Guanine hydrolysis

There is some evidence to suggest that these drugs may owe their activity to inhibition of the enzyme that is responsible for hydrolysis of 3, 5 -cyclic AMP (itself a guanine derivative) and thus prolong the action of cyclic AMP. 

One of the steps in the metabolic degradation of guanine is hydrolysis lo give xanthine. Propose a mechanism. 

Temozolomide undergoes spontaneous hydrolysis and decarboxylation at physiological pH value and thereafter a methyldiazonium ion is released. This ion forms DNA adducts within guanine rich DNA sequences. Temozolomide has high bioavailability and is metabolized in the liver. 

The liver RNA isolated from rats treated with C-NHEX yielded 1,6-hexanediol upon hydrolysis with acid (54). This result indicates that NHEX underwent metabolic a-hydroxylation to give an adduct that may have been formed at 0 of guanine. The initially formed adduct would have been expected to be a 6-oxo-hexyl derivative reduction of the adduct must have occurred in order to produce the observed 1,6-hexanediol. 

The hydrolysis leads to 4-aminoimidazole-5-carboxamide, which under certain conditions can react with various partners (e.g., HCN, dicyan or formamidine) to give purines (i.e., adenine, guanine, hypoxanthine and diaminopurine). 

In vitro studies of DNA interactions with the reactive ben-zo[a]pyrene epoxide BPDE indicate that physical binding of BPDE occurs rapidly on a millisecond time scale forming a complex that then reacts much more slowly on a time scale of minutes (17). Several reactive events follow formation of the physical complex. The most favorable reaction is the DNA catalyzed hydrolysis of BPDE to the tetrol, BPT (3,5,6,8,17). At 25°C and pH=7.0, the hydrolysis of BPDE to BPT in DNA is as much as 80 times faster than hydrolysis without DNA (8). Other reactions which follow formation of physical complexes include those involving the nucleotide bases and possibly the phosphodiester backbone. These can lead to DNA strand scission (9 34, 54-56) and to the formation of stable BPDE-DNA adducts. Adduct formation occurs at the exocyclic amino groups on the nucleotide bases and at other sites (1,2,9,17,20, 28,33,34,57,58). The pathway which leads to hydrocarbon adducts covalently bound to the 2-amino group of guanine has been the most widely studied. 

Initial experiments showed that [0s(ri6-bip)Cl(en)]+ (26) was not cytotoxic towards cancer cells (105), but a later reassessment of the cytotoxic activity of this compound showed that it indeed was active at micromolar concentrations (IC50 values of 7.6 (A2780) and 10 pM (A549)) (112). A possible explanation for the initial lack of activity may be the partial decomposition of the complex in stock test solutions prepared in DMSO, as was evidenced in subsequent studies (112). The cytotoxicity data are now more in line with the chemical properties of the complex, i.e. observed hydrolysis rate and guanine binding. 

When the receptor interacts with its associated G protein, the conformation of the guanine-nucleotide-binding site is altered. The subunits then dissociate, and a phosphatidylinositol-specific phospholipase C (PI-PLC) is activated [5]. The subsequent hydrolysis of phosphatidylinositol bisphosphate then produces inositol triphosphate (IP3) and diacylglycerol (DAG), which are known to be secondary messengers. For example, the water soluble IP3 is released into the cell where its ultimate targets are the calcium storage organelles from which Ca2+ is released [3]. The presence of DAG in cells is known to activate the cellular enzyme protein kinase C (PKC) [6, 7], which phosphorylates a number of cellular... 

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