{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T05:22:56Z","timestamp":1776835376875,"version":"3.51.2"},"reference-count":31,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T00:00:00Z","timestamp":1628553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005357","name":"Agent\u00fara na Podporu V\u00fdskumu a V\u00fdvoja","doi-asserted-by":"publisher","award":["APVV-15-0053, APVV-19-0024, DS-FR-19-0035"],"award-info":[{"award-number":["APVV-15-0053, APVV-19-0024, DS-FR-19-0035"]}],"id":[{"id":"10.13039\/501100005357","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006109","name":"Vedeck\u00e1 Grantov\u00e1 Agent\u00fara M\u0160VVa\u0160 SR a SAV","doi-asserted-by":"publisher","award":["2\/0019\/19, 1\/0504\/20"],"award-info":[{"award-number":["2\/0019\/19, 1\/0504\/20"]}],"id":[{"id":"10.13039\/501100006109","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018886","name":"Laborat\u00f3rio Associado para a Qu\u00edmica Verde","doi-asserted-by":"publisher","award":["UIDB\/50006\/2020"],"award-info":[{"award-number":["UIDB\/50006\/2020"]}],"id":[{"id":"10.13039\/501100018886","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>High levels of hyaluronic acid (HA) in tumors correlate with poor outcomes with several types of cancers due to HA-driven support of adhesion, migration and proliferation of cells. In this study we explored how to enhance the degradation of HA into low-molecular fragments, which cannot prevent the immune system to fight tumor proliferation and metastases. The physiological solution of HA was exposed to oxidative degradation by ascorbate and cupric ions in the presence of either one of three ortho isomeric Mn(III) substituted N-alkyl- and alkoxyalkylpyridylporphyrins or para isomeric Mn(III) N-methylpyridyl analog, commonly known as mimics of superoxide dismutase. The changes in hyaluronan degradation kinetics by four Mn(III) porphyrins were monitored by measuring the alteration in the dynamic viscosity of the HA solution. The ortho compounds MnTE-2-PyP5+ (BMX-010, AEOL10113), MnTnBuOE-2-PyP5+ (BMX-001) and MnTnHex-2-PyP5+ are able to redox cycle with ascorbate whereby producing H2O2 which is subsequently coupled with Cu(I) to produce the \u2022OH radical essential for HA degradation. Conversely, with the para analog, MnTM-4-PyP5+, no catalysis of HA degradation was demonstrated, due to its inertness towards redox cycling with ascorbate. The impact of different Mn(III)-porphyrins on the HA decay was further clarified by electron paramagnetic resonance spectrometry. The ability to catalyze the degradation of HA in a biological milieu, in the presence of cupric ions and ascorbate under the conditions of high tumor oxidative stress provides further insight into the anticancer potential of redox-active ortho isomeric Mn(III) porphyrins.<\/jats:p>","DOI":"10.3390\/ijms22168608","type":"journal-article","created":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T08:57:14Z","timestamp":1628585834000},"page":"8608","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Ortho Isomeric Mn(III) N-Alkyl- and Alkoxyalkylpyridylporphyrins\u2014Enhancers of Hyaluronan Degradation Induced by Ascorbate and Cupric Ions"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8467-893X","authenticated-orcid":false,"given":"Katar\u00edna","family":"Valachov\u00e1","sequence":"first","affiliation":[{"name":"Centre of Experimental Medicine, Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, D\u00fabravsk\u00e1 cesta 9, SK-841 04 Bratislava, Slovakia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6071-3932","authenticated-orcid":false,"given":"Peter","family":"Rapta","sequence":"additional","affiliation":[{"name":"Institute of Physical Chemistry and Chemical Physics, Slovak University of Technology in Bratislava, Radlinsk\u00e9ho 9, SK-812 37 Bratislava, Slovakia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9373-7006","authenticated-orcid":false,"given":"Nuno M. M.","family":"Moura","sequence":"additional","affiliation":[{"name":"LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"given":"Ines","family":"Batinic-Haberle","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA"}]},{"given":"Ladislav","family":"\u0160olt\u00e9s","sequence":"additional","affiliation":[{"name":"Centre of Experimental Medicine, Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, D\u00fabravsk\u00e1 