The prodrug concept has been used to improve undesirable properties of drugs since the late 19th century, although it was only at the end of the 1950s that the actual term prodrug was introduced for the first time. Prodrugs are inactive, bioreversible derivatives of active drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, whi...

Calorimetric technique has aroused considerable interest as a versatile tool in pharmaceutical industry and academia to provide useful information about thermodynamic and kinetic aspects of drug molecules. The present paper utilizes this technique to monitor the hydrolytic degradation of metronidazole and its prodrug with ciprofloxacin, i.e. 2-(2-methyl-5-nitroimidazol-1-yl)ethyl-1-cyclopropyl-...

Three new prodrugs, [prodrug 1: 4-[bis(2-iodoethyl)amino]-phenyloxycarbonyl-L-glutamic acid; prodrug 2: 3-fluoro-4-[bis(2-chlorethyl)amino]benzoyl-L-glutamic acid; and prodrug 3: 3,5-difluoro-4-[bis(2-iodoethyl)amino]benzoyl-L-glutamic acid] have been assessed for use with a mutant of carboxypeptidase G2 (CPG2, glutamate carboxypeptidase, EC 3.4.17.11,) engineered to be tethered to the outer tu...

Chemotherapy has achieved great success in cancer treatment during recent past decades, but it is still challenged by poor solubility, low tumor selectivity, and associated toxicity of most anticancer drugs. The prodrug strategy is one of the most commonly used chemical/biochemical strategies towards improving the therapeutic index of anticancer drugs. A prodrug is defined as a chemically modif...

A disodium phosphonooxymethyl prodrug of the antitumor agent triptolide was prepared from the natural product in three steps (39% yield) and displayed excellent aqueous solubility at pH 7.4 (61 mg/mL) compared to the natural product (17 μg/mL). The estimated shelf life (t90) for hydrolysis of the prodrug at 4 °C and pH 7.4 was found to be two years. In a mouse model of human colon adenocarcinom...

Cytoxicity induced by the herpesvirus thymidine kinase (TK) gene in combination with prodrugs is dependent on cell growth and leads to the elimination of genetically modified cells, thus limiting the duration of expression and efficacy of this treatment in vivo. Here, an effort was made to enhance TK/prodrug efficacy by coexpression of a cyclin-dependent kinase inhibitor (CKI), p27, to render c...

Cancer chemotherapeutic prodrugs, such as the oxazaphosphorines cyclophosphamide and ifosfamide, are metabolized by liver cytochrome P450 enzymes to yield therapeutically active, cytotoxic metabolites. The effective use of these prodrugs is limited by host toxicity associated with the systemic distribution of cytotoxic metabolites formed in the liver. This problem can, in part, be circumvented ...

In antibody-directed enzyme prodrug therapy, an enzyme conjugated to an antitumor antibody is given i.v. and localizes in the tumor. A prodrug is then given, which is converted to a cytotoxic drug selectively in the tumor. Ten patients with colorectal carcinoma expressing carcinoembryonic antigen received antibody-directed enzyme prodrug therapy with A5B7 F(ab')2 antibody to carcinoembryonic an...

Glucuronide prodrugs of 9-aminocamptothecin were synthesized. Prodrug 4, in which 9-aminocamptothecin was connected to glucuronic acid by an aromatic spacer via a carbamate linkage, was stable in both aqueous solution and human plasma. Prodrug 4 and its potassium salt 12 were 20-80-fold less toxic than 9-aminocamptothecin to human tumor cell lines. The simultaneous addition of beta-glucuronidas...