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FIGURE 2.11 Captodative stabilization of radical 2.20.

The stability of 2.20 is due to the captodative effect of the tetrahydrofuranone oxygen atoms (page 103), since the unpaired electron is adjacent to both an electron-withdrawing and an electron-releasing group (Fig. 2.11).

3.4. Allosteric inhibition of RNR

Therapeutically significant inhibition of RNR can also be achieved through a feedback mechanism by accumulation of deoxyguanosine triphosphate (dGTP) as a consequence of the inhibition of purine nucleoside phosphorylase (PNP), the enzyme that catalyzes the phosphorolysis of the N-ribosidic bonds of purine nucleosides and deoxynucleosides to form purine and a-d-phosphorylated ribosyl products. This inhibition leads to increased blood levels of one of its substrates, deoxyguanosine (dG), which is specifically transported and phosphorylated by T-cell deoxynucleoside kinases. This process leads to pathologically elevated levels of dGTP in these cells, which result in allosteric RNR inhibition (Fig. 2.12). PNP is thus a suitable target for inhibitor development aiming at T-cell immune response modulation, and more specifically in the treatment of relapsed or refractory T-cell lymphoblastic lymphoma, acute leukemia, and T-cell prolymphocytic leukemia.12 Immucillin H (forodesine) is a 9-deazanucleoside with a pyrrolidine ring replacing the ribose tetrahydrofuran. It behaves as a very potent inhibitor of PNP because of the analogy of its protonated form with the structure of the transition state, which has oxacarbenium ion character with partial positive charge near C-1'. Immucillin-H has an NH group at N-7 and its charge distribution resembles that of the transition state when N-4' is protonated to the corresponding cation (Fig. 2.13).13'14

We will finally mention that some clinically relevant deoxyadenosine derivatives acting primarily as inhibitors of DNA polymerases are also allosteric inhibitors of RNR after their conversion into the corresponding 5'-triphosphates, as will be discussed in Section 8. Therefore, these compounds have a dual action that has been described as "self-potentiation."

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