{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T22:49:52Z","timestamp":1787870992541,"version":"build-2784847793"},"reference-count":90,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T00:00:00Z","timestamp":1698019200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>South Africa is rich in diverse medicinal plants, and it is reported to have over 35% of the global Helichrysum species, many of which are utilized in traditional medicine. Various phytochemical studies have offered valuable insights into the chemistry of Helichrysum plants, hinting at bioactive components that define the medicinal properties of the plant. However, there are still knowledge gaps regarding the size and diversity of the Helichrysum chemical space. As such, continuous efforts are needed to comprehensively characterize the phytochemistry of Helichrysum, which will subsequently contribute to the discovery and exploration of Helichrysum-derived natural products for drug discovery. Thus, reported herein is a computational metabolomics work to comprehensively characterize the metabolic landscape of the medicinal herb Helichrysum\u00a0splendidum, which is less studied. Metabolites were methanol-extracted and analyzed on a liquid chromatography\u2013tandem mass spectrometry (LC-MS\/MS) system. Spectral data were mined using molecular networking (MN) strategies. The results revealed that the metabolic map of H. splendidum is chemically diverse, with chemical superclasses that include organic polymers, benzenoids, lipid and lipid-like molecules, alkaloids, and derivatives, phenylpropanoids and polyketides. These results point to a vastly rich chemistry with potential bioactivities, and the latter was demonstrated through computationally assessing the binding of selected metabolites with CDK-2 and CCNB1 anti-cancer targets. Molecular docking results showed that flavonoids (luteolin, dihydroquercetin, and isorhamnetin) and terpenoids (tiliroside and silybin) interact strongly with the CDK-2 and CCNB1 targets. Thus, this work suggests that these flavonoid and terpenoid compounds from H. splendidum are potentially anti-cancer agents through their ability to interact with these proteins involved in cancer pathways and progression. As such, these actionable insights are a necessary step for further exploration and translational studies for H. splendidum-derived compounds for drug discovery.<\/jats:p>","DOI":"10.3390\/metabo13101104","type":"journal-article","created":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T01:41:21Z","timestamp":1698025281000},"page":"1104","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["An Integrated Molecular Networking and Docking Approach to Characterize the Metabolome of Helichrysum\u00a0splendidum and Its Pharmaceutical Potentials"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8458-5269","authenticated-orcid":false,"given":"Motseoa Mariam","family":"Lephatsi","sequence":"first","affiliation":[{"name":"Department of Biochemistry, University of Johannesburg, Auckland Park, Johannesburg 2006, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mpho Susan","family":"Choene","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Johannesburg, Auckland Park, Johannesburg 2006, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2521-8957","authenticated-orcid":false,"given":"Abidemi Paul","family":"Kappo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Johannesburg, Auckland Park, Johannesburg 2006, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3341-4114","authenticated-orcid":false,"given":"Ntakadzeni Edwin","family":"Madala","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Microbiology, University of Venda, Thohoyandou 0950, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8172-6599","authenticated-orcid":false,"given":"Fidele","family":"Tugizimana","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Johannesburg, Auckland Park, Johannesburg 2006, South Africa"},{"name":"International Research and Development Division, Omnia Group, Ltd., Bryanston, Johannesburg 2021, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0378-8741(97)00065-2","article-title":"The antimicrobial activity of 3,5,7-trihydroxyflavone isolated from the shoots of Helichrysum aureonitens","volume":"57","author":"Afolayan","year":"1997","journal-title":"J. Ethnopharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1021\/np50020a005","article-title":"Constituents of Anatolian Medicinal Plants; Flavonoids of Helichrysum armenium","volume":"45","year":"1982","journal-title":"J. Nat. Prod."