Preparation and Evaluation of Colon-Targeted Prodrugs of the Microbial Metabolite 3-Indolepropionic Acid as an Anticolitic Agent

Lee, Hanju; Park, Sohee; Ju, Sanghyun; Kim, Soojin; Yoo, Jung‐Woo; Yoon, In‐Soo; Min, Do Sik; Jung, Yunjin

doi:10.1021/acs.molpharmaceut.0c01228

Cited by 17 publications

(16 citation statements)

References 39 publications

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“…In vitro and in vivo assays indicate the involvement of PXR/acyl‐CoA‐binding protein signalling in indole‐3‐propionic acid‐dependent radioprotection (Xiao et al ., 2020 ). A conjugate of indole‐3‐propinic acid (linked with 5‐aminonicotinic acid) mitigated colonic damage and inflammation (Lee et al ., 2021 ). These findings open the possibility of microbiome‐based therapies for radioactive damage.…”

Section: The Exploitation Of Indoles For Therapeutic Purposesmentioning

confidence: 99%

Diverse roles of microbial indole compounds in eukaryotic systems

Kumar

Lee

2021

Biological Reviews

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Indole and its derivatives are widespread across different life forms, functioning as signalling molecules in prokaryotes and with more diverse roles in eukaryotes. A majority of indoles found in the environment are attributed to bacterial enzymes converting tryptophan into indole and its derivatives. The involvement of indoles among lower organisms as an interspecies and intraspecies signal is well known, with many reports showing that inter-kingdom interactions involving microbial indole compounds are equally important as they influence defence systems and even the behaviour of higher organisms. This review summarizes recent advances in our understanding of the functional properties of indole and indole derivatives in diverse eukaryotes. Furthermore, we discuss current perspectives on the role of microbial indoles in human diseases such as diabetes, obesity, atherosclerosis, and cancers. Deciphering the function of indoles as biomarkers of metabolic state will facilitate the formulation of diet-based treatments and open unique therapeutic opportunities.

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Section: The Exploitation Of Indoles For Therapeutic Purposesmentioning

confidence: 99%

Diverse roles of microbial indole compounds in eukaryotic systems

Kumar

Lee

2021

Biological Reviews

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“…Experimental colitis was induced in rats as previously described . Briefly, male SD rats were fasted, but allowed to drink water, for 24 h. Then, they were anesthetized using the Small Animal O 2 Single Flow Anesthesia System (LMS, Pyeongtaek, South Korea), and colitis was induced using isoflurane (Hana Pharm, Hwaseong, South Korea).…”

Section: Methodsmentioning

confidence: 99%

“…Three days after the induction of inflammation, each drug was administered orally or rectally to the rats once per day, and the anti-colitic effects were evaluated after receiving the medication for 6 days. Colonic damage scores (CDSs) were calculated using previously reported criteria . The modified scoring system is shown in Supporting Information 1.…”

Section: Methodsmentioning

confidence: 99%

“…Colon-targeted drug delivery is a pharmaceutical strategy to enhance the therapeutic activities of drugs, especially those intended for the treatment of colonic diseases such as IBD . This delivery technique increases drug availability in the large intestine by decreasing the systemic absorption of the drug and ensuring its delivery to the large intestine without loss in the stomach or small intestine due to systemic absorption and pre-systemic metabolism. , Therefore, colon-targeted delivery of anti-IBD drugs tends to increase potency and safety as compared with drugs for which the technique is not employed . For the pharmaceutical feature of drug delivery, it is suggested that colon-targeted drug delivery is a feasible strategy to facilitate drug repositioning to an anti-colitic drug, especially for a repositioned candidate that requires an elevated dose for new therapeutic applications. , …”

