This review comprehensively describes the recent advances in the synthesis and pharmacological evaluation of steroid polyamines squalamine, trodusquemine, ceragenins, claramine, and their diverse analogs and derivatives, with a special focus on their complete synthesis from cholic acids, as well as an antibacterial and antiviral, neuroprotective, antiangiogenic, antitumor, antiobesity and weight-loss activity, antiatherogenic, regenerative, and anxiolytic properties. Trodusquemine is the most-studied small-molecule allosteric PTP1B inhibitor. The discovery of squalamine as the first representative of a previously unknown class of natural antibiotics of animal origin stimulated extensive research of terpenoids (especially triterpenoids) comprising polyamine fragments. During the last decade, this new class of biologically active semisynthetic natural product derivatives demonstrated the possibility to form supramolecular networks, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids.

Department of Chemistry of Natural Compounds University of Chemistry and Technology Prague Technicka' 5 Prague 6 16628 Prague Czech Republic

Laboratory of Metabotropic Drugs Scientific Center for Innovative Drugs Volgograd State Medical University Novorossiyskaya St 39 400087 Volgograd Russia

Ufa Institute of Chemistry UFA Federal Research Centre of the Russian Academy of Sciences Pr Oktyabrya 450054 Ufa Russia

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Birteksoz-Tan A.S., Zeybek Z., Hacioglu M., Savage P.B., Bozkurt-Guzel C. In vitro activities of antimicrobial peptides and ceragenins against Legionella pneumophila. J. Antibiot. 2019;72:291–297. doi: 10.1038/s41429-019-0148-1. PubMed DOI

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Howell M.D., Streib J.E., Kim B.E., Lesley L.J., Dunlap A.P., Geng D., Feng Y., Savage P.B., Leung D.Y.M. Ceragenins: A class of antiviral compounds to treat orthopox infections. J. Investig. Dermatol. 2009;129:2668–2675. doi: 10.1038/jid.2009.120. PubMed DOI PMC

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Oyardi O., Savage P.B., Akcali A., Erturan Z., Bozkurt-Guzel C. Ceragenins exhibiting promising antimicrobial activity against various multidrug resistant Gram negative bacteria. Istanbul J. Pharm. 2019;48:68–72. doi: 10.26650/IstanbulJPharm.2018.400730. DOI

Dao A., Mills R.J., Kamble S., Savage P.B., Little D.G., Schindeler A. The application of ceragenins to orthopedic surgery and medicine. J. Orthop. Res. 2020;38:1883–1894. doi: 10.1002/jor.24615. PubMed DOI

Mills R.J., Boyling A., Cheng T.L., Peacock L., Savage P.B., Tägil M., Little D.G., Schindeler A. CSA-90 reduces periprosthetic joint infection in a novel rat model challenged with local and systemic Staphylococcus aureus. J. Orthop. Res. 2020;38:2065–2073. doi: 10.1002/jor.24618. PubMed DOI

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Damar-Çelik D., Mataracı-Kara E., Savage P.B., Özbek-Çelik B. Antibacterial and antibiofilm activities of ceragenins against Achromobacter species isolated from cystic fibrosis patients. J. Chemother. 2021;33:216–227. doi: 10.1080/1120009X.2020.1819702. PubMed DOI

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Hacioglu M., Oyardi O., Bozkurt-Guzel C., Savage P.B. Antibiofilm activities of ceragenins and antimicrobial peptides against fungal-bacterial mono and multispecies biofilms. J. Antibiot. 2020;73:455–462. doi: 10.1038/s41429-020-0299-0. PubMed DOI

Hacioglu M., Haciosmanoglu E., Birteksoz-Tan A.S., Bozkurt-Guzel C., Savage P.B. Effects of ceragenins and conventional antimicrobials on Candida albicans and Staphylococcus aureus mono and multispecies biofilms. Diagn. Microbiol. Infect. Dis. 2019;95:114863. doi: 10.1016/j.diagmicrobio.2019.06.014. PubMed DOI

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Savage P.B. 846 Effects of Ceragenins on Pseudomonas Aeruginosa biofilm formation in burn wounds in a porcine model. J. Burn Care Res. 2020;41:S262–S263. doi: 10.1093/jbcr/iraa024.418. DOI

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Ghosh S., Joseph G., Korza G., He L., Yuan J.H., Dong W., Setlow B., Li Y.Q., Savage P.B., Setlow P. Effects of the microbicide ceragenin CSA-13 on and properties of Bacillus subtilis spores prepared on two very different media. J. Appl. Microbiol. 2019;127:109–120. doi: 10.1111/jam.14300. PubMed DOI