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/S1043-6618(05)80097-0","article-title":"Phytochemical characterization and radical scavenger activity of flavonoids from G. Don (compositae)","volume":"22","author":"Facino","year":"1990","journal-title":"Pharmacol. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1515\/znc-2004-5-614","article-title":"Chemical composition and in vitro antimicrobial activity of the essential oils of two Helichrysum species from Tanzania","volume":"59","author":"Bougatsos","year":"2004","journal-title":"Zeitschrift Naturforsch.\u2014Sect. C J. Biosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"485","DOI":"10.3923\/jms.2007.485.488","article-title":"Preliminary evaluation of antiulcerogenic activity of Ceiba pentandra Gaertn and Helicrysum mechowianum klatt in rats","volume":"7","author":"Ibara","year":"2007","journal-title":"J. Med. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.indcrop.2017.06.043","article-title":"Everlasting flower (Helichrysum stoechas Moench) as a potential source of bioactive molecules with antiproliferative, antioxidant, antidiabetic and neuroprotective properties","volume":"108","author":"Les","year":"2017","journal-title":"Ind. Crops Prod."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Babot\u0103, M., Mocan, A., Vlase, L., Crisan, O., Ielciu, I., Gheldiu, A.M., Vodnar, D.C., Cri\u015fan, G., and P\u0103ltinean, R. (2018). Phytochemical analysis, antioxidant and antimicrobial activities of helichrysum arenarium (L.) moench. and antennaria dioica (L.) gaertn. Flowers. Molecules, 23.","DOI":"10.3390\/molecules23020409"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2812","DOI":"10.1016\/j.bmcl.2017.04.076","article-title":"Anti-atherosclerotic activities of flavonoids from the flowers of Helichrysum arenarium L. Moench through the pathway of anti-inflammation","volume":"27","author":"Mao","year":"2017","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.fitote.2015.03.024","article-title":"Identification of anti-HIV active dicaffeoylquinic- and tricaffeoylquinic acids in Helichrysum populifolium by NMR-based metabolomic guided fractionation","volume":"103","author":"Heyman","year":"2015","journal-title":"Fitoterapia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.foodchem.2011.04.078","article-title":"Characterisation of phenolic acid derivatives and flavonoids from different morphological parts of Helichrysum obconicum by a RP-HPLC-DAD-(-)-ESI-MS n method","volume":"129","author":"Gouveia","year":"2011","journal-title":"Food Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.jpba.2014.04.005","article-title":"Identification and quantitative determination of the polar constituents in Helichrysum italicum flowers and derived food supplements","volume":"96","author":"Mari","year":"2014","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1071\/FP02076","article-title":"Understanding plant responses to drought\u2014From genes to the whole plant","volume":"30","author":"Chaves","year":"2003","journal-title":"Funct. Plant Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.jep.2016.01.001","article-title":"Metabolic alteration in obese diabetes rats upon treatment with Centella asiatica extract","volume":"180","author":"Maulidiani","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"AL-Zuaidy, M.H., Mumtaz, M.W., Hamid, A.A., Ismail, A., Mohamed, S., and Razis, A.F.A. (2017). Biochemical characterization and 1H NMR based metabolomics revealed Melicope lunu-ankenda leaf extract a potent anti-diabetic agent in rats. BMC Complement. Altern. Med., 17.","DOI":"10.1186\/s12906-017-1849-2"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"24317","DOI":"10.1021\/acsomega.2c01623","article-title":"Metabolomic Profiling and Identification of Antioxidant and Antidiabetic Compounds from Leaves of Different Varieties of Morus alba Linn Grown in Kashmir","volume":"7","author":"Jan","year":"2022","journal-title":"ACS Omega"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-P\u00e9rez, P., Zhang, L., Miras-Moreno, B., Lozano-Milo, E., Landin, M., Lucini, L., and Gallego, P.P. (2021). The combination of untargeted metabolomics and machine learning predicts the biosynthesis of phenolic compounds in bryophyllum medicinal plants (Genus kalanchoe). Plants, 10.","DOI":"10.3390\/plants10112430"},{"key":"ref_17","first-page":"4751","article-title":"Isolation, chemical characterization, and anti-inflammatory activity of coumarins, flavonoids, and terpenes from Tagetes lucida","volume":"36","author":"Enrique","year":"2022","journal-title":"Nat. Prod. Res."