{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:40:52Z","timestamp":1760146852642,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T00:00:00Z","timestamp":1735516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Okinawa Innovation Ecosystem Joint Research Promotion Project","award":["FT2023-2024","22K20717"],"award-info":[{"award-number":["FT2023-2024","22K20717"]}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science (JSPS)","doi-asserted-by":"publisher","award":["FT2023-2024","22K20717"],"award-info":[{"award-number":["FT2023-2024","22K20717"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Leishmaniasis is a major public health problem, especially affecting vulnerable populations in tropical and subtropical regions. The disease is endemic in 90 countries, and with millions of people at risk, it is seen as one of the ten most neglected tropical diseases. Current treatments face challenges such as high toxicity, side effects, cost, and growing drug resistance. There is an urgent need for safer, affordable treatments, especially for cutaneous leishmaniasis (CL), the most common form. Marine invertebrates have long been resources for discovering bioactive compounds such as sesterterpenoids. Using bioassay-guided fractionations against cutaneous-type leishmaniasis promastigotes, we identified a novel furanosesterterpenoid, petrosaspongin from Okinawan marine sponges and a nudibranch, along with eight known sesterterpenoids, hippospongins and manoalides. The elucidated structure of petrosaspongin features a \u03b2-substituted furane ring, a tetronic acid, and a conjugated triene. The sesterterpenoids with a \u03b3-butenolide group exhibited leishmanicidal activity against Leishmania major promastigotes, with IC50 values ranging from 0.69 to 53 \u03bcM. The structure\u2013activity relationship and molecular docking simulation suggest that \u03b3-lactone is a key functional group for leishmanicidal activity. These findings contribute to the ongoing search for more effective treatments against CL.<\/jats:p>","DOI":"10.3390\/md23010016","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T07:00:37Z","timestamp":1735628437000},"page":"16","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Novel Sesterterpenoid, Petrosaspongin and \u03b3-Lactone Sesterterpenoids with Leishmanicidal Activity from Okinawan Marine Invertebrates"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5866-0341","authenticated-orcid":false,"given":"Takahiro","family":"Jomori","sequence":"first","affiliation":[{"name":"Department of Chemistry, Biology and Marine Science, Faculty of Science, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nanami","family":"Higa","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Biology and Marine Science, Faculty of Science, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shogo","family":"Hokama","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Biology and Marine Science, Faculty of Science, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Trianda Ayuning","family":"Tyas","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Biology and Marine Science, Faculty of Science, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natsuki","family":"Matsuura","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yudai","family":"Ueda","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Kimura","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sei","family":"Arizono","sequence":"additional","affiliation":[{"name":"Faculty of Agriculture, University of Miyazaki, 1-1 Gakuen-kibanadai-nishi, Miyazaki 889-2192, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole Joy","family":"de Voogd","sequence":"additional","affiliation":[{"name":"Naturalis Biodiversity Center, 2300 RA Leiden, The Netherlands"},{"name":"Institute of Environmental Sciences (CML), Leiden University, P.O. Box 9518, 2300 RA Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhiro","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Faculty of Agriculture, University of Miyazaki, 1-1 Gakuen-kibanadai-nishi, Miyazaki 889-2192, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mina","family":"Yasumoto-Hirose","sequence":"additional","affiliation":[{"name":"Tropical Technology Plus, Uruma, Okinawa 904-2234, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8672-7379","authenticated-orcid":false,"given":"Junichi","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Biology and Marine Science, Faculty of Science, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9718-0823","authenticated-orcid":false,"given":"Kanami","family":"Mori-Yasumoto","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,30]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization\/PAHO (2024, November 30). Neglected Tropical Diseases Factsheet. Pan American Health Organization. Available online: https:\/\/www.paho.org\/en\/topics\/leishmaniasis."