Fourteen diterpenes were isolated from methanol extracts of the aerial parts ofColeus comosus,Coleus forsteri "Marginatus", and Plectranthus ciliatus. The compounds belong to the abietane (1-4, 9-11, and 13), ent-clerodane (5-8), and ent-kaurane (14, 15) classes. Three new compounds were isolated from C. comosus, including 3-O-acetylornatin G (2), 3,12-di-O-acetylornatin G (3), ornatin B methyl ester (5), and ornatin F (4), for which we proposed a revised structure. The structures of the compounds were determined by comprehensive spectroscopic data analysis. The isolated diterpenes were examined in silico for their physicochemical and early ADME properties. Their antiproliferative effects were determined in vitro using human breast (MDA-MB-231 and MCF-7), cervical (HeLa), and glioblastoma (U-87 MG) cancer cell lines. The royleanone- and hydroquinone-type abietane diterpenes (9-13)exhibited the most potent antiproliferative activity against all cancer cell lines tested, particularly against glioblastoma cells, with IC50 values ranging from 1.1 to 15.6 μM.

Department of Analytical Chemistry Institute of Chemistry Eötvös Loránd University 1117 Budapest Hungary

Department of Chemistry Faculty of Science Masaryk University 625 00 Brno Czechia

Department of Natural Drugs Faculty of Pharmacy Masaryk University 612 00 Brno Czechia

Department of Pharmaceutical Chemistry Semmelweis University 1092 Budapest Hungary

Department of Pharmacognosy Semmelweis University 1085 Budapest Hungary

HUN REN SZTE Biologically Active Natural Products Research Group 6720 Szeged Hungary

Institute of Pharmacodynamics and Biopharmacy Faculty of Pharmacy University of Szeged 6720 Szeged Hungary

Institute of Pharmacognosy Faculty of Pharmacy University of Szeged 6720 Szeged Hungary

Interdisciplinary Centre of Natural Products University of Szeged 6720 Szeged Hungary

National Center for Biomolecular Research Faculty of Science Masaryk University 625 00 Brno Czechia

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World Health Organization . Cancer. https://www.who.int/news-room/fact-sheets/detail/cancer (accessed Dec 17 2023).

Majolo F.; De Oliveira Becker Delwing L. K.; Marmitt D. J.; Bustamante-Filho I. C.; Goettert M. I. Medicinal plants and bioactive natural compounds for cancer treatment: Important advances for drug discovery. Phytochem. Lett. 2019, 31, 196–207. 10.1016/j.phytol.2019.04.003. DOI

Cragg G. M.; Newman D. J.. Natural products as sources of anticancer agents: Current approaches and perspectives. In Natural Products as source of molecules with therapeutic potential: Research & development, challenges and perspectives; Cechinel Filho V., Ed.; Springer International Publishing: Cham, 2018, pp 309–331.10.1007/978-3-030-00545-0_8 DOI

Cragg G. M.; Newman D. J. Plants as a source of anti-cancer agents. J. Ethnopharmacol. 2005, 100 (1–2), 72–79. 10.1016/j.jep.2005.05.011. PubMed DOI

Paton A. J.; Mwanyambo M.; Govaerts R. H. A.; Smitha K.; Suddee S.; Phillipson P. B.; Wilson T. C.; Forster P. I.; Culham A. Nomenclatural changes in Coleus and Plectranthus (Lamiaceae): A Tale of more than two genera. PhytoKeys 2019, 129, 1–158. 10.3897/phytokeys.129.34988. PubMed DOI PMC

Lukhoba C. W.; Simmonds M. S. J.; Paton A. J. Plectranthus: A review of ethnobotanical uses. J. Ethnopharmacol. 2006, 103 (1), 1–24. 10.1016/j.jep.2005.09.011. PubMed DOI

Mothana R. A.; Khaled J. M.; El-Gamal A. A.; Noman O. M.; Kumar A.; Alajmi M. F.; Al-Rehaily A. J.; Al-Said M. S. Comparative evaluation of cytotoxic, antimicrobial and antioxidant activities of the crude extracts of three Plectranthus species grown in Saudi Arabia. Saudi Pharm. J. 2019, 27 (2), 162–170. 10.1016/j.jsps.2018.09.010. PubMed DOI PMC

Matias D.; Nicolai M.; Saraiva L.; Pinheiro R.; Faustino C.; Diaz Lanza A.; Pinto Reis C.; Stankovic T.; Dinic J.; Pesic M.; Rijo P. Cytotoxic activity of royleanone diterpenes from Plectranthus madagascariensis Benth. ACS Omega 2019, 4 (5), 8094–8103. 10.1021/acsomega.9b00512. PubMed DOI PMC