},{"key":"ref_18","first-page":"153","article-title":"Terpenoids, flavonoids and acetogenins from some Malagasy plants","volume":"11","author":"Nagashima","year":"2016","journal-title":"Nat. Prod. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1163\/22238980-bja10022","article-title":"Cannabis-derived terpenes and flavonoids as potential pharmaceuticals","volume":"68","author":"Ofir","year":"2021","journal-title":"Isr. J. Plant Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.compbiolchem.2011.07.003","article-title":"Drug-target network and polypharmacology studies of a Traditional Chinese Medicine for type II diabetes mellitus","volume":"35","author":"Gu","year":"2011","journal-title":"Comput. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.ejmech.2014.06.037","article-title":"Prediction of anti-tumor chemical probes of a traditional Chinese medicine formula by HPLC fingerprinting combined with molecular docking","volume":"83","author":"Chen","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/978-1-59745-177-2_19","article-title":"Molecular docking","volume":"Volume 443","author":"Morris","year":"2008","journal-title":"Methods in Molecular Biology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1080\/08927022.2022.2045016","article-title":"Structural based investigation of novel pyrazole-thiazole Hybrids as dual CDK-1 and CDK-2 inhibitors for cancer chemotherapy","volume":"48","author":"Obakachi","year":"2022","journal-title":"Mol. Simul."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Cheung, A., Chenoweth, A.M., Quist, J., Sow, H.S., Malaktou, C., Ferro, R., Hoffmann, R.M., Osborn, G., Sachouli, E., and French, E. (2022). CDK Inhibition Primes for Anti-PD-L1 Treatment in Triple-Negative Breast Cancer Models. Cancers, 14.","DOI":"10.3390\/cancers14143361"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1038\/nbt.3597","article-title":"Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking","volume":"34","author":"Wang","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1038\/s41592-020-0933-6","article-title":"Feature-based molecular networking in the GNPS analysis environment","volume":"17","author":"Nothias","year":"2020","journal-title":"Nat. Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4035","DOI":"10.1038\/s41467-018-06082-8","article-title":"Dereplication of microbial metabolites through database search of mass spectra","volume":"9","author":"Mohimani","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e7","DOI":"10.1093\/pcp\/pct176","article-title":"KNApSAcK Metabolite Activity Database for Retrieving the Relationships Between Metabolites and Biological Activities","volume":"55","author":"Nakamura","year":"2014","journal-title":"Plant Cell Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1021\/ed100697w","article-title":"ChemSpider: An Online Chemical Information Resource","volume":"87","author":"Pence","year":"2010","journal-title":"J. Chem. Educ."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"D1202","DOI":"10.1093\/nar\/gkv951","article-title":"PubChem Substance and Compound databases","volume":"44","author":"Kim","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1021\/ci025591m","article-title":"Evaluation of Similarity Measures for Searching the Dictionary of Natural Products Database","volume":"43","author":"Whittle","year":"2003","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s11306-007-0082-2","article-title":"Proposed minimum reporting standards for chemical analysis","volume":"3","author":"Sumner","year":"2007","journal-title":"Metabolomics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s13321-020-00456-1","article-title":"An open source chemical structure curation pipeline using RDKit","volume":"12","author":"Bento","year":"2020","journal-title":"J. Cheminform."