Cladribine : Cl-dAdo is often a deoxyadenosine analogue that was accepted in 1992 for that treatment of hairy-cell leukemia.53 The sugar part of this compound could be the typical deoxyribose instead of an arabinose, and this compound is readily phosphorylated by deoxycytidine kinase to Cl-dAdo nucleotides. Cl-dATP can be a fantastic substrate for DNA polymerases, exactly where it is incorporated to the expanding DNA chain and is extended greater than arabinoside analogues such Selumetinib as F-araA.48,53 DNA polymerase ? quickly extended the DNA chain past the incorporation of the single Cl-dAdo residue but was stopped by three successive integrated Cl-dAdo residues.53 Cl-dATP is usually a considerably more potent inhibitor of ribonucleotide reductase than is F-araATP,48,53 and as a result, inhibition of this enzyme is even more significant to its mechanism of action. As with dFdC and F-araA, inhibition of ribonucleotide reductase can potentiate the inhibition of DNA polymerases by nucleotide analogues. Considering that the incorporation of 3 successive dAdo residues is known as a very likely occasion within the replication of the genome, Cl-dAdo could nevertheless induce considerable chain termination. Like F-araA, Cl-dAdo is just not a substrate for adenosine deaminase, because of the presence of chlorine in the 2 position.
two.three.2.3. Clofarabine : Cl-F-araA was accepted to the treatment of relapsed and refractory pediatric acute lymphoblastic leukemia Bergenin in 2004.54,fifty five The structure of Cl-F-araA differs from that of Cl-dAdo in that it contains a fluorine atom at the 2? position while in the deoxyribose portion of the molecule. Comparison of these two FDA approved medication may be the most beneficial example of how modest structural distinctions can result in dramatic clinical differences. This modest structural variation drastically increases the stability of your glycosidic bond, leading to enhanced acid stability of your compound likewise as fantastic oral bioavailability. The mechanism of action of Cl-F-araA is much like that of Cl-dAdo and FaraA in that it can be activated by deoxycytidine kinase to Cl-F-araA 5?-triphosphate, which inhibits DNA replication on account of its potent inhibition of each ribonucleotide reductase and DNA polymerase.48,56,57 The potency of Cl-F-araA with respect to inhibition of ribonucleotide reductase is just like that of Cl-dAdo. Additionally, its readily integrated into the DNA chain but features a chain-terminating effect alot more much like F-araA than Cl-dAdo. Hence, Cl- F-araA combines into one molecule the options of Cl-dAdo and F-araA that happen to be accountable for their antitumor action. Like dFdC, Cl-F-araA-TP has become proven to possess an extended intracellular retention time,56 and Cl-F-araA has demonstrated excellent activity towards quite a few human reliable tumor xenografts in mice.58?60 Much like Cl-dAdo, Cl-F-araA will not be a substrate for adenosine deaminase. 2.three.two.four.