 83:770-803. https://doi.org/10.1021/acs.jnatprod.9b01285.

[4] Inuzuka T, Kawazoe Y, Kobayashi S, et al. Haebaruol, a 9,11-secosteroid isolated from the soft coral Clavularia sp. Chem Lett. 2016; 45:81-82. https://doi.org/10.1246/cl.150938.

[5] Cheng MY, Chuang YT, Chang HW, et al. Chemical constituents from soft coral Clavularia spp. Demonstrate antiproliferative effects on oral cancer cells. Mar Drugs. 2023; 21:529-538. https://doi.org/10.3390/md21100529.

[6] Chang CH, Wen ZH, Wang SK, et al. New anti-inflammatory steroids from the Formosan soft coral Clavularia viridis. Steroids. 2008; 73:562-567. https://doi.org/10.1016/j.steroids.2008.01.007.

[7] Chiu CY, Ling XH, Wang SK, et al. Ubiquitin-proteasome modulating dolabellanes and secosteroids from soft coral Clavularia flava. Mar Drugs. 2020; 18:39. https://doi.org/10.3390/md18010039.

[8] Shen YC, Lo KL, Chang JY, et al. New cytotoxic prostanoids from Taiwanese soft coral Clavularia viridis. Chem Biodivers. 2010; 7:2702-2708. https://doi.org/10.1002/cbdv.200900378.

[9] Gao Y, Xiao W, Liu HC, et al. Clavuridins A and B, two new trinor-guaiane sesquiterpenes isolated from the Xisha soft coral Clavularia viridis. Chin J Nat Med. 2017; 15(11):855-859. https://doi.org/10.1016/S1875-5364(18)30019-.

[10] Gao Y, Du YQ, Zang Y, et al. Dolabellane diterpenoids from the Xisha soft coral Clavularia viridis. ACS Omega. 2022; 7:3052-3059. https://doi.org/10.1021/acsomega.1c06156.

[11] Du YQ, Gao Y, Zang Y, et al. Extending the record of dolabellane-type diterpenoids from the soft coral Clavularia viridis: structures and stereochemistry. Phytochemistry. 2023; 210:113671. https://doi.org/10.1016/j.phytochem.2023.113671.

[12] Morikawa T, Xu F, Kashima Y, et al. Novel dolabellane-type diterpene alkaloids with lipid metabolism promoting activities from the seeds of Nigella sativa. Org Lett. 2004; 6(6):869-872. https://doi.org/10.1021/ol036239.

[13] Wei X, Rodríguez AD, Baran P, et al. Dolabellane-type diterpenoids with antiprotozoan activity from a Southwestern Caribbean gorgonian octocoral of the genus Eunicea. J Nat Prod. 2010; 73:925-934. https://doi.org/10.1021/np100074.

[14] Wang SK, Huang MJ, Duh CY. Cytotoxic constituents from the Formosan soft coral Clavularia inflata var. luzoniana. J Nat Prod. 2006; 69:1411-1416. https://doi.org/10.1021/np0601253.

[15] Shen YC, Pan YL, Ko CL, et al. New dolabellanes from the Taiwanese soft coral Clavularia inflata. J Chin Chem Soc. 2003; 50:471-476. https://doi.org/10.1002/jccs.200300074.

[16] Gao Y, Xiao W, Liu HC, et al. Clavirolide G, a new rare dolabellane-type diterpenoid from the Xisha soft coral Clavularia viridis. Chin Chem Lett. 2017; 15:905-908. https://doi.org/10.1016/j.cclet.2017.01.004.

[17] Donia M, Hamann MT. Marine natural products and their potential applications as anti-infective agents. Lancet Infect Dis. 2003; 3:338-348. https://doi.org/10.1016/S1473-3099(03)00655-.

[18] Jarmusch SA, Van der Hooft JJJ, Dorrestein PC, et al. Advancements in capturing and mining mass spectrometry data are transforming natural products research. Nat Prod Rep. 2021; 38:2066-2082. https://doi.org/10.1039/D1NP00040.

[19] Blunt JW, Carroll AR, Copp BR, et al.Marine natural products. Nat Prod Rep. 2018; 35:8-53. https://doi.org/10.1039/c7np00052.

[20] Iguchi K, Fukaya T, Yasumoto A, et al. New marine sesquiterpenoids and diterpenoids from the Okinawan soft coral Clavularia koellikeri. J Nat Prod. 2004; 67:577-583. https://doi.org/10.1021/np0304013.

[21] Iwashima M, Matsumoto Y, Takenaka Y, et al. New marine diterpenoids from the Okinawan soft coral Clavularia koellikeri. J Nat Prod. 2002; 65:1441-1446. https://doi.org/10.1021/np0200156.

[22] Yang BY, He Y, Lin S, et al. Antimicrobial dolabellanes and atranones from a marine-derived strain of the toxigenic fungus Stachybotrys chartarum. J Nat Prod. 2019; 82:1923-1929. https://doi.org/10.1021/acs.jnatprod.9b00305.

[23] Dong X, Wu JS, Jia HL, et al. Targeted isolation of dolabellane diterpenoids from the soft coral Clavularia viridis using molecular networking. ACS Omega. 2023; 8:21254-21264. https://doi.org/10.1021/acsomega.3c02429.

[24] Luo XC, Wang Q, Tang XL, et al. Cytotoxic manoalide-type sesterterpenes from the sponge Luffariella variabilis collected in the South China Sea. J Nat Prod. 2021; 84:61-70. https://doi.org/10.1021/acs.jnatprod.0c01026.

[25] Han X, Luo XC, Xue L, et al. Dolabellane diterpenes and elemane alkaloids from the soft coral Clavularia inflata collected in the South China Sea. J Nat Prod. 2022; 85:276-283. https://doi.org/10.1021/acs.jnatprod.1c01103.