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Safran, M., Dalah, I., Alexander, J., Rosen, N., Iny Stein, T., Shmoish, M., Nativ, N., Bahir, I., Doniger, T., and Krug, H. (2010). GeneCards Version 3: The human gene integrator. Database J. Biol. Databases Curation, 2010.","DOI":"10.1093\/database\/baq020"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING database in 2021: Customizable protein\u2013protein networks, and functional characterization of user-uploaded gene\/measurement sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"D437","DOI":"10.1093\/nar\/gkaa1038","article-title":"RCSB Protein Data Bank: Powerful new tools for exploring 3D structures of biological macromolecules for basic and applied research and education in fundamental biology, biomedicine, biotechnology, bioengineering and energy sciences","volume":"49","author":"Burley","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1093\/nar\/gkp456","article-title":"PubChem: A public information system for analyzing bioactivities of small molecules","volume":"37","author":"Wang","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An open chemical toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminform."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/978-1-4939-2269-7_19","article-title":"Small-Molecule Library Screening by Docking with PyRx","volume":"Volume 1263","author":"Dallakyan","year":"2015","journal-title":"Methods in Molecular Biology"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ernst, M., Kang, K.B., Caraballo-Rodr\u00edguez, A.M., Nothias, L.-F., Wandy, J., Chen, C., Wang, M., Rogers, S., Medema, M.H., and Dorrestein, P.C. (2019). MolNetEnhancer: Enhanced Molecular Networks by Integrating Metabolome Mining and Annotation Tools. Metabolites, 9.","DOI":"10.1101\/654459"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2715","DOI":"10.1093\/jxb\/erac125","article-title":"Plant lipids: Trends and beyond","volume":"73","author":"Suh","year":"2022","journal-title":"J. Exp. Bot."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Kim, H.U. (2020). Lipid Metabolism in Plants. Plants, 9.","DOI":"10.3390\/plants9070871"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"McClements, D.J., and \u00d6zt\u00fcrk, B. (2021). Utilization of nanotechnology to improve the handling, storage and biocompatibility of bioactive lipids in food applications. Foods, 10.","DOI":"10.3390\/foods10020365"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6676","DOI":"10.33263\/BRIAC106.66766687","article-title":"Bioactive lipids: Chemistry & health benefits","volume":"10","author":"Duhan","year":"2020","journal-title":"Biointerface Res. Appl. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.abb.2018.06.001","article-title":"Carotenoids in human nutrition and health","volume":"652","author":"Eggersdorfer","year":"2018","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/978-3-030-01099-7_2","article-title":"Biomolecular Targets of Oxyprenylated Phenylpropanoids and Polyketides","volume":"Volume 108","author":"Fiorito","year":"2019","journal-title":"Progress in the Chemistry of Organic Natural Products"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1111\/j.1365-313X.2008.03436.x","article-title":"Nature\u2019s assembly line: Biosynthesis of simple phenylpropanoids and polyketides","volume":"54","author":"Yu","year":"2008","journal-title":"Plant J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"111471","DOI":"10.1016\/j.indcrop.2019.111471","article-title":"Everlasting flowers: Phytochemistry and pharmacology of the genus Helichrysum","volume":"138","author":"Akaberi","year":"2019","journal-title":"Ind. Crops Prod."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/nrc3138","article-title":"Cancer research: Past, present and future","volume":"11","author":"Cao","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"547","DOI":"10.3892\/or.2015.4029","article-title":"The role of targeting kinase activity by natural products in cancer chemoprevention and chemotherapy (Review)","volume":"34","author":"Luo","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.fitote.2004.12.006","article-title":"Flavonoids of Helichrysum compactum and their antioxidant and antibacterial activity","volume":"76","author":"Houghton","year":"2005","journal-title":"Fitoterapia"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"127650","DOI":"10.1016\/j.foodchem.2020.127650","article-title":"Novel insights on the multi-functional properties of flavonol glucosides from red onion (Allium cepa L) solid waste\u2014In vitro and in silico approach","volume":"335","author":"Nile","year":"2021","journal-title":"Food Chem."},{"key":"ref_55","first-page":"25","article-title":"Isorhamnetin flavonoid synergistically enhances the anticancer activity and apoptosis induction by cis-platin and carboplatin in non-small cell lung carcinoma (NSCLC)","volume":"8","author":"Zhang","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"627","DOI":"10.5455\/njppp.2016.6.0617727072016","article-title":"Antiproliferative properties of tiliroside from Guazuma ulmifolia lamk on T47D and MCF7 cancer cell lines","volume":"6","author":"Dai","year":"2016","journal-title":"Natl. J. Physiol. Pharm. