{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T20:46:37Z","timestamp":1764103597678,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science, Research and Innovation Fund (NSRF)","award":["B16F640099","R2566C053","2564\/1"],"award-info":[{"award-number":["B16F640099","R2566C053","2564\/1"]}]},{"name":"Program Management Unit for Human Resources &amp; Institutional Development, Research and Innovation","award":["B16F640099","R2566C053","2564\/1"],"award-info":[{"award-number":["B16F640099","R2566C053","2564\/1"]}]},{"name":"Ministry of Higher Education, Science, Research and Innovation (MHESI)","award":["B16F640099","R2566C053","2564\/1"],"award-info":[{"award-number":["B16F640099","R2566C053","2564\/1"]}]},{"name":"Reinventing University Program 2023, Global and Frontier Research University Fund, Naresuan University","award":["B16F640099","R2566C053","2564\/1"],"award-info":[{"award-number":["B16F640099","R2566C053","2564\/1"]}]},{"name":"National Research Council of Thailand (NRCT)","award":["B16F640099","R2566C053","2564\/1"],"award-info":[{"award-number":["B16F640099","R2566C053","2564\/1"]}]},{"DOI":"10.13039\/501100005076","name":"Agricultural Research Development Agency (ARDA)","doi-asserted-by":"publisher","award":["B16F640099","R2566C053","2564\/1"],"award-info":[{"award-number":["B16F640099","R2566C053","2564\/1"]}],"id":[{"id":"10.13039\/501100005076","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Naresuan University and the Center of Excellence for Innovation in Chemistry (PERCH-CIC)","award":["B16F640099","R2566C053","2564\/1"],"award-info":[{"award-number":["B16F640099","R2566C053","2564\/1"]}]},{"name":"Franco\u2013Thai Scholarship Program","award":["B16F640099","R2566C053","2564\/1"],"award-info":[{"award-number":["B16F640099","R2566C053","2564\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The inhibition of steroid 5-alpha reductase (S5AR), a key mechanism for managing dihydrotestosterone-dependent conditions, has been demonstrated in teak (Tectona grandis L.f.) leaf extracts. Our recent clinical study confirmed the effectiveness of a hair growth formulation containing teak leaf extract in males with androgenic alopecia. However, significant variability in S5AR inhibitory activity among teak leaf samples from different regions underscores the need for quality control of raw materials. This study applied a metabolomics approach to investigate the influence of leaf age, harvesting period, and geographic origin on chemical composition and S5AR inhibitory activity, as well as to identify active S5AR inhibitors. Geographic origin emerged as the primary determinant of variations in chemical profiles and S5AR inhibitory activity. Using orthogonal partial least squares analysis, six diterpenoid S5AR inhibitors were identified, including four compounds reported for the first time as S5AR inhibitors: rhinocerotinoic acid, 7-oxo-8-labden-15-oic acid, 8-hydroxy-labd-13-en-15-oic acid, and a novel diterpene, 7-hydroxy-labd-8,13-dien-15-oic acid. These findings highlight the potential of metabolomics as a powerful tool for discovering bioactive compounds and optimizing raw material selection. By prioritizing proven geographic sources, consistent bioactivity can be achieved, supporting the therapeutic potential of teak leaves in managing S5AR-related conditions.<\/jats:p>","DOI":"10.3390\/molecules30142895","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T09:12:48Z","timestamp":1751965968000},"page":"2895","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Geographic Influence and Metabolomics-Driven Discovery of 5-Alpha Reductase Inhibitors in Tectona grandis L.f. (Teak) Leaves"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3350-9017","authenticated-orcid":false,"given":"Nutchaninad","family":"Tanuphol","sequence":"first","affiliation":[{"name":"Center of Excellence for Natural Health Product Innovation and Center of Excellence for Innovation in Chemistry, Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand"},{"name":"Universit\u00e9 Marie et Louis Pasteur, EFS, INSERM RIGHT (UMR1098), F-25000 Besan\u00e7on, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5116-1395","authenticated-orcid":false,"given":"Corine","family":"Girard","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Marie et Louis Pasteur, EFS, INSERM RIGHT (UMR1098), F-25000 Besan\u00e7on, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prapapan","family":"Temkitthawon","sequence":"additional","affiliation":[{"name":"Center of Excellence for Natural Health Product Innovation and Center of Excellence for Innovation in Chemistry, Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3767-8387","authenticated-orcid":false,"given":"Nungruthai","family":"Suphrom","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Sciences, Naresuan University, Phitsanulok 65000, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nitra","family":"Nuengchamnong","sequence":"additional","affiliation":[{"name":"Science Laboratory Center, Faculty of Science, Naresuan University, Phitsanulok 65000, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tongchai","family":"Saesong","sequence":"additional","affiliation":[{"name":"Center of Excellence for Natural Health Product Innovation and Center of Excellence for Innovation in Chemistry, Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamonlak","family":"Insumrong","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Sciences, Naresuan University, Phitsanulok 65000, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdulaziz","family":"Wadeng","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla 