{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T12:19:16Z","timestamp":1788956356191,"version":"build-2803163510"},"reference-count":62,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T00:00:00Z","timestamp":1657670400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001322","name":"South African Medical Research Council","doi-asserted-by":"publisher","award":["SAMRC"],"award-info":[{"award-number":["SAMRC"]}],"id":[{"id":"10.13039\/501100001322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The scarcity of novel and effective therapeutics for the treatment of cancer is a pressing and alarming issue that needs to be prioritized. The number of cancer cases and deaths are increasing at a rapid rate worldwide. Doxorubicin, an anticancer agent, is currently used to treat several types of cancer. It disrupts myriad processes such as histone eviction, ceramide overproduction, DNA-adduct formation, reactive oxygen species generation, Ca2+, and iron hemostasis regulation. However, its use is limited by factors such as drug resistance, toxicity, and congestive heart failure reported in some patients. The combination of doxorubicin with other chemotherapeutic agents has been reported as an effective treatment option for cancer with few side effects. Thus, the hybridization of doxorubicin and other chemotherapeutic drugs is regarded as a promising approach that can lead to effective anticancer agents. This review gives an update on hybrid compounds containing the scaffolds of doxorubicin and its derivatives with potent chemotherapeutic effects.<\/jats:p>","DOI":"10.3390\/molecules27144478","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T00:12:40Z","timestamp":1657757560000},"page":"4478","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":113,"title":["Doxorubicin-Based Hybrid Compounds as Potential Anticancer Agents: A Review"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6935-905X","authenticated-orcid":false,"given":"Sijongesonke","family":"Peter","sequence":"first","affiliation":[{"name":"Department of Chemistry, University of Fort Hare, Alice 5700, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7100-4007","authenticated-orcid":false,"given":"Sibusiso","family":"Alven","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Fort Hare, Alice 5700, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rejoice Bethusile","family":"Maseko","sequence":"additional","affiliation":[{"name":"Department of Chemistry, School of Science and Technology, Sefako Makgatho Health Sciences University, Ga-Rankuwa 0208, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blessing Atim","family":"Aderibigbe","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Fort Hare, Alice 5700, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"119527","DOI":"10.1016\/j.lfs.2021.119527","article-title":"A comprehensive review on time-tested anticancer drug doxorubicin","volume":"278","author":"Sritharan","year":"2021","journal-title":"Life Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1111\/j.2042-7158.2012.01567.x","article-title":"Doxorubicin: An update on anticancer molecular action, toxicity and novel drug delivery systems","volume":"65","author":"Tacar","year":"2013","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Sung","year":"2021","journal-title":"Canc. J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/S1470-2045(19)30163-9","article-title":"Estimates of global chemotherapy demands and corresponding physician workforce requirements for 2018 and 2040: A population-based study","volume":"20","author":"Wilson","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Aderibigbe, B.A., and Peter, S. (2019). Ferrocene-Based Compounds with Antimalaria\/Anticancer Activity. Molecules, 24.","DOI":"10.3390\/molecules24193604"},{"key":"ref_6","unstructured":"International Agency for Research on Cancer (2018). Latest Global Cancer Data: Cancer Burden Rises to 18.1 Million New Cases and 9.6 Million Cancer Deaths in 2018, International Agency for Research on Cancer."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/CAD.0000000000000572","article-title":"Autophagy and Doxorubicin resistance in cancer","volume":"29","author":"Chen","year":"2018","journal-title":"Anti-Cancer Drugs."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9","DOI":"10.32931\/io1902r","article-title":"Anthracycline Derivatives and Their Anticancer Activity","volume":"2","author":"Moiseeva","year":"2019","journal-title":"Ineos Open."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"74","DOI":"10.4103\/2141-9248.126619","article-title":"An evaluation of hepatotoxicity in breast cancer patients receiving injection Doxorubicin","volume":"4","author":"Damodar","year":"2014","journal-title":"Ann. Med. Health Sci. