Catalysis of Hydrogen–Deuterium Exchange Reactions by 4-Substituted Proline Derivatives

The identification and understanding of structure–activity relationships is vital for rational catalyst design. A kinetic study of the hydrogen–deuterium exchange reaction of cyclohexanone in aqueous solution, as catalyzed by proline derivatives, has revealed valuable structure–activity relationships. In phosphate-buffered solution, cis-4-fluoroproline is more active than the trans isomer, a distinction that appears to originate from a destabilizing interaction between the fluorine atom and phosphate anion during general acid-catalyzed dehydration of the carbinolamine intermediate. trans-4-Ammoniumprolines are exceptionally active catalysts owing to favorable Coulombic interactions involving the ammonium group and the alkoxide moiety formed upon 1,2-addition of the proline derivative to the ketone. These results could be used for the optimization of proline catalysts, especially in transformations where the formation of the putative iminium ion is rate-limiting.National Institutes of Health (U.S.). (Grant R01 AR044276)National Institutes of Health (U.S.). (Grant R01 GM04478

The quest for effective pain control during suture adjustment after strabismus surgery: a study evaluating supplementation of 2% lidocaine with 0.4% ropivacaine

Howard D Palte, Kara M Cavuoto, Lalitha Sundararaman, Steven Gayer, Joyce Schiffman, Hilda CapoBascom Palmer Eye Institute, Miami, FL, USAPurpose: To determine whether the addition of 0.4% ropivacaine to the standard 2% lidocaine peribulbar anesthetic block improves pain scores during suture adjustment in patients undergoing strabismus surgery with adjustable sutures.Methods: Prospective, double-blind study of 30 adult patients aged 21–84 years scheduled for elective strabismus surgery with adjustable sutures. Patients were divided into two groups of 15 patients each based on the local anesthetic. Group A received 2% lidocaine and Group B received 2% lidocaine/0.4% ropivacaine. Pain was assessed using the visual analog scale (VAS) preoperatively and at 2, 4, and 6 hours postoperatively. The Lancaster red-green test was used to measure ocular motility at the same time points.Results: The pain scores in the two groups were low and similar at all measurement intervals. The VAS for Group A versus Group B at 2 hours (1.7 versus 2.4, P=0.5) and 4 hours (3.5 versus 3.7, P=0.8) showed no benefit from the addition of ropivacaine. At 6 hours, the VAS (3.7 versus 2.7) was not statistically significant, but the 95% confidence interval indicated that ropivacaine may provide some benefit. A repeated measures ANOVA did not find a statistically significant difference in VAS scores over time (P=0.9). In addition, the duration of akinesia was comparable in both groups (P=0.7).Conclusion: We conclude that the 50:50 mixture of 2% lidocaine with 0.4% ropivacaine as compared to 2% lidocaine in peribulbar anesthetic blocks in adjustable-suture strabismus surgery does not produce significant improvements in pain control during the postoperative and adjustment phases. In addition, ropivacaine did not impair return of full ocular motility at 6 hours, which is advantageous in adjustable-suture strabismus surgery.Keywords: adjustable-suture strabismus surgery, postoperative ocular motility, local anesthetic block, postoperative pai

Boronate-Mediated Biologic Delivery

Inefficient cellular delivery limits the landscape of macromolecular drugs. Boronic acids readily form boronate esters with the 1,2- and 1,3-diols of saccharides, such as those that coat the surface of mammalian cells. Here pendant boronic acids are shown to enhance the cytosolic delivery of a protein toxin. Thus, boronates are a noncationic carrier that can deliver a polar macromolecule into mammalian cells

Sub-picomolar Inhibition of HIV-1 Protease with a Boronic Acid

Boronic acids have been typecast as moieties for covalent complexation and are employed only rarely as agents for non-covalent recognition. By exploiting the profuse ability of a boronic acid group to form hydrogen bonds, we have developed an inhibitor of HIV-1 protease with extraordinary affinity. Specifically, we find that replacing an aniline moiety in darunavir with a phenylboronic acid leads to 20-fold greater affinity for the protease. X-ray crystallography demonstrates that the boronic acid group participates in three hydrogen bonds, more than the amino group of darunavir or any other analog. Importantly, the boronic acid maintains its hydrogen bonds and its affinity for the drug-resistant D30N variant of HIV-1 protease. The BOH···OC hydrogen bonds between the boronic acid hydroxy group and Asp30 (or Asn30) of the protease are short (rO···O = 2.2 Å), and density functional theory analysis reveals a high degree of covalency. These data highlight the utility of boronic acids as versatile functional groups in the design of small-molecule ligands. Keywords: peptides and proteins; crystal structure; inhibitors; noncovalent interactions; functional groupsNational Institutes of Health (U.S.) (Grant T32 GM008349)National Institutes of Health (U.S.) (Grant R01 GM044783)National Science Foundation (U.S.) (Grant MCB 1518160

Ribonuclease-Activated Cancer Prodrug

Cancer chemotherapeutic agents often have a narrow therapeutic index that challenges the maintenance of a safe and effective dose. Consistent plasma concentrations of a drug can be obtained by using a timed-release prodrug strategy. We reasoned that a ribonucleoside 3′-phosphate could serve as a pro-moiety that also increases the hydrophilicity of a cancer chemotherapeutic agent. Herein, we report an efficient route for the synthesis of the prodrug uridine 3′-(4-hydroxytamoxifen phosphate) (UpHT). UpHT demonstrates timed-released activation kinetics with a half-life of approximately 4 h at the approximate plasma concentration of human pancreatic ribonuclease (RNase 1). MCF-7 breast cancer cells treated with UpHT showed decreased proliferation upon coincubation with RNase 1, consistent with the release of the active drug4-hydroxytamoxifen. These data demonstrate the utility of a human plasma enzyme as a useful activator of a prodrug

Ultrasound-guided bilateral transversus abdominis plane blocks in conjunction with intrathecal morphine for postcesarean analgesia

To determine whether transversus abdominis plane (TAP) blocks administered in conjunction with intrathecal morphine provided superior analgesia to intrathecal morphine alone. Randomized, double-blind, placebo-controlled study. Operating room of a university hospital. 51 women undergoing elective Cesarean delivery with a combined spinal-epidural technique that included intrathecal morphine. Subjects were randomized to receive a bilateral TAP block with 0.5% ropivacaine or 0.9% saline. Postoperative analgesics were administered on request and selected based on pain severity. Patients were evaluated at 2, 24, and 48 hours after the TAP blocks were performed. Verbal rating scale (VRS) pain scores at rest, with movement, and for colicky pain were recorded, as was analgesic consumption. Patients rated the severity of opioid side effects and their satisfaction with the procedure and analgesia. 51 subjects received TAP blocks with ropivacaine (n = 26) or saline (n = 25). At two hours, the ropivacaine group reported less pain at rest and with movement (0.5 and 1.9 vs 2.8 and 4.9 in the saline group [VRS scale 0 – 10]; P < 0.001) and had no requests for analgesics; there were several requests for analgesia in the saline group. At 24 hours, there was no difference in pain scores or analgesic consumption. At 48 hours, the ropivacaine group received more analgesics for moderate pain (P = 0.04) and the saline group received more analgesics for severe pain (P = 0.01). Transversus abdominis plane blocks in conjunction with intrathecal morphine provided superior early postcesarean analgesia to intrathecal morphine alone. By 24 hours there was no difference in pain scores or analgesic consumption