Mustafa Y F et al. / Pharmacie Globale (IJCP) 2015, 04 (06) 1 Pharmacie Globale © (IJCP), Vol. 06, Issue 04 Available online at www.pharmacie-globale.info PHARMACIE GLOBALE INTERNATIONAL JOURNAL OF COMPREHENSIVE PHARMACY DESIGN, SYNTHESIS AND KINETIC STUDY OF COUMARIN-BASED TRIPLE MUTUAL PRODRUG FOR LUNG CANCER Yasser Fakri Mustafa* and Nohad Abdul-alwahhab Al-Omari Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq. Received: 22 Oct 2015; Revised: 2 Nov 2015; Accepted: 30 Nov 2015; Available online: 5 Dec 2015 INTRODUCTION Non-small cell lung cancer (NSCLC) is a heterogeneous disease that is hard to treat, and remains the leading cause of cancer-related mortality worldwide 1 . In recent years, despite the recent advances in surgery, irradiation and targeted chemotherapy; the survival rate of patients with advanced stage NSCLC is very low (about five years) 2 . The synthetic fluoropyrimidine, 5-Fluorouracil (5-FU), has a broad spectrum of activity against solid tumors as colorectal, breast, gastric, pancreatic, prostate, bladder and lung cancers 3 . However, 5-Fu has heavy toxic side effects including little affinity to tumor cells, a short plasma half-life (so it is administered by intravenous infusion) and irregular absorption with unpredictable plasma level after oral use 4 . As a pyrimidine analog, 5-FU is converted intracellularly to several active metabolites: 5-fluorodeoxyuridine triphosphate (5-FdUTP), 5-fluorodeoxyuridine monophosphate (5-FdUMP) and 5-fluorouridine triphosphate; these active metabolites disrupt RNA synthesis and the action of thymidylate synthase (TS) 5 . Although a host of compounds has been suggested to *Corresponding Author: Yasser Fakri Mustafa Assistant professor, Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq. Email: yassermusel@yahoo.com enhance the clinical effects of 5-FU 6-8 , the most intensively studied and widely used biochemical modulator is leucovorin (LV, folinic acid, 5′-formyltetrahydrofolate) 9 . LV improves the inhibitory effect of 5-FU (more precisely of 5-FdUMP) on TS, which is the key enzyme in the de novo synthesis of thymidine and the most important target of 5- FU in cancer cells. LV is transported through the cell membrane by the reduced folate carrier and anabolized to methylene tetrahydrofolate (CH2-THF), the increased intracellular concentration of which results in expansion of the cellular concentration of CH2-THFand stabilization of its ternary complex with TS and 5-FdUMP 10-12 . Additionally, polyglutamates of CH2-THF that are formed by the action of folylpolyglutamate synthase may enhance the inhibition of TS 13 . According to huge number of in vivo studies, the potentiation of antitumor activity of 5-FU by LV is usually associated with prevention of rebound TS induction and with a more significant inhibition 14-20 . 4-Aryl coumarins (neoflavones) are known to exhibit several important biological activities such as antitumor, antimalarial, antibacterial, anti-inflammatory, anti-HIV, antidiabetic, antiviral and antiprotozoal 21 . 5,7-dimethoxy- 4-phenylcoumarin, isolated from endophytic Streptomyces aureofaciens CMUAc130, showed a significant in-vivo antitumor activity against NSCLC. Additionally, it may be effective in preventing or in delaying the formation of ABSTRACT Owing to our interest in the coumarin-based prodrug system, a novel prodrug of 5-fluorouracil, leucovorin and 5,7-dimethoxy-4-phenylcoumarin was designed, synthesized and evaluated as a promising chemotherapeutic agent for lung cancer depending on in-vitro stability study in HCl buffer (pH 1.2) and in phosphate buffer (pH 7.4), as well as in vitro release study in human serum. The synthetic plan was designed to be a modification to that described by Wang et al, and was consist of a series of 7 linear steps starting from 5,7-dimethoxy-4- phenylcoumarin. This coumarin derivative was reduced to diol with relatively low yield; the allylic hydroxyl group was selectively protected via ether formation whereas the phenolic hydroxyl group was esterified with folinyl chloride. When the protective group was cleaved in an acidic medium, the resulted allylic hydroxyl group was selectively oxidized to aldehyde using a selective oxidizing agent, manganese oxide. The allylic carboxylic group resulted from aldehyde oxidation by sodium chlorite was coupled with 5-flourouracil using dicyclohexyl carbodiimide to form the target prodrug. The chemical structure of prodrug was established by analyzing its FTIR, 1H NMR, 13C NMR and MS-ESI spectra. The results of in-vitro kinetic study indicated that the prodrug was significantly stable in both buffers with half-lives of about 36hr and 20hr respectively, and was hydrolyzed in human serum followed pseudo first order kinetics with half-life of about 8hr. Consequently, it is believed that the synthesized prodrug may be a potential candidate as oral prodrug for treatment of lung cancer, and is a first agent belongs to a new prodrug strategy, which is a coumarin-based triple mutual prodrug. Keywords: Coumarin; prodrug; 5-fluorouracil; leucovorin; kinetics. Research Article ISSN 0976-8157