Concept of Prodrug
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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, which can then elicit its desired pharmacological effect in the body. In most cases, prodrugs are simple chemical derivatives that are only one or two chemical or enzymatic steps away from the active parent drug. However, some prodrugs lack an obvious carrier or promoiety but instead result from a molecular modification of the prodrug itself, which generates a new active compound. Numerous prodrugs designed to overcome formulation, delivery, and toxicity barriers to drug utilization have reached the market. In fact, approximately 20% of all small molecular drugs approved during the period 2000 to 2008 were prodrugs. Although the development of a prodrug can be very challenging, the prodrug approach represents a feasible way to improve the erratic properties of investigational drugs or drugs already on the market. This review introduces in depth the rationale behind the use of the prodrug approach from past to present, and also considers the possible problems that can arise from inadequate activation of prodrugs.
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Background: The Carrier linked prodrug as per literature is known to be a pharmacologically inactive chemical derivative and could be used to change the physicochemical properties of compounds. Codrugs is a type of carrier linked prodrug, and consist of two usually synergistic drugs or moieties attached to each other. Keywords: Prodrugs, codrugs, carrier linked prodrugs, spacer, benorylate.
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The oral administration of the standard cytotoxic agent 5-fluorouracil is extensively limited in the last three decades. This limitation has owing to the inconsistent intestinal absorption of this drug because of the mutable activity of the enzyme housed in the intestinal mucosa named dihydropyrimidine dehydrogenase. In this report, a prodrug consists of 5-fluorouracil and 5-ethynyluracil was designed to providethe mutual release of these two active drugs using a lactonization-facilitated release method.The synthesis of the target prodrug was proceeded through seven subsequent steps using coumarin as a precursor. The spectra obtained from different spectrophotometers, including FTIR, 1H-NMR, and 13C-NMR, were confirmed the chemical backbones of the synthetic intermediate compounds and the target prodrug. The chemical stability of the target prodrug was investigated chemically in the HCl- (pH 1.2) and phosphate-(pH 6.8) buffers. Also, the capacity of the prodrug to release its active portions was evaluated utilizinghuman serum. The results gathered from the chemical stability studies indicated that the targeted prodrug hassubstantial stability in the HCl-bufferwith t1/2 of 33.18 hours, and in the phosphate-buffered saline with t1/2 of 18.14 hours, adapting pseudo-first-order kinetics. Besides, the prodrug can free the two active drugswith t1/2of 4.62 hr in human serum adapting zero-order kinetics. The authors concluded that the target prodrug may represent a potential applicant as a mutual prodrug for the oral intake ofthe 5-fluorouracil and 5-ethynyluracil.
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Abstract Directed enzyme prodrug therapy is a highly promising anti-cancer strategy. However, the current technology is limited by inefficient prodrug activation and the dose-limiting toxicity associated with the prodrugs being tested; to overcome these limitations, the dinitrobenzamide mustard prodrugs, PR-104A and SN27686, have been developed. The present study will assess both of these prodrugs for their potential uses in a novel magnetic-nanoparticle directed enzyme prodrug therapy strategy by determining their kinetic parameters, assessing the products formed during enzymatic reduction using HPLC and finally their ability to cause cell death in the ovarian cancer cell line, SK-OV-3. It was shown for the first time that the dinitrobenzamide mustard prodrugs are able to be reduced by the genetically modified nitroreductases, NfnB-cys and YfkO-cys, and that these enzyme/prodrug combinations can induce a significant cell death in the SK-OV-3 cell line, highlighting the potential for both enzyme/prodrug combinations for use in magnetic-nanoparticle directed enzyme prodrug therapy.
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A prodrug is a medicine that is primarily used after administration, that is metabolized into a pharmacologically active drug. A prodrug is generally a precursor form of a drug. A prodrug is used to selectively improve the drug that directly interacts with cells used in any form of treatment like chemotherapy. The drug, when taken separately, does not have much effect, whereas, a drug taken in after the administration of prodrug acts very effectively. Prodrugs are often used in the pharmaceutical field. Prodrug alters certain properties of prodrugs, such as physicochemical properties to enhance their efficacy and reduce their toxicity. The cancer cells are first injected with a gene that expresses an enzyme that has the ability to convert a non-toxic prodrug into its active cytotoxic form. Various applications of prodrugs include improving drug penetration through biological membranes, increasing site-specificity of a drug; it mainly improves patient's acceptance. Prodrugs stabilize the active drug and prevent drug metabolism. This review was written with an aim to highlight the important aspects of prodrugs and its use in cancer therapy.
Cancer Chemotherapy
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Chemotherapy is one of the main tumor therapy in clinic,but the system toxicity of antitumor agent and its low concentration in the specific tumor position are still important disturbing factors in tumor treatment.Prodrug,which is from the modification of active drug constructure or pharmaceutical dosage form,greatly overcome the defect of chemotherapy agent and open a new way in target tumor treatment.At present,new advanced antitumor prodrugs contain directed-enzyme activated prodrug,carrier prodrug,lipophilic prodrug and so on.Several antitumor prodrugs have been reviewed.
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