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1021\/jm201653u","article-title":"Synthesis, anticancer activities, and cellular uptake studies of lipophilic derivatives of doxorubicin succinate","volume":"55","author":"Chhikara","year":"2012","journal-title":"J. Med Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"540","DOI":"10.3109\/03602532.2011.609174","article-title":"Possibilities to increase the effectiveness of doxorubicin in cancer cells killing","volume":"43","year":"2011","journal-title":"Drug Metab. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.reprotox.2021.04.003","article-title":"Mechanisms of doxorubicin-mediated reproductive toxicity\u2014A review","volume":"102","author":"Mohan","year":"2021","journal-title":"Reprod. Toxicol."},{"key":"ref_13","first-page":"6095","article-title":"New insights into the activities and toxicities of the old anticancer drug doxorubicin","volume":"288","author":"Qiao","year":"2020","journal-title":"FEBS J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.repbio.2018.03.002","article-title":"Effect of short-and medium-term toxicity of doxorubicin on spermatogenesis in adult Wistar rats","volume":"18","author":"Silva","year":"2018","journal-title":"Reprod. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/j.etp.2011.01.006","article-title":"Impact of ellagic acid on adriamycin-induced testicular histopathological lesions, apoptosis, lipid peroxidation and sperm damages","volume":"64","author":"Sakin","year":"2012","journal-title":"Exp. Toxicol. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1002\/bdr2.1535","article-title":"The impact of mesenchymal stem cells on doxorubicin-induced testicular toxicity and progeny outcome of male prepubertal rats","volume":"111","author":"Abdelaziz","year":"2019","journal-title":"Birth Defects Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e12603","DOI":"10.1111\/and.12603","article-title":"Therapeutic effect of ozone and rutin on adriamycin-induced testicular toxicity in an experimental rat model","volume":"49","author":"Salem","year":"2017","journal-title":"Andrologia"},{"key":"ref_18","first-page":"36","article-title":"Preserving fertility in young women diagnosed with breast Cancer","volume":"23","author":"Jukkala","year":"2009","journal-title":"Oncology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.yrtph.2016.09.002","article-title":"The comparison of animal models for premature ovarian failure established by several different source of inducers","volume":"81","author":"Zhang","year":"2016","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.lfs.2018.03.023","article-title":"Toxicity of Doxorubicin (Dox) to different experimental organ systems","volume":"200","author":"Pugazhendhi","year":"2018","journal-title":"Life Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.hjb.2016.02.001","article-title":"The effect of mangiferin against brain damage caused by oxidative stress and inflammation in- duced by doxorubicin","volume":"23","author":"Siswanto","year":"2016","journal-title":"HAYATI J. Biosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"20030","DOI":"10.1038\/srep20030","article-title":"Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs","volume":"6","author":"Oleaga","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"241","DOI":"10.4103\/0971-6580.103656","article-title":"A study on the toxic effects of doxorubicin on the histology of certain organs","volume":"19","author":"Shivakumar","year":"2012","journal-title":"Toxicol. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3267","DOI":"10.2174\/092986709788803312","article-title":"Doxorubicin: The Good, the Bad and the Ugly Effect","volume":"16","author":"Carvalho","year":"2009","journal-title":"Curr. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3877","DOI":"10.1039\/C8CP06776G","article-title":"Molecular mechanism and binding free energy of doxorubicin intercalation in DNA","volume":"21","author":"Jawad","year":"2019","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"853","DOI":"10.4103\/0973-1482.139267","article-title":"An overview of doxorubicin formulations in cancer therapy","volume":"10","author":"Rivankar","year":"2014","journal-title":"J. Cancer Res. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.lfs.2017.04.009","article-title":"Structural modifications in the sugar moiety as a key to improving the anticancer effectiveness of doxorubicin","volume":"178","author":"Marczak","year":"2017","journal-title":"Life Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e20210571","DOI":"10.1084\/jem.20210571","article-title":"Activation of the Integrated Stress Response in drug-tolerant melanoma cells confers vulnerability to mitoribosome-targeting antibiotics","volume":"218","author":"Vendramin","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Lovitt, C.J., Shelper, T.B., and Avery, V.M. (2018). Doxorubicin resistance in breast cancer cells is mediated by extracellular matrix proteins. BMC Cancer, 18.","DOI":"10.1186\/s12885-017-3953-6"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"57","DOI":"10.2217\/hep.15.41","article-title":"Mechanisms of doxorubicin resistance in hepatocellular carcinoma","volume":"3","author":"Cox","year":"2016","journal-title":"Hepatic Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.bmcl.2017.01.048","article-title":"Synthesis of cholesteryl doxorubicin and its anti-cancer activity","volume":"27","author":"Choi","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1016\/j.ejmech.2011.02.056","article-title":"Fatty-acyl amide derivatives of doxorubicin: Synthesis and in vitro anticancer activities","volume":"46","author":"Chhikara","year":"2011","journal-title":"Eur. J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5427","DOI":"10.1016\/j.bbagen.2013.03.032","article-title":"Fatty acid binding to serum albumin: Molecular simulation approaches","volume":"1830","author":"Fujiwara","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.jconrel.2013.05.023","article-title":"Site-specific fatty acid-conjugation to prolong protein half-life in vivo","volume":"170","author":"Lim","year":"2013","journal-title":"J. Control. Release"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.jconrel.2011.11.028","article-title":"Clinical impact of serum proteins on drug delivery","volume":"161","author":"Kratz","year":"2012","journal-title":"J. Control. Release"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"310186","DOI":"10.1155\/2013\/310186","article-title":"Dietary omega-3 polyunsaturated fatty acid DHA: A potential adjuvant in the treatment of cancer","volume":"2013","author":"Merendino","year":"2013","journal-title":"BioMed Res. Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1080\/07315724.2011.10719969","article-title":"Long-chain polyunsaturated fatty acids promote paclitaxel cytotoxicity via inhibition of the MDR1 gene in the human colon cancer Caco-2 cell line","volume":"30","author":"Kuan","year":"2011","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1002\/biof.181","article-title":"Docosahexaenoic acid: A natural powerful adjuvant that improves efficacy for anticancer treatment with no adverse effects","volume":"37","author":"Siddiqui","year":"2011","journal-title":"BioFactors"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1016\/j.ejmech.2010.01.037","article-title":"Modulation of doxorubicin activity in cancer cells by conjugation with fatty acyl and terpenyl hydrazones","volume":"45","author":"Effenberger","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"485","DOI":"10.5414\/CPP48485","article-title":"New doxorubicin N-acyl hydrazones with improved efficacy and cell line specificity show modes of action different from the parent drug","volume":"48","author":"Effenberger","year":"2010","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1021\/mp4004139","article-title":"Synthesis of doxorubicin \u03b1-linolenic acid conjugate and evaluation of its antitumor activity","volume":"2014","author":"Liang","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1007\/s00044-019-02443-0","article-title":"Synthesis and anticancer effects of conjugates of doxorubicin and unsaturated fatty acids (LNA and DHA)","volume":"28","author":"Struga","year":"2019","journal-title":"Med. Chem. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1007\/s10637-008-9208-2","article-title":"INNO-206, the (6-maleimidocaproyl hydrazone derivative of doxorubicin), shows superior antitumor efficacy compared to doxorubicin in different tumor xenograft models and in an orthotopic pancreas carcinoma model","volume":"28","author":"Graeser","year":"2010","journal-title":"Investig. New Drugs"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5307","DOI":"10.1016\/j.bmcl.2013.07.070","article-title":"Doxorubicin-antioxidant co-drugs","volume":"2013","author":"Chegaev","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1007\/s13346-017-0379-2","article-title":"Mechanistically elucidating the in vitro safety and efficacy of a novel doxorubicin derivative","volume":"7","author":"Alrushaid","year":"2017","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.etap.2014.11.023","article-title":"Cytotoxicity and induction of apoptosis by formamidinodoxorubicins in comparison to doxorubicin in human ovarian adenocarcinoma cells","volume":"39","author":"Marczak","year":"2015","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1007\/s00228-009-0734-4","article-title":"Uptake of anthracyclines in vitro and in vivo in acute myeloid leukemia cells in relation to apoptosis and clinical response","volume":"65","author":"Bogason","year":"2009","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_48","first-page":"4439","article-title":"In vitro induction of apoptosis and necrosis by new derivatives of daunorubicin","volume":"33","author":"Stojak","year":"2013","journal-title":"Anticancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"970","DOI":"10.3892\/ol.2013.1487","article-title":"Inhibitory effects of tamoxifen and doxorubicin, alone and in combination, on the proliferation of the MG63 human osteosarcoma cell line","volume":"6","author":"Ouyang","year":"2013","journal-title":"Oncol. Lett."