90112, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wiyada","family":"Khangkhachit","sequence":"additional","affiliation":[{"name":"Center of Excellence for Natural Health Product Innovation and Center of Excellence for Innovation in Chemistry, Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8794-4375","authenticated-orcid":false,"given":"Andy","family":"Zedet","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Marie et Louis Pasteur, EFS, INSERM RIGHT (UMR1098), F-25000 Besan\u00e7on, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ratchadaree","family":"Intayot","sequence":"additional","affiliation":[{"name":"Center of Excellence for Innovation in Chemistry, Department of Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5943-6878","authenticated-orcid":false,"given":"Siriporn","family":"Jungsuttiwong","sequence":"additional","affiliation":[{"name":"Center of Excellence for Innovation in Chemistry, Department of Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2340-7220","authenticated-orcid":false,"given":"Anuchit","family":"Plubrukarn","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla 90112, 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Hypotheses"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e13379","DOI":"10.1111\/dth.13379","article-title":"5-Alpha reductase inhibitors in androgenetic alopecia: Shifting paradigms, current concepts, comparative efficacy, and safety","volume":"33","author":"Dhurat","year":"2020","journal-title":"Dermatol. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1016\/j.sjbs.2021.11.026","article-title":"Tectona grandis Lf: A comprehensive review on its patents, chemical constituents, and biological activities","volume":"29","author":"Asdaq","year":"2022","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2338","DOI":"10.1080\/14786419.2018.1440217","article-title":"Tectona grandis (teak)\u2014A review on its phytochemical and therapeutic potential","volume":"33","author":"Vyas","year":"2019","journal-title":"Nat. Prod. Res."},{"key":"ref_5","first-page":"1352","article-title":"Tectona grandis, a potential active ingredient for hair growth promotion","volume":"42","author":"Fachrunniza","year":"2020","journal-title":"Songklanakarin J. Sci. Technol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2515690X241291141","DOI":"10.1177\/2515690X241291141","article-title":"Effectiveness and Safety of Hair Growth Formulation Containing Tectona grandis L.f (Teak) Leaf Extract: A Randomized, Double-Blind, Placebo-Controlled Study on Males with Androgenic Alopecia","volume":"29","author":"Tanuphol","year":"2024","journal-title":"J. Evid. Based Integr. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Insumrong, K., Ingkaninan, K., Waranuch, N., Tanuphol, N., Wisuitiprot, W., Promgool, T., and Suphrom, N. (2022). Isolation and HPLC quantitative determination of 5\u03b1-reductase inhibitors from Tectona grandis L.f leaf extract. Molecules, 27.","DOI":"10.3390\/molecules27092893"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.plaphy.2020.01.006","article-title":"The effect of developmental and environmental factors on secondary metabolites in medicinal plants","volume":"148","author":"Li","year":"2020","journal-title":"Plant Physiol. Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8894","DOI":"10.3390\/cimb45110558","article-title":"Plant metabolomics: Current initiatives and future prospects","volume":"45","author":"Manickam","year":"2023","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Saesong, T., Allard, P.-M., Ferreira Queiroz, E., Marcourt, L., Nuengchamnong, N., Temkitthawon, P., Khorana, N., Wolfender, J.-L., and Ingkaninan, K. (2019). Discovery of lipid peroxidation inhibitors from Bacopa species prioritized through multivariate data analysis and multi-informative molecular networking. Molecules, 24.","DOI":"10.3390\/molecules24162989"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"140977","DOI":"10.1016\/j.foodchem.2024.140977","article-title":"Seasonal variations and sensory profiles of oolong tea: Insights from metabolic analysis of Tieguanyin cultivar","volume":"462","author":"Zhou","year":"2025","journal-title":"Food Chem."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Sehlakgwe, P.F., Lall, N., and Prinsloo, G. (2020). 1H-NMR Metabolomics and LC-MS Analysis to Determine Seasonal Variation in a Cosmeceutical Plant Leucosidea sericea. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.00219"},{"key":"ref_13","first-page":"54","article-title":"Effect of reverse osmosis concentration coupled with drying processes on polyphenols and antioxidant activity obtained from Tectona grandis leaf aqueous extracts","volume":"2","author":"Koffi","year":"2015","journal-title":"J. Appl. Res. Med. Aromat. Plants"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1111\/cote.12594","article-title":"Utilisation of Tectona grandis (teak) leaf extracts as natural hair dyes","volume":"138","author":"Tibkawin","year":"2022","journal-title":"Color. Technol."},{"key":"ref_15","unstructured":"Nayeem, N., and Karvekar, M. (2010). Comparative phytochemical and pharmacological screening of the methanolic extracts of the frontal and mature leaves of Tectona grandis. Int. J. Pharma Bio Sci., 1."