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Agarwal, C., Wadhwa, R., Deep, G., Biedermann, D., Ga\u017e\u00e1k, R., K\u0159en, V., and Agarwal, R. (2013). Anti-Cancer Efficacy of Silybin Derivatives\u2014A Structure-Activity Relationship. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060074"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Caparica, R., J\u00falio, A., Ara\u00fajo, M.E.M., Baby, A.R., Fonte, P., Costa, J.G., and de Almeida, T.S. (2020). Anticancer activity of rutin and its combination with ionic liquids on renal cells. Biomolecules, 10.","DOI":"10.3390\/biom10020233"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Imran, M., Rauf, A., Abu-Izneid, T., Nadeem, M., Shariati, M.A., Khan, I.A., Imran, A., Orhan, I.E., Rizwan, M., and Atif, M. (2019). Luteolin, a flavonoid, as an anticancer agent: A review. Biomed. Pharmacother., 112.","DOI":"10.1016\/j.biopha.2019.108612"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Das, A., Baidya, R., Chakraborty, T., Samanta, A.K., and Roy, S. (2021). Pharmacological basis and new insights of taxifolin: A comprehensive review. Biomed. Pharmacother., 142.","DOI":"10.1016\/j.biopha.2021.112004"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1002\/biof.5520120108","article-title":"Role of diet modification in cancer prevention","volume":"12","author":"Abdulla","year":"2000","journal-title":"BioFactors"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1007\/s11418-007-0223-y","article-title":"Anticarcinogenic compounds in the Uzbek medicinal plant, Helichrysum maracandicum","volume":"62","author":"Yagura","year":"2008","journal-title":"J. Nat. Med."},{"key":"ref_63","first-page":"1","article-title":"Introductory chapter: Terpenes and terpenoids","volume":"Volume 1","author":"Perveen","year":"2018","journal-title":"Terpenes and Terpenoids"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12935-016-0369-3","article-title":"Anticancer properties of ester derivatives of betulin in human metastatic melanoma cells (Me-45)","volume":"17","author":"Drag","year":"2017","journal-title":"Cancer Cell Int."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1002\/mc.20638","article-title":"Betulin induces mitochondrial cytochrome c release associated apoptosis in human cancer cells","volume":"49","author":"Li","year":"2010","journal-title":"Mol. Carcinog."},{"key":"ref_66","first-page":"7319","article-title":"Betulin induces cytochrome c release and apoptosis in colon cancer cells via NOXA","volume":"15","author":"Zhou","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_67","first-page":"78","article-title":"Ursolic and Oleanolic Acids as Potential Anticancer Agents Acting in the Gastrointestinal Tract","volume":"16","author":"Paduch","year":"2019","journal-title":"Mini. Rev. Org. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Tang, Z.Y., Li, Y., Tang, Y.T., Ma, X.D., and Tang, Z.Y. (2022). Anticancer activity of oleanolic acid and its derivatives: Recent advances in evidence, target profiling and mechanisms of action. Biomed. Pharmacother., 145.","DOI":"10.1016\/j.biopha.2021.112397"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2146","DOI":"10.1021\/ci6002043","article-title":"Parallel Screening:\u2009 A Novel Concept in Pharmacophore Modeling and Virtual Screening","volume":"46","author":"Steindl","year":"2006","journal-title":"J. Chem. Inf. Model."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/wcms.18","article-title":"Outstanding challenges in protein\u2013ligand docking and structure-based virtual screening","volume":"1","author":"Waszkowycz","year":"2011","journal-title":"WIREs Comput. Mol. Sci."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"George, B.P., Chandran, R., and Abrahamse, H. (2021). Role of phytochemicals in cancer chemoprevention: Insights. Antioxidants, 10.","DOI":"10.3390\/antiox10091455"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"11255","DOI":"10.1038\/s41598-018-29308-7","article-title":"Flavonoids inhibit cell proliferation and induce apoptosis and autophagy through downregulation of PI3K\u03b3 mediated PI3K\/AKT\/mTOR\/p70S6K\/ULK signaling pathway in human breast cancer cells","volume":"8","author":"Zhang","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s12551-013-0130-2","article-title":"Receptor-ligand molecular