Thiourea Modified Doxorubicin: A Perspective pH-Sensitive Prodrug

Abstract

A novel approach to the synthesis of pH-sensitive prodrugs has been proposed: thiourea drug modification. Resulting prodrugs can release the cytotoxic agent and the biologically active 2-thiohydantoin in the acidic environment of tumor cells. The concept of acid-catalyzed cyclization of thioureas to 2-thiohydantoins has been proven using a FRET model. Dual prodrugs of model azidothymidine, cytotoxic doxorubicin, and 2-thiohydantoin albutoin were obtained, which release the corresponding drugs in the acidic environment. The resulting doxorubicin prodrug was tested on prostate cancer cells and showed that the thiourea-modified prodrug is less cytotoxic (average IC50 ranging from 0.5584 to 0.9885 μM) than doxorubicin (IC50 ranging from 0.01258 to 0.02559 μM) in neutral pH 7.6 and has similar toxicity (average IC50 ranging from 0.4970 to 0.7994 μM) to doxorubicin (IC50 ranging from 0.2303 to 0.8110 μM) under mildly acidic conditions of cancer cells. Cellular and nuclear accumulation in PC3 tumor cells of Dox prodrug is much higher than accumulation of free doxorubicin.

Switching on prodrugs using radiotherapy

“…( g ) Survival curves for HT29 tumour bearing mice. Mice were aged until moribund or the tumour volume reached 2000mm 3 (n = 5).…”

“…Aldoxorubicin (INNO-206) which is an albumin-binding prodrug with release of doxorubicin under acidic conditions. 3 – 6 There are a number of prodrugs in the pipeline and in clinical trials. For instance, Apadaz™ releases its parent drug (hydrocodone) by enzymatic cleavage in the gastrointestinal tract.…”

Chiral Thioureas—Preparation and Significance in Asymmetric Synthesis and Medicinal Chemistry

“…[348] and sulfoximine [41]. Krasonvskaya et al described a preparation of a thiourea-modified doxorubicin as a pH-sensitive prodrug capable of releasing cytotoxic component as well as anticonvulsant albutoin in a weakly acidic medium [349]. Thioureas containing a chiral isosteviol moiety [350][351][352], terpenes [77], camphor [353] or steroid scaffold [354] have been also reported.…”

Functionalization of Polyethyleneimine with Hollow Cyclotriveratrylene and Its Subsequent Supramolecular Interaction with Doxorubicin

“…While the drug is highly potent, it also carries the risk of cardiotoxicity, as it had been shown to damage healthy cardiomyocytes (cardiac muscle cells) [5,[7][8][9][10]. So far, the main strategies for the coordination and delivery of Doxorubicin involves the supramolecular encapsulation [11][12][13][14] as well as the coordination by a labile covalent bond that is possible through the exploitation of the amino group within the Daunosamine unit [15][16][17][18][19]. In many drug delivery systems, supramolecular coordination is often more preferred over other interactions type due to its better response in the presence of external stimuli that could be further finetuned through the modulation of the coordination/releasing processes [20].…”