{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:46:36Z","timestamp":1760147196199,"version":"build-2065373602"},"reference-count":52,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T00:00:00Z","timestamp":1673827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Monash university"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Drug targeting is necessary to deliver drugs to a specific site of action at a rate dictated by therapeutic requirements. The pharmacological action of a drug can thereby be optimised while minimising adverse effects. Numerous colonic drug delivery systems have been developed to avoid such undesirable side effects; however, these systems lack site specificity, leaving room for further improvement. The objective of the present study was to explore the potential of amino-alkoxycarbonyloxymethyl (amino-AOCOM) ether prodrugs as a general approach for future colonic delivery. To circumvent inter- and intra-subject variabilities in enzyme activities, these prodrugs do not rely on enzymes but rather are activated via a pH-triggered intramolecular cyclisation\u2013elimination reaction. As proof of concept, model compounds were synthesised and evaluated under various pH conditions, simulating various regions of the gastrointestinal tract (GIT). Probe 15 demonstrated excellent stability under simulated stomach- and duodenum-like conditions and protected 60% of the payload in a small intestine-like environment. Moreover, 15 displayed sustained release at colonic pH, delivering &gt;90% of the payload over 38 h. Mesalamine (Msl) prodrugs 21 and 22 were also synthesised and showed better stability than probe 15 in the simulated upper GIT but relatively slower release at colonic pH (61\u201368% of Msl over 48 h). For both prodrugs, the extent of release was comparable to that of the commercial product Asacol. This study provides initial proof of concept regarding the use of a cyclisation-activated prodrug for colon delivery and suggests that release characteristics still vary on a case-by-case basis.<\/jats:p>","DOI":"10.3390\/pharmaceutics15010303","type":"journal-article","created":{"date-parts":[[2023,1,17]],"date-time":"2023-01-17T02:10:32Z","timestamp":1673921432000},"page":"303","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Design, Development, and Optimisation of Smart Linker Chemistry for Targeted Colonic Delivery\u2014In Vitro Evaluation"],"prefix":"10.3390","volume":"15","author":[{"given":"Heba S.","family":"Abd-Ellah","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, VI 3052, Australia"},{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3495-0648","authenticated-orcid":false,"given":"Ramesh","family":"Mudududdla","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, VI 3052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Glen P.","family":"Carter","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, VI 3001, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan B.","family":"Baell","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Nanjing Tech University, No. 30 South Puzhu Road, Nanjing 211816, China"},{"name":"Institute of Drug Discovery Technology (IDDT), Ningbo University, 818 Fenghua Road, Ningbo 315211, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.addr.2004.08.011","article-title":"New oral delivery systems for treatment of inflammatory bowel disease","volume":"57","author":"Friend","year":"2005","journal-title":"Adv. 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