docking","volume":"6","author":"Guedes","year":"2014","journal-title":"Biophys. Rev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1038\/nbt1007-1110","article-title":"Network pharmacology","volume":"25","author":"Hopkins","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nchembio.118","article-title":"Network pharmacology: The next paradigm in drug discovery","volume":"4","author":"Hopkins","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.1093\/bioinformatics\/btq550","article-title":"Investigating the correlations among the chemical structures, bioactivity profiles and molecular targets of small molecules","volume":"26","author":"Cheng","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_77","first-page":"17","article-title":"Protein-protein interaction networks (PPI) and complex diseases","volume":"7","author":"Taghizadeh","year":"2014","journal-title":"Gastroenterol. Hepatol. Bed Bench"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1038\/nrd4504","article-title":"The history and future of targeting cyclin-dependent kinases in cancer therapy","volume":"14","author":"Asghar","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1073\/pnas.1111317109","article-title":"Chemical-genetic analysis of cyclin dependent kinase 2 function reveals an important role in cellular transformation by multiple oncogenic pathways","volume":"109","author":"Horiuchi","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_80","first-page":"1913","article-title":"CDK inhibitors in cancer therapy, an overview of recent development","volume":"11","author":"Zhang","year":"2021","journal-title":"Am. J. Cancer Res."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Kciuk, M., Gieleci\u0144ska, A., Mujwar, S., Mojzych, M., and Kontek, R. (2022). Cyclin-Dependent Kinase Synthetic Lethality Partners in DNA Damage Response. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073555"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"214","DOI":"10.3390\/futurepharmacol2030015","article-title":"Therapeutic Potential of Mitotic Kinases\u2019 Inhibitors in Cancers of the Gastrointestinal System","volume":"2","author":"Javed","year":"2022","journal-title":"Future Pharmacol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/nrd.2016.230","article-title":"A comprehensive map of molecular drug targets","volume":"16","author":"Santos","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1016\/j.tet.2017.12.049","article-title":"Application of a catalyst-free Domino Mannich\/Friedel-Crafts alkylation reaction for the synthesis of novel tetrahydroquinolines of potential antitumor activity","volume":"74","author":"Castillo","year":"2018","journal-title":"Tetrahedron"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.ejmech.2012.08.039","article-title":"Synthesis of novel quinoline-2-one based chalcones of potential anti-tumor activity","volume":"57","author":"Abonia","year":"2012","journal-title":"Eur. J. Med. Chem."},{"key":"ref_86","first-page":"30","article-title":"The kinetics of G2 and M transitions regulated by B cyclins","volume":"8","author":"Huang","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1158\/0008-5472.CAN-05-3389","article-title":"Cyclin B1 and other cyclins as tumor antigens in immunosurveillance and immunotherapy of cancer","volume":"66","author":"Egloff","year":"2006","journal-title":"Cancer Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1111\/j.1349-7006.2007.00444.x","article-title":"Nuclear cyclin B1 in human breast carcinoma as a potent prognostic factor","volume":"98","author":"Suzuki","year":"2007","journal-title":"Cancer Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.ccell.2021.03.010","article-title":"Targeting cell-cycle machinery in cancer","volume":"39","author":"Suski","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s10549-022-06801-2","article-title":"The clinical significance of cyclin B1 (CCNB1) in invasive breast cancer with emphasis on its contribution to lymphovascular invasion development","volume":"198","author":"Aljohani","year":"2023","journal-title":"Breast Cancer Res. Treat."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/10\/1104\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:10:01Z","timestamp":1760130601000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/10\/1104"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,23]]},"references-count":90,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["metabo13101104"],"URL":"https:\/\/doi.org\/10.3390\/metabo13101104","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,23]]}}}