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Abstract
5-Fluorouracil (5-FU) is used widely as an anticancer drug to treat solid cancers, such as colon, breast, rectal, and pancreatic cancers; although it’s clinical application is greatly limited by its short plasma half-life, poor tumor affinity, myelosuppression, and gastrointestinal toxicity. To tackle these problems, numerous modifications of the 5- Fu structure have been performed.Thus, 5-Fu as possible colon specific prodrugs were synthesized in which 5-Fu is attached to amino acids (alanine & phenylalanine) using succinate group as a spacer via amide or ester bond. An approach to improve the properties of 5-fluorouracil is the chemical transformation into bioreversible derivatives (prodrugs) which are converted to the parent drug by enzymatic and / or chemical hydrolysis. The synthesis of the target compounds were accomplished following multistep reaction procedures, the chemical reaction followed up and the purity of the products were checked by TLC. The structures of the final compounds were confirmed by their melting points, infrared spectroscopy and 1H-NMR spectra. The hydrolysis of compounds III, IV, V, and VI in aqueous buffer solutions of pH 1.2 and pH 7.4 were studied. Compounds III, IV, V and VI had enough stability at pH 1.2 (t = 429.874min, t =429.874min, t=334.336min and t =376.139min respectively) and at pH 7.4 (t=601.823min, t=601.823min, t=429.874min and t=501.519min respectively); expecting that hydrolysis of these compounds by microbial enzymes in the colon will deliver 5-fluorouracil spontaneously.
Highlights
Colon cancer is the second cause of cancer related deaths in the world
Improvements have been made in surgical techniques and in chemotherapies, the survival rate is still low [1]. 5-fluorouracil is an antimetabolite of the pyrimidine analogue type, which is frequently used for treating solid tumors, such as colorectal, gastric tract, and liver carcinomas [2, 3]
Kinetic study: The max of fluorouracil 265 nm was the same max of compounds III, IV, V and VI, but they differ in molar absorpitivity (E) according to the Beer-Lambert equation [29]: A=E c b -------- equation (1)
Summary
Colon cancer is the second cause of cancer related deaths in the world. improvements have been made in surgical techniques and in chemotherapies, the survival rate is still low [1]. 5-fluorouracil is an antimetabolite of the pyrimidine analogue type, which is frequently used for treating solid tumors, such as colorectal, gastric tract, and liver carcinomas [2, 3]. The clinical applications of 5-FU are greatly limited by its short plasma half-life, poor tumor affinity, myelosuppression, and strong intestinal toxicity To tackle these problems, numerous modifications of the 5- Fu structure have been performed, a series of 5-Fu prodrugs in which 5-Fu is attached to amino acids, peptides, phospholipids, and polymers have been reported [4,5,6,7]. The term “prodrug”, first introduced by Albert, refers to a chemically modified form of a drug [8] that is devoid of pharmacological activity, but that can be converted to the active form of the drug in a biological system, where it exerts the desired action This strategy can improve the limitations associated with the effective transport into tumor cells, catabolic inactivation before the cytotoxic entity can reach the tumor, and short plasma half-1ife [9, 10]. The spacers increase the distance between the parent molecule and the promoiety and are usually cleaved spontaneously after the enzymatic or chemical decomposition of the prodrug bond between the promoiety and the spacer [22]
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