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.tiv.2013.11.006","article-title":"Pro-apoptotic activity of new analog of anthracyclines--WP 631 in advanced ovarian cancer cell line","volume":"28","author":"Gajek","year":"2014","journal-title":"Toxicol. Vitr."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.cbi.2014.06.013","article-title":"Induction of apoptosis by doxorubicin-transferrin conjugate compared to free doxorubicin in the human leukemia cell lines","volume":"220","author":"Szwed","year":"2014","journal-title":"Chem. Biol. Interact."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.2147\/DDDT.S168588","article-title":"Doxorubicin-conjugated dexamethasone induced MCF-7 apoptosis without entering the nucleus and able to overcome MDR-1-induced resistance","volume":"12","author":"Chaikomon","year":"2018","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1021\/acscentsci.1c00040","article-title":"Synthesis and Cytotoxic Evaluation of Arimetamycin A and Its Daunorubicin and Doxorubicin Hybrids","volume":"7","author":"Huseman","year":"2021","journal-title":"ACS Cent. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"12814","DOI":"10.1021\/acs.jmedchem.0c01191","article-title":"Doxorubicin and Aclarubicin: Shuffling Anthracycline Glycans for Improved Anticancer Agents","volume":"63","author":"Wander","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.bmcl.2018.12.017","article-title":"Synthesis and characterization of a photoresponsive doxorubicin\/combretastatin A4 hybrid prodrug","volume":"29","author":"Liu","year":"2019","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_56","first-page":"23","article-title":"Design, synthesis, and initial biological evaluation of a steroidal anti-estrogen\u2013doxorubicin bioconjugate for targeting estrogen receptor-positive breast cancer cells","volume":"18","author":"Dao","year":"2012","journal-title":"Bioconjugate Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"7441","DOI":"10.1039\/C6TB00746E","article-title":"Molecular simulation of pH-dependent diffusion, loading, and release of doxorubicin in graphene and graphene oxide drug delivery systems","volume":"4","author":"Mahdavi","year":"2016","journal-title":"J. Mater. Chem. B"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1007\/s11095-020-02881-1","article-title":"Engineering the pH-Sensitivity of the Graphene and Carbon Nanotube Based Nanomedicines in Smart Cancer Therapy by Grafting Trimetyl Chitosan","volume":"37","author":"Khoshoei","year":"2020","journal-title":"Pharm. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"101948","DOI":"10.1016\/j.mtcomm.2020.101948","article-title":"Simultaneous doxorubicin encapsulation and in-situ microfluidic micellization of bio-targeted polymeric nanohybrids using dichalcogenide monolayers: A molecular in-silico study","volume":"26","author":"Maleki","year":"2021","journal-title":"Mater. Today Commun."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s11030-020-10131-0","article-title":"Unravelling the anticancer potency of 1,2,4-triazole-N-arylamide hybrids through inhibition of STAT3: Synthesis and in silico mechanistic studies","volume":"25","author":"Turky","year":"2021","journal-title":"Mol. Divers."},{"key":"ref_61","first-page":"1","article-title":"Computational model of doxorubicin conjugate with docosahexaenoic acid and integrin \u03b1v \u03b23 ligand for anticancer","volume":"8","author":"Hidayat","year":"2018","journal-title":"J. Appl. Pharm. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"6343","DOI":"10.1038\/s41598-017-06445-z","article-title":"Influence of doxorubicin on model cell membrane properties: Insights from in vitro and in silico studies","volume":"7","author":"Alves","year":"2017","journal-title":"Sci. Rep."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/14\/4478\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:49:35Z","timestamp":1760140175000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/14\/4478"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,13]]},"references-count":62,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["molecules27144478"],"URL":"https:\/\/doi.org\/10.3390\/molecules27144478","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,13]]}}}