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Choi, H.L., Jain, S., Ruiz Postigo, J.A., Borisch, B., and Dagne, D.A. (2021). The global procurement landscape of leishmaniasis medicines. PLoS Negl. Trop. Dis., 15.","DOI":"10.1371\/journal.pntd.0009181"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.actatropica.2011.02.007","article-title":"Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the New World","volume":"118","author":"Oliveira","year":"2011","journal-title":"Acta Trop."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"102863","DOI":"10.1016\/j.parint.2024.102863","article-title":"A review on potential therapeutic targets for the treatment of leishmaniasis","volume":"100","author":"Sheikh","year":"2024","journal-title":"Parasitol. Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e2220934120","DOI":"10.1073\/pnas.2220934120","article-title":"Terpene biosynthesis in marine sponge animals","volume":"120","author":"Wilson","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Avila, C., and Angulo-Preckler, C. (2022). Bioactive compounds from marine Heterobranchs. Mar. Drugs, 18.","DOI":"10.3390\/md18120657"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1039\/b604586c","article-title":"Heterocyclic terpenes: Linear furano- and pyrroloterpenoids","volume":"23","author":"Liu","year":"2006","journal-title":"Nat. Prod. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1021\/np020497l","article-title":"Three new cytotoxic sesterterpenes from a marine sponge Spongia sp","volume":"66","author":"Tsukamoto","year":"2003","journal-title":"J. Nat. Prod."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1021\/np960130e","article-title":"Three new cytotoxic sesterterpenes from the marine sponge Hyrtios cf","volume":"59","author":"Ryu","year":"1996","journal-title":"erectus. J. Nat. Prod."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5993","DOI":"10.1016\/0040-4020(72)88132-8","article-title":"Scalarin, a new pentacyclic C-25 terpenoid from the sponge Cacospongia scalaris","volume":"28","author":"Fattorusso","year":"1972","journal-title":"Tetrahedron"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1002\/cmdc.201000302","article-title":"Hypoxia-selective growth inhibition of cancer cells by furospinosulin-1, a furanosesterterpene isolated from an Indonesian marine sponge","volume":"5","author":"Arai","year":"2010","journal-title":"ChemMedChem"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/cbic.201500519","article-title":"Furospinosulin-1, marine spongean furanosesterterpene, suppresses the growth of hypoxia-adapted cancer cells by binding to transcriptional regulators p54(nrb) and LEDGF\/p75","volume":"17","author":"Arai","year":"2016","journal-title":"ChemBioChem"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1016\/S0040-4039(00)77766-5","article-title":"Manoalide, an antibiotic sesterterpenoid from the marine sponge Luffariella variabilis (polejaff)","volume":"21","author":"Scheuer","year":"1980","journal-title":"Tetrahedron"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7234","DOI":"10.1016\/S0021-9258(17)39598-4","article-title":"Cobra venom phospholipase A2 inhibition by manoalide","volume":"260","author":"Lombardo","year":"1985","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"313","DOI":"10.3390\/md8020313","article-title":"Bioactive sesterterpenes and triterpenes from marine sponges: Occurrence and pharmacological significance","volume":"8","author":"Ebada","year":"2010","journal-title":"Mar. Drugs"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1039\/a809395d","article-title":"Marine natural products","volume":"17","author":"Faulkner","year":"2000","journal-title":"Nat. Prod. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1016\/S0040-4039(00)84462-7","article-title":"Hippospongin, a novel furanosesterterpene possessing antispasmodic activity from the Okinawan marine sponge Hippospongia sp","volume":"27","author":"Kobayashi","year":"1986","journal-title":"Tetrahedron"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1021\/np000060i","article-title":"Hipposulfates A and B, new sesterterpene sulfates from an Okinawan sponge, Hippospongia cf","volume":"64","author":"Musman","year":"2001","journal-title":"metachromia. J. Nat. Prod."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1021\/np020456p","article-title":"New cytotoxic furanosesterterpenes from an Okinawan marine sponge, Ircinia sp","volume":"66","author":"Issa","year":"2003","journal-title":"J. Nat. Prod."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3147","DOI":"10.1016\/S0040-4039(01)81849-9","article-title":"Three new sesterterpenoid antibiotics from the marine sponge Luffariella variabilis (polejaff)","volume":"22","author":"Scheuer","year":"1981","journal-title":"Tetrahedron Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1021\/np50056a026","article-title":"Chemistry of sponges III. Manoalide monoacetate and thorectolide monoacetate, two new sesterterpenoids from Thorectandra excavatus","volume":"51","author":"Cambie","year":"1988","journal-title":"J. Nat. Prod."