5'-Esters of 2'-deoxyadenosine and 2-chloro-2'-deoxyadenosine with cell differentiation-provoking agents.

Abstract

Phenylacetic and retinoic acids are carboxyacidic cell differentiating agents displaying anticancer activities. We report on a new class of compounds including the 5¢-esters of 2¢-deoxyadenosine (dA) or 2-chloro-2¢-deoxyadenosine (cladribine, 2CdA) and the aforementioned acids. The rationale behind the synthesis of these esters was that if they are hydrolyzed inside the lymphoid cells, either dA will be removed from the intracellular environment by deamination, or 2CdA will be phosphorylated and accumulated. In either case targetted delivery of the differentiating agent to the lymphoid cells may be envisaged. The said compounds were synthesized by the Mitsunobu procedure employing triphenylphosphine and azadicarboxylic acid esters, and their stability was tested against various esterases. Esters of dA and 2CdA with phenylacetic acids were found to be resistant to enzymatic hydrolysis, whereas those with retinoic acids were efficiently hydrolyzed by commercially available hepatic esterase as well as by esterases present in the blood plasma and in diluted human lymphocyte lysate. Susceptibility to enzymatic hydrolysis was found to be a prerequisite of cytotoxic and/or differentiating activity of these esters in leukemic cell lines.

Simple Synthesis of Cladribine-Based Anticancer Polymer Prodrug Nanoparticles with Tunable Drug Delivery Properties

“…Conversely, CdA-digly-PI nanoparticles ( P1d–P4d ) with M n ranging from 1470 g mol –1 to 4980 g mol –1 led to significant cytotoxicity (Figure b) with half maximal inhibitory concentrations (IC 50 ) varying between 660 nM and 1430 nM. These results are totally consistent with the drug release profiles of the different CdA-based prodrugs (because P4d nanoparticles gave significant CdA release in human serum, compared to P3 nanoparticles, which gave almost no CdA release) and with previous literature about small CdA prodrug molecules. , They indeed confirmed (i) the too-high stability of the ester bond directly formed from the CdA hydroxyl group, even in a biological environment, and (ii) the more-efficient CdA release from CdA-digly-PI nanoparticles, compared to CdA-PI , because of the enhanced lability of the diglycolate linker. CdA-free PI nanoparticles were also prepared by nanoprecipitation of AMA-digly-PI ( P0d ) ( M n = 2650 g mol –1 ) and gave no cytotoxicity up to at least ∼6 μM (Figure b).…”

Synthesis of New Potential Lipophilic Co‐Drugs of 2‐Chloro‐2′‐deoxyadenosine (Cladribine, 2‐CdA, Mavenclad®, Leustatin®) and 6‐Azauridine (z6U) with Valproic Acid

“…The 5'-O-valproyl derivative, however, proved to be almost inactive, probably due to the resistance to an enzymatic deacylation in the tested cells preventing thereby the 5'-monophosphorylation of the free C5'-OH group. [33] Deeper investigations are required to decipher the molecular mechanism of cladribine and its derivatives as well as their cytotoxic effects after treatment of other cancer cell lines derived from glioblastoma multiforme (GBM) tumors after operative resection. The possibility of a photochemical conversion of the nucleolipids of cladribine into corresponding valproic acid derivatives of 2'-deoxyisoguanosine opens the opportunity for the preparation of a wide range of crotonoside nucleolipids.…”

“…If this nucleolipid gets phosphorylated by intracellular kinases up to the 5'-triphosphate, a polymerase could add it to a growing nucleic acid. Hence, the 3'-OH end of the nucleic acid would be blocked and a termina- [33]…”

“…[19,30,32] For an improvement of the cladribine activity, several different approaches have been followed. Grieb et al [33] prepared 5'-O-acyl derivatives with phenylacetic acid as well as retinoic acid via a Mitsunobu reaction at the 5'-position of 2-CdA (Figure 3). The aim of this work was to find out if the 5'-esters are hydrolysable and if the acids cleaved off exert a cytotoxic effect.…”

“…It could be shown that the cladribine-5'-phenylacetate is resistant towards an enzymatic hydrolysis but not the cladribine-5'-retinoic acid ester, the latter is cleaved off by various esterases. Moreover, Grieb's group [33] demonstrated that the 5'-OH group is essential for the cladribine activation by phosphorylation; if this group is blocked, its cytotoxic activity is abolished. Levy et al [34] synthesized in 1996 a nonhydrolysable nucleotide analog with an isosteric difluoromethylene bridge between the ribose and the phosphate moiety, an analog of 2-CdA-monophosphate.…”