125515-31-3Relevant articles and documents
Design, synthesis and molecular modeling study of conjugates of ADP and morpholino nucleosides as a novel class of inhibitors of PARP‐1, PARP‐2 and PARP‐3
Abramova, Tatyana V.,Belousova, Ekaterina A.,Eltsov, Ilia V.,Ivanisenko, Nikita V.,Ivanisenko, Vladimir A.,Kurgina, Tatjana A.,Kutuzov, Mikhail M.,Lavrik, Olga I.,Peshkov, Roman Y.,Sherstyuk, Yuliya V.,Silnikov, Vladimir N.,Sukhanova, Maria V.,Zakharenko, Alexandra L.
, (2020/01/28)
We report on the design, synthesis and molecular modeling study of conjugates of adenosine diphosphate (ADP) and morpholino nucleosides as potential selective inhibitors of poly(ADP‐ribose)polymerases‐1, 2 and 3. Sixteen dinucleoside pyrophosphates containing natural heterocyclic bases as well as 5‐haloganeted pyrimidines, and mimicking a main substrate of these enzymes, nicotinamide adenine dinucleotide (NAD+)‐molecule, have been synthesized in a high yield. Morpholino nucleosides have been tethered to the β‐phosphate of ADP via a phosphoester or phosphoramide bond. Screening of the inhibiting properties of these derivatives on the autopoly(ADP‐ribosyl)ation of PARP‐1 and PARP‐2 has shown that the effect depends upon the type of nucleobase as well as on the linkage between ADP and morpholino nucleoside. The 5‐ iodination of uracil and the introduction of the P–N bond in NAD+‐mimetics have shown to increase inhibition properties. Structural modeling suggested that the P–N bond can stabilize the pyrophosphate group in active conformation due to the formation of an intramolecular hydrogen bond. The most active NAD+ analog against PARP‐1 contained 5‐iodouracil 2?-aminomethylmorpholino nucleoside with IC50 126 ± 6 μM, while in the case of PARP‐2 it was adenine 2?‐aminomethylmorpholino nucleoside (IC50 63 ± 10 μM). In silico analysis revealed that thymine and uracil‐based NAD+ analogs were recognized as the NAD+‐analog that targets the nicotinamide binding site. On the contrary, the adenine 2?‐aminomethylmorpholino nucleoside-based NAD+ analogs were predicted to identify as PAR‐analogs that target the acceptor binding site of PARP‐2, representing a novel molecular mechanism for selective PARP inhibition. This discovery opens a new avenue for the rational design of PARP‐1/2 specific inhibitors.
Improved protocol for the synthesis of flexibly protected morpholino monomers from unprotected ribonucleosides
Pattanayak, Sankha,Paul, Sibasish,Nandi, Bappaditya,Sinha, Surajit
, p. 763 - 782 (2013/01/16)
An inexpensive and much improved protocol has been developed for the synthesis of protected morpholino monomers from unprotected ribonucleosides in high overall yield, using oxidative glycol cleavage and reductive amination strategy. Unlike the previous methods, the present strategy allows installing the exocyclic amine protections at a later stage, and thus avoids the use of expensive, or commercially unavailable, exocyclic amine-protected ribonucleosides as starting materials. To demonstrate the flexibility of the present method in choosing protecting groups, the monomers have been protected with several such groups of different deblocking properties at the exocyclic amine position.