cesta 9, SK-841 04 Bratislava, Slovakia"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1089\/ars.2017.7453","article-title":"Mn porphyrin-based redox-active drugs: Differential effects as cancer therapeutics and protectors of normal tissue against oxidative injury","volume":"29","author":"Tovmasyan","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101139","DOI":"10.1016\/j.redox.2019.101139","article-title":"Thiol regulation by Mn porphyrins, commonly known as SOD mimics","volume":"25","author":"Tome","year":"2019","journal-title":"Redox Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1142\/S1088424619300283","article-title":"25 years of development of Mn porphyrins\u2014From SOD mimics to thiol signaling to clinical trials. The story of our life in USA","volume":"23","author":"Spasojevic","year":"2019","journal-title":"J. Porphyr. Phthalocya."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4011","DOI":"10.1021\/ic990118k","article-title":"The relationship between redox potentials, proton dissociation constants of pyrrolic nitrogens, and in vitro and in vivo superoxide dismutase activities of manganese(III) and iron(III) cationic and anionic porphyrins","volume":"38","author":"Benov","year":"1999","journal-title":"Inorg. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"24521","DOI":"10.1074\/jbc.273.38.24521","article-title":"The ortho effect makes manganese(III) meso-tetrakis-(N-methylpyridinium-2-yl)porphyrin a powerful and potentially useful superoxide dismutase mimic","volume":"273","author":"Benov","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1021\/tx980245d","article-title":"Catalytic Scavenging of Peroxynitrite by Isomeric Mn(III) N-Methylpyridylporphyrins in the Presence of Reductants","volume":"12","author":"Spasojevic","year":"1999","journal-title":"Chem. Res. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1089\/ars.2009.2876","article-title":"Superoxide dismutase mimics: Chemistry, pharmacology, and therapeutic potential","volume":"13","author":"Reboucas","year":"2010","journal-title":"Antioxid. Redox Signal."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"14757","DOI":"10.1039\/c3dt50767j","article-title":"Acid\u2013base and electrochemical properties of manganese meso(ortho- and meta-N-ethylpyridyl)-porphyrins: Voltammetric and chronocoulometric study of protolytic and redox equilibria","volume":"41","author":"Weitner","year":"2013","journal-title":"Dalton Trans."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12970-019-0269-8","article-title":"Effects of ascorbic acid supplementation on oxidative stress markers in healthy women following a single bout of exercise","volume":"16","author":"Yimcharoen","year":"2019","journal-title":"J. Int. Soc. Sports Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Pehlivan, F.E. (2017). Vitamin C: An antioxidant agent. Vitamin C, IntechOpen. Chapter 2.","DOI":"10.5772\/intechopen.69660"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.carbpol.2016.04.063","article-title":"Hydrogen peroxide generation by the Weissberger biogenic oxidative system during hyaluronan degradation","volume":"148","author":"Valachova","year":"2016","journal-title":"Carbohydr. Polym."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s12291-014-0446-0","article-title":"Free radicals: Properties, sources, targets, and their implication in various diseases","volume":"30","author":"Phaniendra","year":"2015","journal-title":"Ind. J. Clin. Biochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.jpba.2011.06.015","article-title":"Free-radical degradation of high-molecular-weight hyaluronan induced by ascorbate plus cupric ions. Testing of bucillamine and its SA981-metabolite as antioxidants","volume":"56","author":"Valachova","year":"2011","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1083\/jcb.201910070","article-title":"Don\u2019t sugarcoat it: How glycocalyx composition influences cancer progression","volume":"219","author":"Buffone","year":"2020","journal-title":"J. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"79","DOI":"10.4103\/0973-0168.197974","article-title":"Understanding the basic role of glycocalyx during cancer","volume":"17","author":"Lahir","year":"2016","journal-title":"J. Rad. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nrc3239","article-title":"The blockade of immune checkpoints in cancer immunotherapy","volume":"12","author":"Pardoll","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1152\/ajpcell.00285.2013","article-title":"Physical Biology in Cancer. 3. The role of cell glycocalyx in vascular transport of circulating tumor cells","volume":"306","author":"Mitchell","year":"2014","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2826","DOI":"10.1016\/j.carres.2006.09.019","article-title":"Hyaluronan degradation by copper(II) chloride and ascorbate: Rotational viscometric, EPR spin-trapping, and MALDI\u2013TOF mass spectrometric investigations","volume":"341","author":"Soltes","year":"2006","journal-title":"Carbohydr. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/j.freeradbiomed.2015.10.416","article-title":"Anticancer therapeutic potential of Mn porphyrin\/ascorbate system","volume":"89","author":"Tovmasyan","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_20","unstructured":"Kulkarni, S., Rawat, N.K., and Haghi, A.K. (2021). Manganese porphyrins as pro-oxidants in high-molar-mass hyaluronan oxidative degradation-possible implications in anticancer effects. Green Chemistry and Green Engineering. Processing Technologies, Properties and Applications, Apple Academic Press. Chapter 12."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/B978-0-12-800092-2.00002-2","article-title":"Targeting hyaluronic acid family for cancer chemoprevention and therapy","volume":"123","author":"Lokeshwar","year":"2014","journal-title":"Adv. Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1089\/ars.2014.5921","article-title":"Complex chemistry and biology of redox-active compounds, commonly known as SOD mimics, affect their therapeutic effects","volume":"20","author":"Spasojevic","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.freeradbiomed.2016.02.036","article-title":"MnTE-2-PyP reduces prostate cancer growth and metastasis by suppressing p300 activity and p300\/HIF-1\/CREB binding to the promoter region of the PAI-1 gene","volume":"94","author":"Tong","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.redox.2018.10.016","article-title":"The manganese(III) porphyrin MnTnHex-2-PyP5+ modulates intracellular ROS and breast cancer cell migration: Impact on doxorubicin-treated cell","volume":"20","author":"Saraiva","year":"2019","journal-title":"Redox Biol."},{"key":"ref_25","first-page":"23","article-title":"H2O2\u2013driven anticancer activity of Mn porphyrins and the underlying molecular pathways","volume":"2021","author":"Tovmasyan","year":"2021","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1475-2867-13-89","article-title":"Acidic extracellular microenvironment and cancer","volume":"13","author":"Kato","year":"2013","journal-title":"Cancer Cell Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"17279","DOI":"10.3390\/molecules191117279","article-title":"Radical Intermediates in Photoinduced Reactions on TiO2 (An EPR Spin Trapping Study)","volume":"19","year":"2014","journal-title":"Molecules"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1006\/niox.2000.0303","article-title":"Nitrosylation of manganese(II) tetrakis(N-ethylpyridinium-2-yl)porphyrin","volume":"4","author":"Spasojevic","year":"2000","journal-title":"Nitric Oxide"},{"key":"ref_29","first-page":"1256","article-title":"Hyaluronan-based hydrogels as versatile tumor-like models: Tunable ECM and stiffness with genipin-crosslinking","volume":"108A","author":"Thoumire","year":"2020","journal-title":"J. Biomed. Mat. Res."},{"key":"ref_30","first-page":"102","article-title":"Hyaluronic acid and its biomedical applications: A review","volume":"1","author":"Dovedytis","year":"2020","journal-title":"Eng. Regen."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1016\/j.carres.2007.02.018","article-title":"Solution properties of high-molar-mass hyaluronans: The biopolymer degradation by ascorbate","volume":"342","author":"Soltes","year":"2007","journal-title":"Carbohydr. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8608\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:43:35Z","timestamp":1760165015000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8608"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,10]]},"references-count":31,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22168608"],"URL":"https:\/\/doi.org\/10.3390\/ijms22168608","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,10]]}}}