Gáborová M.; Šmejkal K.; Kubínová R. Abietane diterpenes of the genus Plectranthus sensu lato. Molecules 2021, 27 (1), 166.10.3390/molecules27010166. PubMed DOI PMC

Ito T.; Rakainsa S. K.; Nisa K.; Morita H. Three new abietane-type diterpenoids from the leaves of Indonesian Plectranthus scutellarioides. Fitoterapia 2018, 127, 146–150. 10.1016/j.fitote.2018.02.013. PubMed DOI

Mesquita L. S. F.; Matos T. S.; Ávila F. d. N.; Batista A. d. S.; Moura A. F.; de Moraes M. O.; da Silva M. C. M.; Ferreira T. L. A.; Nascimento N. R. F.; Monteiro N. K. V.; Pessoa O. D. L. Diterpenoids from leaves of cultivated Plectranthus ornatus. Planta Med. 2021, 87 (01/02), 124–135. 10.1055/a-1209-3252. PubMed DOI

Ávila F. N.; Pinto F. C. L.; Sousa T. S.; Torres M. C. M.; Costa-Lotufo L. V.; Rocha D. D.; de Vasconcelos M. A.; Cardoso-Sá N.; Teixeira E. H.; Albuquerque M. R. J. R.; Silveira E. R.; Pessoa O. D. L. Miscellaneous Diterpenes from the aerial parts of Plectranthus ornatus Codd. J. Braz. Chem. Soc. 2016, 28 (6), 1014–1022. 10.21577/0103-5053.20160255. DOI

Rijo P.; Gaspar-Marques C.; Simões M. F.; Duarte A.; del Carmen Apreda-Rojas M.; Cano F. H.; Rodríguez B. Neoclerodane and labdane diterpenoids from Plectranthus ornatus. J. Nat. Prod. 2002, 65 (10), 1387–1390. 10.1021/np020203w. PubMed DOI

Oliveira P. M.; Ferreira A. A.; Silveira D.; Alves R. B.; Rodrigues G. V.; Emerenciano V. P.; Raslan D. S. Diterpenoids from the aerial parts of Plectranthus ornatus. J. Nat. Prod. 2005, 68 (4), 588–591. 10.1021/np049827n. PubMed DOI

Rijo P.; Fátima Simões M.; Rodríguez B. Structural and spectral assignment of three forskolin-like diterpenoids isolated from Plectranthus ornatus. Magn. Reson. Chem. 2005, 43 (7), 595–598. 10.1002/mrc.1600. PubMed DOI

Rijo P.; Gaspar-Marques C.; Simões M. F.; Jimeno M. L.; Rodríguez B. Further Diterpenoids from Plectranthus ornatus and P. grandidentatus. Biochem. Syst. Ecol. 2007, 35 (4), 215–221. 10.1016/j.bse.2006.10.011. DOI

Kubínová R.; Švajdlenka E.; Schneiderová K.; Hanáková Z.; Dall’Acqua S.; Farsa O. Polyphenols and diterpenoids from Plectranthus forsteri “Marginatus”. Biochem. Syst. Ecol. 2013, 49, 39–42. 10.1016/j.bse.2013.03.029. DOI

Wellsow J.; Grayer R. J.; Veitch N. C.; Kokubun T.; Lelli R.; Kite G. C.; Simmonds M. S. J. Insect-antifeedant and antibacterial activity of diterpenoids from species of Plectranthus. Phytochemistry 2006, 67 (16), 1818–1825. 10.1016/j.phytochem.2006.02.018. PubMed DOI

Nicolas M.; Lasalo M.; Chow S.; Antheaume C.; Huet K.; Hnawia E.; Guillemin G. J.; Nour M.; Matsui M. Anti-inflammatory activities of Coleus forsteri (formerly Plectranthus forsteri) extracts on human macrophages and chemical characterization. Front. Pharmacol 2023, 13, 1081310.10.3389/fphar.2022.1081310. PubMed DOI PMC

Saeed M. E. M.; Meyer M.; Hussein A.; Efferth T. Cytotoxicity of South-African medicinal plants towards sensitive and multidrug-resistant cancer cells. J. Ethnopharmacol. 2016, 186, 209–223. 10.1016/j.jep.2016.04.005. PubMed DOI

