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  • chemical i was reading this Substitution with certain functi

    2018-10-31

    Substitution with certain functional groups at the 2′-position of both 2′-deoxyribo- as well as 2′ –deoxyarabinopyrimidine nucleosides not only alters susceptibility to enzymatic deactivation, but also modifies the biological activity (e.g., 2′-fluoro-5-iodoarabinosylcytidine and 2′-nitro-l-3-d-arabinofuranosylcytosine [11,12]. It has been reported that 2′-deoxy – 2′-fluoro β-d-arabinofuranosylcytosine is a potent cell growth inhibitor of murine Leukemia L 51784 cells, although it is susceptible to the deaminase [13]. Purine nucleosides are important agents in the treatment of hematological malignancies. 2-chloro-2′-deoxyadenosine (CdA) and 9-β-d-arabinofuranosyl-2′-fluoroadenine (Fara-A) have been used successfully in the treatment of chronic lymphocytic leukemia and low grade lymphoma [14,15]. Nucleoside analogs are prodrugs that require activation by phosphorylation for cytotoxicity. Ribonucleotide reductase (RNR) converts the nucleoside diphosphates to the corresponding deoxynucleoside diphosphates [16]. The specifity and the overall activity of RNR is controlled by binding ATP and dNTP allosteric effectors to a specificity site and an activity site on M1 subunit [17,18]. CdA, CAFdA and Fara-A target RNR, resulting in alternation of the deoxynucleoside triphosphates generated in large amounts by RNR that may compete with nucleotide analogs for uncorporation into DNA. RNR may also be unsensitive to allosteric regulation due to the mutations or altered regulation of the enzyme [19] (Fig. 2). In 1991, a new type of antineoplastic nucleoside, 2′-deoxy-2′methylidenecytidine (DMDC) has been synthesized from the corresponding 2′-keto pyrimidine nucleosides. Certain analogs of 2′-deoxycytidine bearing a 2′-“up” substituent are much more effective in terms of biological activity than those having a 2′-“down”-substituent [20] (Fig. 3). The allylic alcohol system is found in nucleoside chemical i was reading this such as angustmycin A, neplanocin and DMDC [21] (Fig. 3). Nucleoside analogs are prodrugs that require activation by phosphorylation for cytotoxicity. ribonucleotide reductase converts the nucleoside diphosphates to the corresponding deoxynucleoside diphosphates [22]. The specifity and the overall activity of RNR is controlled by binding ATP and dNTP allosteric effectors to a specificity site and an activity site on M1 subunit. It was reported that although nucleoside, 1- β -d-arabinofuranosylcytosine (ara-C, Fig. 1), is a potent inhibitor of growth of the leukemic cells, it shows a short half-life in plasma due to deamination to the chemotherapeutically inactive 1- β -arabinofuranosyluracil. It was reported also that when nucleoside analog act as antimetabolite, it must be phosphorylated to some extent at the 5′-hydroxyl group by the corresponding nucleoside kinase [23]. For such enzyme recognition, therefore, the overall shape of the nucleoside sugar conformation, glycosyl tortion angle, and spatial position of the 5′-hydroxyl group, seems to be critical. From these consideration, one approach to design nucleoside analogs (adenine analogs) that exert a broad spectrum of activity toward cancer cell lines and HIV that should: Since the halogen group at the 2- position greatly enhance activity, it was felt that substitution of groups that have better electron withdrawing capability would enhance activity even further. Topliss [26] published an operational scheme for the rationale design of analogs. This scheme suggests that if electronic properties of a substituent improves activity, then further drug design operations should concentrate on trying to enhance the electronic parameter while keeping the lipophilic and steric properties relatively constant. If this does not yield better analog, the lipophilic and/or steric parameters may have to be changed. Analogs that are being proposed to be synthesized during the course of this study, have been designed keeping this rationale in view. The electronic parameter δ will be used as a measure of the electron withdrawing properties of the substituent. However, since the coefficient for δ is small and the span in the range of the data for biological activity so narrow that unless more compounds with substitutions at the 2- and 6- positions are available, it will be difficult to predict the exact nature of the forces involved in drug binding. In addition, the amino group at the 6- position will be replaced by an electron withdrawing group so that it is protected from deamination by the deaminase enzymes [27]. This, it is felt, will yield analogs that cannot only stay for a long time in the body but will also have enhanced activity.