Section: Introductionmentioning

confidence: 99%

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A Colon-Targeted Prodrug of Riluzole Improves Therapeutic Effectiveness and Safety upon Drug Repositioning of Riluzole to an Anti-Colitic Drug

et al. 2022

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Riluzole (RLZ) is a neuroprotective drug indicated for amyotrophic lateral sclerosis. To examine the feasibility of RLZ for repositioning as an anti-inflammatory bowel disease (IBD) drug, RLZ (2, 5, and 10 mg/kg) was administered orally to rats with colitis induced by 2,4-dinitrobenzenesulfonic acid. Oral RLZ was effective against rat colitis in a dose-dependent manner, which was statistically significant at doses over 5 mg/kg. To address safety issues upon repositioning and further improve anti-colitic effectiveness, RLZ was coupled with salicylic acid (SA) via an azobond to yield RLZ-azo-SA (RAS) for the targeted colonic delivery of RLZ. Upon oral gavage, RAS (oral RAS) was efficiently delivered to and activated to RLZ in the large intestine, and systemic absorption of RLZ was substantially reduced. Oral RAS ameliorated colonic damage and inflammation in rat colitis and was more effective than oral RLZ and sulfasalazine, a current anti-IBD drug. Moreover, oral RAS potently inhibited glycogen synthase kinase 3β (GSK3β) in the inflamed distal colon, leading to the suppression of NFκB activity and an increase in the level of the anti-inflammatory cytokine interleukin-10. Taken together, RAS, which enables RLZ to be delivered to and inhibit GSK3β in the inflamed colon, may facilitate repositioning of RLZ as an anti-IBD drug.

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“…Experimental colitis was induced in rats as previously described [ 27 ]. Briefly, before the induction of colitis, male SD rats (250–260 g) were not fed for 24 h, except for drinking water.…”

Section: Methodsmentioning

confidence: 99%

Dapsone Azo-Linked with Two Mesalazine Moieties Is a “Me-Better” Alternative to Sulfasalazine

Kang

Kim

et al. 2022

Pharmaceutics

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Dapsone (DpS) is an antimicrobial and antiprotozoal agent, especially used to treat leprosy. The drug shares a similar mode of action with sulfonamides. Additionally, it possesses anti-inflammatory activity, useful for treating autoimmune diseases. Here, we developed a “me-better” alternative to sulfasalazine (SSZ), a colon-specific prodrug of mesalazine (5-ASA) used as an anti-inflammatory bowel diseases drug; DpS azo-linked with two molecules of 5-ASA (AS-DpS-AS) was designed and synthesized, and its colon specificity and anti-colitic activity were evaluated. AS-DpS-AS was converted to DpS and the two molecules of 5-ASA (up to approximately 87% conversion) within 24 h after incubation in the cecal contents. Compared to SSZ, AS-DpS-AS showed greater efficiency in colonic drug delivery following oral gavage. Simultaneously, AS-DpS-AS substantially limited the systemic absorption of DpS. In a dinitrobenzene sulfonic acid-induced rat colitis model, oral AS-DpS-AS elicited better efficacy against rat colitis than oral SSZ. Moreover, intracolonic treatment with DpS and/or 5-ASA clearly showed that combined treatment with DpS and 5-ASA was more effective against rat colitis than the single treatment with either DpS or 5-ASA. These results suggest that AS-DpS-AS may be a “me-better” drug of SSZ with higher therapeutic efficacy, owing to the combined anti-colitic effects of 5-ASA and DpS.

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Preparation and Evaluation of Colon-Targeted Prodrugs of the Microbial Metabolite 3-Indolepropionic Acid as an Anticolitic Agent

Cited by 17 publications

References 39 publications

Diverse roles of microbial indole compounds in eukaryotic systems

Diverse roles of microbial indole compounds in eukaryotic systems

A Colon-Targeted Prodrug of Riluzole Improves Therapeutic Effectiveness and Safety upon Drug Repositioning of Riluzole to an Anti-Colitic Drug

Dapsone Azo-Linked with Two Mesalazine Moieties Is a “Me-Better” Alternative to Sulfasalazine

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