TY - JOUR
T1 - Synthesis and biological evaluation of 2′,4′- and 3′,4′-bridged nucleoside analogues
AU - Nicolaou, K. C.
AU - Ellery, Shelby P.
AU - Rivas, Fatima
AU - Saye, Karen
AU - Rogers, Eric
AU - Workinger, Tyler J.
AU - Schallenberger, Mark
AU - Tawatao, Rommel
AU - Montero, Ana
AU - Hessell, Ann
AU - Romesberg, Floyd
AU - Carson, Dennis
AU - Burton, Dennis
N1 - Funding Information:
We thank Dr. D. H. Huang and Dr. L. Pasternack for NMR spectroscopic assistance and Dr. G. Siuzdak for mass spectrometric assistance. Financial support for this work was provided by the National Institutes of Health (USA) and the Skaggs Institute for research, along with fellowships from Novartis (to S.P.E.) and UCSD/SDSU IRACDA (to F.R.).
PY - 2011/9/15
Y1 - 2011/9/15
N2 - Most nucleosides in solution typically exist in equilibrium between two major sugar pucker forms, N-type and S-type, but bridged nucleosides can be locked into one of these conformations depending on their specific structure. While many groups have researched these bridged nucleosides for the purpose of determining their binding affinity for antisense applications, we opted to look into the potential for biological activity within these conformationally-locked structures. A small library of 2′,4′- and 3′,4′-bridged nucleoside analogues was synthesized, including a novel 3′,4′- carbocyclic bridged system. The synthesized compounds were tested for antibacterial, antitumor, and antiviral activities, leading to the identification of nucleosides possessing such biological activities. To the best of our knowledge, these biologically active compounds represent the first example of 2′,4′-bridged nucleosides to demonstrate such properties. The most potent compound, nucleoside 33, exhibited significant antiviral activity against pseudoviruses SF162 (IC 50 = 7.0 μM) and HxB2 (IC 50 = 2.4 μM). These findings render bridged nucleosides as credible leads for drug discovery in the anti-HIV area of research.
AB - Most nucleosides in solution typically exist in equilibrium between two major sugar pucker forms, N-type and S-type, but bridged nucleosides can be locked into one of these conformations depending on their specific structure. While many groups have researched these bridged nucleosides for the purpose of determining their binding affinity for antisense applications, we opted to look into the potential for biological activity within these conformationally-locked structures. A small library of 2′,4′- and 3′,4′-bridged nucleoside analogues was synthesized, including a novel 3′,4′- carbocyclic bridged system. The synthesized compounds were tested for antibacterial, antitumor, and antiviral activities, leading to the identification of nucleosides possessing such biological activities. To the best of our knowledge, these biologically active compounds represent the first example of 2′,4′-bridged nucleosides to demonstrate such properties. The most potent compound, nucleoside 33, exhibited significant antiviral activity against pseudoviruses SF162 (IC 50 = 7.0 μM) and HxB2 (IC 50 = 2.4 μM). These findings render bridged nucleosides as credible leads for drug discovery in the anti-HIV area of research.
KW - Antiviral
KW - Cytotoxic
KW - Nucleosides
KW - Synthesis
UR - http://www.scopus.com/inward/record.url?scp=80052576631&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80052576631&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2011.07.022
DO - 10.1016/j.bmc.2011.07.022
M3 - Article
C2 - 21840722
AN - SCOPUS:80052576631
SN - 0968-0896
VL - 19
SP - 5648
EP - 5669
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 18
ER -