Kubínová R.; Pořízková R.; Navrátilová A.; Farsa O.; Hanáková Z.; Bačinská A.; Čížek A.; Valentová M. Antimicrobial and enzyme inhibitory activities of the constituents of Plectranthus madagascariensis (Pers.) Benth. J. Enzyme Inhib. Med. Chem. 2014, 29 (5), 749–752. 10.3109/14756366.2013.848204. PubMed DOI

Kubínová R.; Gazdová M.; Hanáková Z.; Jurkaninová S.; Dall’Acqua S.; Cvačka J.; Humpa O. New diterpenoid glucoside and flavonoids from Plectranthus scutellarioides (L.) R. Br. South Afr. J. Bot. 2019, 120, 286–290. 10.1016/j.sajb.2018.08.023. DOI

Ntungwe E. N.; Stojanov S. J.; Duarte N. M.; Candeias N. R.; Díaz-Lanza A. M.; Vágvölgyi M.; Hunyadi A.; Pešić M.; Rijo P. C20-nor-abietane and three abietane diterpenoids from Plectranthus mutabilis leaves as P-glycoprotein modulators. ACS Med. Chem. Lett. 2022, 13 (4), 674–680. 10.1021/acsmedchemlett.1c00711. PubMed DOI PMC

Schmid J. M.; Rüedi P.; Eugster C. H. Diterpenoide drüsenfarbstoffe aus Labiaten: 22 Neue coleone und royleanone aus Plectranthus lanuginosus. Helv. Chim. Acta 1982, 65 (7), 2136–2163. 10.1002/hlca.19820650721. DOI

Gaspar-Marques C.; Simões M. F.; Rodríguez B. Further labdane and kaurane diterpenoids and other constituents from Plectranthus fruticosus. J. Nat. Prod. 2004, 67 (4), 614–621. 10.1021/np030490j. PubMed DOI

Stavri M.; Paton A.; Skelton B. W.; Gibbons S. Antibacterial diterpenes from Plectranthus ernstii. J. Nat. Prod. 2009, 72 (6), 1191–1194. 10.1021/np800581s. PubMed DOI

Hensch M.; Rüedi P.; Eugster C. H. Horminon, taxochinon und weitere royleanone aus 2 abessinischen Plectranthus -spezies (Labiatae). Helv. Chim. Acta 1975, 58 (7), 1921–1934. 10.1002/hlca.19750580707. DOI

Rüedi P.; Eugster C. H. Struktur von Coleon C, einem neuen blattfarbstoff aus Coleus aquaticus Gürcke. Helv. Chim. Acta 1971, 54 (6), 1606–1621. 10.1002/hlca.19710540612. DOI

Śliwiński T.; Sitarek P.; Skała E.; M. S. Isca V.; Synowiec E.; Kowalczyk T.; Bijak M.; Rijo P. Diterpenoids from Plectranthus spp. as potential chemotherapeutic agents via apoptosis. Pharmaceuticals 2020, 13 (6), 123.10.3390/ph13060123. PubMed DOI PMC

Meier H.; Rüedi P.; Eugster C. H. Synthese Und charakterisierung der 8 isomeren, im ring B mono- bzw. dihydroxylierten royleanone. Helv. Chim. Acta 1981, 64 (3), 630–642. 10.1002/hlca.19810640304. DOI

Syamasundar K. V.; Vinodh G.; Srinivas K. V. N. S.; Srinivasulu B. A New abietane diterpenoid from Plectranthus bishopianus Benth. Helv. Chim. Acta 2012, 95 (4), 643–646. 10.1002/hlca.201100425. DOI

Miyase T.; Rüedi P.; Eugster C. H. Diterpenoide drüsenfarbstoffe aus Labiaten: Coleone U, V, W Und 14-O-formyl-coleon-V sowie 2 royleanone aus Plectranthus myrianthus BRIQ.; Cis- und trans-A/B-6, 7-dioxoroyleanon. Helv. Chim. Acta 1977, 60 (8), 2770–2779. 10.1002/hlca.19770600830. DOI

Gustafson K. R.; Munro M. H. G.; Blunt J. W.; Cardellina J. H.; McMahon J. B.; Gulakowski R. J.; Cragg G. M.; Cox P. A.; Brinen L. S.; Clardy J.; Boyd M. R. HIV inhibitory natural products. 3. Diterpenes from Homalantus acuminatus and Chrysobalanus icaco. Tetrahedron 1991, 47 (26), 4547–4554. 10.1016/S0040-4020(01)86461-9. DOI

Fuller R. W.; Cardellina J. H.; Boyd M. R. Hiv-inhibitory natural products. 28. Diterpene carboxylic acid from Fruits of Xylopia Sp. Nat. Prod. Lett. 1996, 8 (3), 169–172. 10.1080/10575639608044890. DOI