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1248\/cpb.57.885","article-title":"Deoxymanoalides from the nudibranch Chromodoris willani","volume":"57","author":"Uddin","year":"2009","journal-title":"Chem. Pham. Bull."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1002\/hlca.19770600425","article-title":"Ircinianin, a novel sesterterpene from a marine sponge","volume":"60","author":"Hofheinz","year":"1977","journal-title":"Helv. Chim. Acta"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1007\/BF01963243","article-title":"Palinurin, a new linear sesterterpene from a marine sponge","volume":"35","author":"Alfano","year":"1979","journal-title":"Experientia"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1021\/np50026a022","article-title":"On the stereochemistry and biogenesis of C21 linear furanoterpenes in Ircinia sp","volume":"46","author":"Barrientos","year":"1983","journal-title":"J. Nat. Prod."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s00436-007-0469-z","article-title":"Antileishmanial potential of a marine sponge, Haliclona exigua (Kirkpatrick) against experimental visceral leishmaniasis","volume":"10","author":"Dube","year":"2007","journal-title":"Parasitol. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e20211090","DOI":"10.1590\/0001-3765202220211090","article-title":"Anti-Leishmania amazonensis activity of the marine sponge Dercitus (Stoeba) latex (Porifera) from S\u00e3o Pedro and S\u00e3o Paulo Archipelago, Pernambuco, Brazil","volume":"94","author":"Barreto","year":"2022","journal-title":"An. Acad. Bras. Cienc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.sjbs.2021.08.068","article-title":"Promising antiparasitic agents from marine sponges","volume":"29","author":"Mostafa","year":"2022","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1021\/acs.jnatprod.7b00876","article-title":"Isolation, Derivative Synthesis, and Structure-Activity Relationships of Antiparasitic Bromopyrrole Alkaloids from the Marine Sponge Tedania brasiliensis","volume":"81","author":"Parra","year":"2018","journal-title":"J. Nat. Prod."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1021\/acs.jnatprod.5b00070","article-title":"Anti-parasitic Guanidine and Pyrimidine Alkaloids from the Marine Sponge Monanchora arbuscula","volume":"78","author":"Santos","year":"2015","journal-title":"J. Nat. Prod."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2566","DOI":"10.1021\/acs.jnatprod.7b00543","article-title":"Antiprotozoal Linear Furanosesterterpenoids from the Marine Sponge Ircinia oros","volume":"80","author":"Chianese","year":"2017","journal-title":"J. Nat. Prod."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Majer, T., Bhattarai, K., Straetener, J., Pohlmann, J., Cahill, P., Zimmermann, M.O., H\u00fcbner, M.P., Kaiser, M., Svenson, J., and Schindler, M. (2022). Discovery of Ircinianin Lactones B and C-Two New Cyclic Sesterterpenes from the Marine Sponge Ircinia wistarii. Mar. Drugs, 20.","DOI":"10.3390\/md20080532"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1111\/j.1476-5381.2009.00609.x","article-title":"16\u03b1-Hydroxycleroda-3,13(14)Z-dien-15,16-olide from Polyalthia longifolia: A safe and orally active antileishmanial agent","volume":"159","author":"Misra","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"W324","DOI":"10.1093\/nar\/gkae300","article-title":"SwissDock 2024: Major enhancements for small-molecule docking with Attracting Cavities and AutoDock Vina","volume":"52","author":"Bugnon","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1016\/j.jmb.2006.01.022","article-title":"The structure of the transition state of the heterodimeric topoisomerase I of Leishmania donovani as a vanadate complex with nicked DNA","volume":"357","author":"Davies","year":"2006","journal-title":"J. Mol. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.ijpddr.2019.06.003","article-title":"Route map for the discovery and pre-clinical development of new drugs and treatments for cutaneous leishmaniasis","volume":"11","author":"Caridha","year":"2019","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1021\/np0498354","article-title":"Antitubercular sesterterpenes from the Thai sponge Brachiaster sp","volume":"67","author":"Wonganuchitmeta","year":"2004","journal-title":"J. Nat. Prod."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/23\/1\/16\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:56:15Z","timestamp":1760115375000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/23\/1\/16"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,30]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["md23010016"],"URL":"https:\/\/doi.org\/10.3390\/md23010016","relation":{},"ISSN":["1660-3397"],"issn-type":[{"type":"electronic","value":"1660-3397"}],"subject":[],"published":{"date-parts":[[2024,12,30]]}}}