1104192-41-7Relevant academic research and scientific papers
Synthesis of 2′,4′-propylene-bridged (Carba-ENA) thymidine and its analogues: The engineering of electrostatic and steric effects at the bottom of the minor groove for nuclease and thermodynamic stabilities and elicitation of RNase H
Liu, Yi,Xu, Jianfeng,Karimiahmadabadi, Mansoureh,Zhou, Chuanzheng,Chattopadhyaya, Jyoti
experimental part, p. 7112 - 7128 (2010/12/25)
2′,4′-Propylene-bridged thymidine (carba-ENA-T) and five 8′-Me/NH2/OH modified carba-ENA-T analogues have been prepared through intramolecular radical addition to C=N of the tethered oxime-ether. These carba-ENA nucleosides have been subsequently incorporated into 15mer oligodeoxynucleotides (AON), and their affinity toward cDNA and RNA, nuclease resistance, and RNase H recruitment capability have been investigated in comparison with those of the native and ENA counterparts. These carba-ENAs modified AONs are highly RNA-selective since all of them led to slight thermal stabilization effect for the AON:RNA duplex, but quite large destabilization effect for the AON:DNA duplex. It was found that different C8′ substituents (at the bottom of the minor groove) on carba-ENA-T only led to rather small variation of thermal stability of the AON:RNA duplexes. We, however, observed that the parent carba-ENA-T modified AONs exhibited higher nucleolytic stability than those of the ENA-T modified counterparts. The nucleolytic stability of carba-ENA-T modified AONs can be further modulated by C8′ substituent to variable extents depending on not only the chemical nature but also the stereochemical orientation of the C8′ substituents: Thus, (1) 8′S-Me on carba-ENA increases the nucleolytic stability but 8′R-Me leads to a decreased effect; (2) 8′R-OH on carba-ENA had little, if any, effect on nuclease resistance but 8′S-OH resulted in significantly decreased nucleolytic stability; and (3) 8′-NH2 substituted carba-ENA leads to obvious loss in the nuclease resistance. The RNA strand in all of the carba-ENA derivatives modified AON:RNA hybrid duplexes can be digested by RNase H1 with high efficiency, even at twice the rate of those of the native and ENA modified counterpart.
Unusual radical 6-endo cyclization to carbocyclic-ENA and elucidation of its solution conformation by 600 MHz NMR and ab initio calculations
Zhou, Chuanzheng,Plashkevych, Oleksandr,Chattopadhyaya, Jyoti
experimental part, p. 4627 - 4633 (2009/03/12)
In our previous paper (J. Am. Chem. Soc., 2007, 129, 8362), we reported the synthesis of 7′-Me-Carba-LNA and 8′-Me-Carba-ENA thymidine through 5-hexenyl or 6-heptenyl radical cyclization. Both 5-hexenyl and 6-heptenyl radical cyclized exclusively in the exo form, giving unwanted exocyclic C7′-methyl group. In the present study, we showed that the regioselectivity of the 5-hexenyl radical cyclization could be favorably tuned by introduction of a hydroxyl group β to the olefinic double bond, yielding about 9% of the 6-endo cyclization product. Possible pathways to give 6-endo cyclization product 9 compared to the intermediates responsible to give the 5-exo cyclization product 5 has been discussed. Based on this unique 6-endo cyclization strategy, a carbocyclic ENA modified thymidine (carba-ENA) has been successfully synthesized, which also enabled us to perform its full solution conformation analysis by using NMR (1H at 600 MHz) observables for the first time.
