Objective(s): 4-aminosalicylic acid (4-ASA) is an isomer of mesalazine that has recently been shown to be effective against inflammatory bowel disease (IBD), and more specifically, ulcerative colitis. However, the majority of orally administered 4-ASA is readily and extensively absorbed from the stomach and small intestine, so only a small amount is transported to the colon. A mutual ester and azo PRODRUG of 4-ASA was synthesized with polyethylene glycol (PEG) and dimethylaniline, respectively, to overcome this issue. Materials and Methods: The 4-ASA PRODRUG was synthesized via a two-step process and then characterized by 1H-NMR. The stability of the PRODRUG was evaluated in simulated gastric fluid (pH 1. 2). Furthermore, the in vitro release profiles of the drug conjugate was evaluated at pH 1. 2, as well as pH 6. 8 in the absence or presence of rat cecal content. Results: The prepared PRODRUG was stable at pH 1. 2, indicating that it could be protected from the acidic environment of the stomach. Also, the results of drug release at pH 6. 8 showed that the amount of 4-ASA released was 63% within 12 hr in the absence of rat cecal content, while in the presence of rat cecal content, 97% of 4-ASA was released from the PRODRUG in 6 hr. Conclusion: Overall, the synthesized PEGylated azo-based 4-ASA PRODRUG could be a potential candidate for targeted drug delivery to the inflamed gut tissue in IBD.

Breast cancer is the most important kind of cancer in pre and postmenopausal women. In the treatment of cancers, specially metastatic breast cancer, doxorubicin has the broadest spectrum among of any drugs presently available, but it produces a dose dependent cardiomyopathy and other side effects which limit its clinical usefulness. To overcome this undesired side effect, one solution was to synthesis doxorubicin based PRODRUGs which can specifically enter into turnor cells, with less distribution in normal tissues. For this purpose estrogen receptors, present in higher amount in cancer cells than normal one, was considered as a target and therefore doxorubicin was linked to estrone as a compound with high affinity to estrogen receptors. In this study, first the 17-keto group of estrone was linked to amine groups on spacer groups such as 4-amino-I-butanol or 5-amino-l-pentanol via schiff s base reaction to prepare an imine functional group that readily reduce to an amine compound. Then resulted amine was reacted with succinic anhydride to yield an acidic derivative of estrone. Isobutylchloro format, afterwards, was used to catalys the final reaction that was an amide bond formation between carboxylic derivative of estrone and amine group located on the danosamine moiety of doxorubicin to yield the final proposed PRODRUG in 43%. Analytical spectrometric methods such as IR, MS and NMR confirmed the successful synthesis of doxorubicin-estrone PRODRUG which is potentially active against estrogen receptor positive breast cancers.

Background: Intestinal absorption of levofloxacin (LFX) is decreased by the concomitant administration of antacids due to the formation of insoluble chelate complexes with various metal cations. Methods: The following four ester PRODRUGs of LFX—, cilexetil ester (LFX-CLX), medoxomil ester (LFX-MDX), ethoxycarbonyl 1-ethyl hemiacetal ester (LFX-EHE) and pivaloyloxymethyl ester (LFX-PVM)—, were synthesized. Then, the lipophilicity, in vitro chelate formation with aluminum chloride (AlCl3), chemical and enzymatic stability, minimum inhibitory concentrations (MICs) against some bacteria, and the efficacy in preventing chelate formation of PRODRUGs with aluminum hydroxide (Al(OH)3) in rabbits were evaluated. Results: The synthesized ester PRODRUGs of LFX exhibited high purity and higher lipophilicities than LFX depending on the ester moieties. MICs of the PRODRUGs against S. aureus, E. coli, and P. aeruginosa were more than 10 times higher than those of LFX. PRODRUGs were stable chemically but unstable enzymatically and generated LFX in biological specimens. When AlCl3 solution was mixed with LFX solution in vitro, insoluble chelate complex was formed immediately. In rabbits, co-administration of Al(OH)3 with LFX reduced the oral bioavailability of LFX by approximately 40%. In contrast, no precipitation was observed when AlCl3 solution was mixed with each PRODRUG solution in vitro, and co-administration of Al(OH)3 exerted no significant effect on the oral bioavailability of LFX when each PRODRUG was administered in rabbits. Conclusion: The ester PRODRUG approach of LFX could be a feasible strategy for avoiding chelate formation with aluminum ion in vivo.