Preface [Hot topic: Antimetabolic Agents (Executive Editor : Galal Hamza Elgemeie)]

Antimetabolites are structural analogs of naturally occurring compounds. Antimetabolites interfere with the production of nucleic acids. They work through a variety of mechanisms including competition for binding sites on enzymes and incorporation into nucleic acids. The FdUMP metabolite of 5-FU can even act as a suicide inhibitor of thymidylate synthase. Some antimetabolites are prodrugs, i.e., they must be biochemically converted to their active form. Clinically useful antimetabolites ultimately inhibit DNA synthesis as their major anticancer mechanism although their site of action may be several steps removed. In some cases, e.g., 5-FU, inhibition of RNA processing may also be important. The relative importance of altered DNA versus RNA synthesis and function may be tumor-type dependent. Antimetabolites profoundly inhibit replication of bone marrow cells. Some cause even greater GI toxicity. As their parent category implies, these agents are highly cell cycle-specific when inhibition of DNA synthesis is the dominant effect. Because cells are far more sensitive to some antimetabolites while in the S phase, those antimetabolites are further categorized as phase-specific. There are three categories of antimetabolites: antifolates, purine analogs and pyrimidine antimetabolites. This issue of “Current Pharmaceutical Design” contains the text of five invited review articles. The selection of topics and authors was made with the intention of balancing reports derived from largely chemical expertise with discussions on the biological aspects of new drug development relating to antimetabolites. Science presented in these papers is state of art and will be of interest to those working in the corresponding field. The article by Professor Nair [1] will focus on the major classes of compounds that have been discovered as inhibitors of HIV integrase. The viral enzyme, HIV integrase, is one of three key enzymes of the pol gene of HIV. The various classes include nucleotides, oligonucleotides and dinucleotides. In his review Professor Antonin Holy [2] will discuss the synthetic approaches to acyclic nucleoside phosphonates (ANP). Major focus is placed on structure-activity relationships, biological activities, and mode of action of ANPs, with emphasis to selected drugs or drug candidates. A review on anticancer antifolates, authored by Dr. John McGuire, [3] describes the efforts to design more therapeutically selective antifolates than methotrexate (MTX), the only antifolate anticancer agent in clinical use to this date. Professor Roy Kisliuk, [4] with his article on deaza analogues of folic acid as antitumor agents, highlight on a group of compounds structurally related to deaza derivatives of aminopterin and folic acid. The review focus on deaza antifolates which are presently under clinical development and also on those less developed which represent novel approaches. Compounds are grouped according to their enzyme targets and also according to their membrane transport mechanism into cells. Lastly, the chapter written by me [5] outlines approaches to the development of thioguanine and mercaptopurine structurally related compounds which might find use in treating the cancer and HIV. The aim of this issue was to address the use of antimetabolite agents in drug discovary and development. I am sincerely grateful to Professor Cyril Parkanyi from Florida Atlantic University for his sincere help during the innovative steps of this work and also to the individuals who contributed to this body of work. All are experts in their fields. They devoted a large amount of time to the production of these in-depth reviews. Thanks to them all. References [1] Nair V. Novel Inhibitors of HIV Integrase: The Discovery of Potential Anti-HIV Therapeutic Agents. Curr Pharm Design 2003; 9(31): 2553-2565. [2] Holy A. Phosphonomethoxyalkyl Analogs of Nucleotides. Curr Pharm Design 2003; 9(31): 2567-2592. [3] McGuire JJ. Anticancer Antifolates: Current Status and Future Directions. Curr Pharm Design 2003; 9(31): 2593-2613. [4] Kisliuk RL. Deaza Analogues of Folic Acid as Antitumor Agents. Curr Pharm Design 2003; 9(31): 2615-2625. [5] Elgemeie GH. Thioguanine, Mercaptopurine: Their Analogs and Nucleosides as Antimetabolites. Curr Pharm Design 2003; 9(31): 2627-2642.