Chmielewska S.J., Skłodowski K., Piktel E., Suprewicz Ł., Fiedoruk K., Daniluk T., Wolak P., Savage P.B., Bucki R. NDM-1 carbapenemase-producing Enterobacteriaceae are highly susceptible to ceragenins CSA-13, CSA-44, and CSA-131. Infect. Drug Resist. 2020;13:3277–3294. doi: 10.2147/IDR.S261579. PubMed DOI PMC

Bozkurt-Guzel C., Inci G., Oyardi O., Savage P.B. Synergistic activity of ceragenins against carbapenem-resistant Acinetobacter baumannii strains in both checkerboard and dynamic time-kill assays. Curr. Microbiol. 2020;77:1419–1428. doi: 10.1007/s00284-020-01949-w. PubMed DOI PMC

Wnorowska U., Piktel E., Durnaś B., Fiedoruk K., Savage P.B., Bucki R., Durna B., Fiedoruk K., Savage P.B., Bucki R. Use of ceragenins as a potential treatment for urinary tract infections. BMC Infect. Dis. 2019;19:369. doi: 10.1186/s12879-019-3994-3. PubMed DOI PMC

Ozbek-Celik B., Damar-Celik D., Mataraci-Kara E., Bozkurt-Guzel C., Savage P.B. Comparative in vitro activities of first and second-generation ceragenins alone and in combination with antibiotics against Multidrug-Resistant Klebsiella pneumoniae strains. Antibiotics. 2019;8:130. doi: 10.3390/antibiotics8030130. PubMed DOI PMC

Durnaś B., Wnorowska U., Pogoda K., Deptuła P., Wątek M., Piktel E., Głuszek S., Gu X., Savage P.B., Niemirowicz K., et al. Candidacidal activity of selected ceragenins and human cathelicidin LL-37 in experimental settings mimicking infection sites. PLoS ONE. 2016;11:e0157242. doi: 10.1371/journal.pone.0157242. PubMed DOI PMC

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Hacioglu M., Guzel C.B., Savage P.B., Tan A.S.B. Antifungal susceptibilities, in vitro production of virulence factors and activities of ceragenins against Candida spp. isolated from vulvovaginal candidiasis. Med. Mycol. 2019;57:291–299. doi: 10.1093/mmy/myy023. PubMed DOI

Niemirowicz K., Piktel E., Wilczewska A., Markiewicz K., Durnaś B., Wątek M., Puszkarz I., Wróblewska M., Niklińska W., Savage P.B., et al. Core–shell magnetic nanoparticles display synergistic antibacterial effects against Pseudomonas aeruginosa and Staphylococcus aureus when combined with cathelicidin LL-37 or selected ceragenins. Int. J. Nanomed. 2016;11:5443–5455. doi: 10.2147/IJN.S113706. PubMed DOI PMC

Durnaś B., Piktel E., Wątek M., Wollny T., Góźdź S., Smok-Kalwat J., Niemirowicz K., Savage P.B., Bucki R. Anaerobic bacteria growth in the presence of cathelicidin LL-37 and selected ceragenins delivered as magnetic nanoparticles cargo. BMC Microbiol. 2017;17:167. doi: 10.1186/s12866-017-1075-6. PubMed DOI PMC

Niemirowicz K., Durnaś B., Tokajuk G., Piktel E., Michalak G., Gu X., Kułakowska A., Savage P.B., Bucki R. Formulation and candidacidal activity of magnetic nanoparticles coated with cathelicidin LL-37 and ceragenin CSA-13. Sci. Rep. 2017;7:4610. doi: 10.1038/s41598-017-04653-1. PubMed DOI PMC

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Kuroda K., Fukuda T., Okumura K., Yoneyama H., Isogai H., Savage P.B., Isogai E. Ceragenin CSA-13 induces cell cycle arrest and antiproliferative effects in wild-type and p53 null mutant HCT116 colon cancer cells. Anticancer Drugs. 2013;24:826–834. doi: 10.1097/CAD.0b013e3283634dd0. PubMed DOI

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Niemirowicz K., Prokop I., Wilczewska A., Wnorowska U., Piktel E., Wątek M., Savage P., Bucki R. Magnetic nanoparticles enhance the anticancer activity of cathelicidin LL-37 peptide against colon cancer cells. Int. J. Nanomed. 2015;10:3843–3853. doi: 10.2147/IJN.S76104. PubMed DOI PMC

Piktel E., Markiewicz K.H., Wilczewska A.Z., Daniluk T., Chmielewska S., Niemirowicz-Laskowska K., Mystkowska J., Paprocka P., Savage P.B., Bucki R. Quantification of synergistic effects of ceragenin CSA-131 combined with iron oxide magnetic nanoparticles against cancer cells. Int. J. Nanomed. 2020;15:4573–4589. doi: 10.2147/IJN.S255170. PubMed DOI PMC

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