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10142","DOI":"10.1021\/jf8016833","article-title":"Revealing the metabonomic variation of rosemary extracts using 1H NMR spectroscopy and multivariate data analysis","volume":"56","author":"Xiao","year":"2008","journal-title":"J. Agric. Food Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/S0031-9422(97)00147-7","article-title":"Diterpenoids and flavonoids from Ophryosporus charrua","volume":"45","author":"Favier","year":"1997","journal-title":"Phytochemistry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.indcrop.2014.06.012","article-title":"Isolation, analytical quantification and seasonal variation of labdanolic acid from the Portuguese-grown Cistus ladaniferus","volume":"60","author":"Martins","year":"2014","journal-title":"Ind. Crops Prod."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9991","DOI":"10.1016\/S0040-4020(01)92289-6","article-title":"Ambergis compounds from labdanolic acid","volume":"48","author":"Urones","year":"1992","journal-title":"Tetrahedron"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5657","DOI":"10.1016\/S0040-4020(01)00493-8","article-title":"The synthesis of (\u2212)-Ambrox\u00ae starting from labdanolic acid","volume":"57","author":"Bolster","year":"2001","journal-title":"Tetrahedron"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1515\/znc-1977-9-1009","article-title":"Tectograndinol, ein neues Diterpen aus Tectona grandis L. fil.\/Tectograndinol, a New Diterpene from Tectona grandis L. fil","volume":"32","author":"Rimpler","year":"1977","journal-title":"Z. Naturforsch. C"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s11418-006-0025-7","article-title":"First isolation of three diterpenes as naturally-occurring compounds from Sindora siamensis","volume":"61","author":"Aoki","year":"2007","journal-title":"J. Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1021\/ja01273a044","article-title":"A new substance, cativic acid, and its preparation, properties and derivatives","volume":"60","author":"Kalman","year":"1938","journal-title":"J. Am. Chem. Soc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1016\/0031-9422(81)80124-0","article-title":"Labdane diterpenes from Cistus symphytifolius","volume":"20","author":"Calabuig","year":"1981","journal-title":"Phytochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1021\/np500022w","article-title":"Absolute configuration of (13 R)-and (13 S)-labdane diterpenes coexisting in Ageratina jocotepecana","volume":"77","year":"2014","journal-title":"J. Nat. Prod."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1007\/s00044-017-1869-y","article-title":"Anti-androgenic curcumin analogues as steroid 5-alpha reductase inhibitors","volume":"26","author":"Srivilai","year":"2017","journal-title":"Med. Chem. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1007\/s10886-010-9769-3","article-title":"Isolation and phytotoxicity of terpenes from Tectona grandis","volume":"36","author":"Lacret","year":"2010","journal-title":"J. Chem. Ecol."},{"key":"ref_28","first-page":"33","article-title":"Studies of South African medicinal plants: Pt. 7","volume":"41","author":"Dekker","year":"1988","journal-title":"S. Afr. J. Chem."},{"key":"ref_29","unstructured":"Gallego, J.C.A. (2006). Influencia de los Factores Clim\u00e1ticos en la S\u00edntesis y Actividad de Compuestos Fitot\u00f3xicos Secretados por Cistus ladanifer L.. [Ph.D. Thesis, Universidad de Extremadura]. Available online: https:\/\/www.researchgate.net\/publication\/39379903."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6","DOI":"10.3390\/plants1010006","article-title":"Seasonal variation of Cistus ladanifer L. diterpenes","volume":"1","author":"Sosa","year":"2012","journal-title":"Plants"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S0367-326X(98)00035-5","article-title":"Constituents of the pods of Piliostigma thonningii","volume":"70","author":"Baratta","year":"1999","journal-title":"Fitoterapia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1021\/acs.jnatprod.5b00166","article-title":"Structure and absolute configuration of diterpenoids from Hymenaea stigonocarpa","volume":"78","author":"Monteiro","year":"2015","journal-title":"J. Nat. Prod."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Insumrong, K., Waranuch, N., Ingkaninan, K., Tanuphol, N., Mishra, A.P., Wisuitiprot, W., Wongwad, E., Ngamdokmai, N., and Suphrom, N. (2025). In Vitro Skin Penetration of 5\u03b1-Reductase Inhibitors from Tectona grandis L.f Leaf Extracts. Molecules, 30.","DOI":"10.3390\/molecules30051151"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1042\/bj2850557","article-title":"Inhibition of steroid 5 \u03b1-reductase by specific aliphatic unsaturated fatty acids","volume":"285","author":"Liang","year":"1992","journal-title":"Biochem. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.steroids.2009.10.005","article-title":"An overview on 5\u03b1-reductase inhibitors","volume":"75","author":"Aggarwal","year":"2010","journal-title":"Steroids"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.steroids.2016.10.007","article-title":"A new label-free screen for steroid 5\u03b1-reductase inhibitors using LC-MS","volume":"116","author":"Srivilai","year":"2016","journal-title":"Steroids"},{"key":"ref_37","unstructured":"Rijo, P. (2011). Phytochemical Study and Biological Activities of Diterpenes and Derivatives from Plectranthus species. [Ph.D. Thesis, Universidade de Lisboa]."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/14\/2895\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:06:35Z","timestamp":1760033195000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/14\/2895"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,8]]},"references-count":37,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["molecules30142895"],"URL":"https:\/\/doi.org\/10.3390\/molecules30142895","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2025,7,8]]}}}