Formation of Unimolecular G-Quadruplex Macrocycles from N9-Modified Guanine Derivatives

Our genetic information is protected by single-stranded, guanine-rich DNA sequences called telomeres, which have been shown to form guanine quadruplex structures in vivo. When stabilized, G-quadruplexes inhibit the activity of telomerase, an enzyme that contributes to the immortality of cancer cells. Due to recent interest in the anticancer potential of guanine quadruplexes, the need exists for understanding their self-assembly. As such, recent studies have focused on the formation of these structures from guanine derivatives. We have successfully synthesized G-quadruplex forming subunits from the coupling of N2-acetylguanine and 3,5-di-substituted benzylbromide derivatives followed by amide deprotection. Upon addition of potassium salts, these subunits were confirmed, though nuclear magnetic resonance (NMR) analysis, to form G-quartets. Following cation-templated ring-closing metathesis using Grubb’s 2nd generation catalyst, G-quadruplex macrocycles were successfully formed. Future studies will investigate the macrocycles\u27 ability to bind G-quadruplex stabilizing ligands and determine their potential to serve as model G-quadruplexes and aid in the search for new anti-cancer drugs

NCEO Core Staff

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Inosine to Increase Serum and Cerebrospinal Fluid Urate in Parkinson Disease

Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD). To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial. The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled. Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month. The prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability. Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD. clinicaltrials.gov Identifier: NCT00833690