Rüedi P.; Schmid J. M.; Prewo R.; Bieri J. H.; Eugster C. H. Spirocoleone: Synthese und charakterisierung von vier diastereomeren spiro (methylcyclopropan)-substrukturen; Revision der konfiguration an C(12) und C(15) von Coleon P und derivaten sowie von Coleon-Z-derivaten; Röntgenstrukturanalysen von Lanugon J und weiteren spirocoleonen. Helv. Chim. Acta 1983, 66 (2), 429–449. 10.1002/hlca.19830660205. DOI

Garbarino J. A.; Cristina Chamy M.; Piovano M.; Espinoza L.; Belmonte E. Diterpenoids from Calceolaria inamoena. Phytochemistry 2004, 65 (7), 903–908. 10.1016/j.phytochem.2004.02.003. PubMed DOI

Gaspar-Marques C.; Fátima Simões M.; Luísa Valdeira M.; Rodríguez B. Terpenoids and phenolics from Plectranthus strigosus, bioactivity screening. Nat. Prod. Res. 2008, 22 (2), 167–177. 10.1080/14786410701654560. PubMed DOI

Lipinski C. A. Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods 2000, 44 (1), 235–249. 10.1016/S1056-8719(00)00107-6. PubMed DOI

Lipinski C. A.; Lombardo F.; Dominy B. W.; Feeney P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25. 1. Adv. Drug Delivery Rev. 2001, 46 (1–3), 3–26. 10.1016/S0169-409X(00)00129-0. PubMed DOI

Wager T. T.; Hou X.; Verhoest P. R.; Villalobos A. Central nervous system multiparameter optimization desirability: Application in drug discovery. ACS Chem. Neurosci. 2016, 7 (6), 767–775. 10.1021/acschemneuro.6b00029. PubMed DOI

Predict Molecular Properties | Percepta Software. ACD/Labs. https://www.acdlabs.com/products/percepta-platform/ (accessed July 04, 2023).

Egan W. J.; Merz K. M.; Baldwin J. J. Prediction of drug absorption using multivariate statistics. J. Med. Chem. 2000, 43 (21), 3867–3877. 10.1021/jm000292e. PubMed DOI

Cao Y.; Shi Y.; Cai Y.; Hong Z.; Chai Y. The Effects of traditional Chinese medicine on P-glycoprotein-mediated multidrug resistance and approaches for studying the herb-P-glycoprotein interactions. Drug Metab. Dispos. 2020, 48 (10), 972–979. 10.1124/dmd.120.000050. PubMed DOI

Garcia C.; Isca V. M. S.; Pereira F.; Monteiro C. M.; Ntungwe E.; Sousa F.; Dinic J.; Holmstedt S.; Roberto A.; Díaz-Lanza A.; Reis C. P.; Pesic M.; Candeias N. R.; Ferreira R. J.; Duarte N.; Afonso C. A. M.; Rijo P. Royleanone derivatives from Plectranthus spp. as a novel class of P-glycoprotein inhibitors. Front. Pharmacol 2020, 11, 557789.10.3389/fphar.2020.557789. PubMed DOI PMC

Marques C. G.; Pedro M.; Simões M. F.; Nascimento M. S. J.; Pinto M. M. M.; Rodríguez B. Effect of abietane diterpenes from Plectranthus grandidentatus on the growth of human cancer cell lines. Planta Med. 2002, 68 (9), 839–840. 10.1055/s-2002-34407. PubMed DOI

Vinodh G.; Naveen P.; Venkatesan C. S.; Rajitha G.; Shree A. J. Pharmacological evaluation of abietane diterpenoids from Plectranthus bishopianus as potent antibacterial, antioxidant and their cytotoxic agents. Nat. Prod. J. 2019, 9 (3), 229–237. 10.2174/2210315508666181120105219. DOI

Leeson P. D.; Springthorpe B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat. Rev. Drug Discovery 2007, 6 (11), 881–890. 10.1038/nrd2445. PubMed DOI

Edwards M. P.; Price D. A.. Chapter 23 - Role of physicochemical properties and ligand lipophilicity efficiency in addressing drug safety risks. In Annu. Rep. Med. Chem.; Macor J. E., Ed.; Academic Press, 2010; Vol. 45, pp 380–391.10.1016/S0065-7743(10)45023-X DOI

Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods 1983, 65 (1–2), 55–63. 10.1016/0022-1759(83)90303-4. PubMed DOI