Design, synthesis and evaluation of novel intercalator analogs targeting therapeutically important polymerases and folded RNA

Title from title page, viewed on June 24, 2013Dissertation advisor: Simon H. FriedmanVitaIncludes bibliographic references (pages 366-386)Thesis (Ph.D.)--School of Pharmacy and Dept. of Chemistry. University of Missouri--Kansas City, 2013Polymerases and ribonucleic acids have been found to play major roles in the causation and progression of several diseases. Targeting such important therapeutic targets using small molecules can help achieve their specific recognition and inhibition thereby intercepting key stages involved in the progression of various diseases. This dissertation work is directed towards the design of intercalator based analogs that would allow specific targeting of important targets. Two such therapeutically important targets representing polymerases and RNA discussed in this dissertation are HIV-1 reverse transcriptase and miRNA-21. HIV-1 reverse transcriptase plays a key role in the viral life cycle by reverse transcribing viral RNA into replication competent cDNA via formation of a key RNA/DNA heteroduplex. Since reverse transcriptase remains in close association with this RNA/DNA heteroduplex during the reverse transcription step, targeting of this key heteroduplex could offer a unique approach to inhibit reverse transcriptase with high affinity and specificity. In this dissertation work, several bis-intercalator analogs with linkers of varying lengths and rigidities were designed, synthesized and evaluated for their inhibitory activity against reverse transcriptase. While strong intercalators such as ethidium and acridine-based analogs were able to achieve bis-intercalation, binding of such analogs appeared to be mostly driven by intercalation as opposed to the linkers connecting the two intercalators raising specificity concerns. Hence, multiple weak intercalators based bis-intercalator libraries were designed using weak intercalators such as tryptophan, naproxen and quinoxaline-2-carboxylic acid. Interesting leads were observed from tryptophan and quinoxaline-2-carboxylic acid based libraries. Tryptophan-based leads were non-promiscuous inhibitors, but unfortunately their testing against human DNA polymerase-α found these to be non-specific inhibitors of reverse transcriptase. Interesting leads were obtained from cyclic quinoxaline-2-carboxylic acid based bis-intercalator library with low μM affinities towards reverse transcriptase. Most importantly these leads were found to be both non-promiscuous and specific inhibitors of reverse transcriptase. The final portion of this dissertation details efforts towards developing a general tool for the sequence specific recognition of therapeutically important RNAs. For this effort multiple cyclic peptide based-libraries were designed, synthesized and screened against therapeutically important RNAs such as miRNA-21 using affinity selection chromatography. An important feature of these libraries was that these were devoid of any positive charges. Binding of molecules in such libraries would hence be driven by their ability to identify and map unique structural features of folded RNA such as bulges and loops.Introduction -- Inhibition of reverse transcriptase by targeting the key RNA/DNA heteroduplex -- Screening of strong intercalator based bis-intercalator libraries -- Design, synthesis and screening of multiple weak intercalator based bis-intercalator libraries -- Summary and conclusions of HIV-1 RT project -- Development of a general tool for sequence specific recognition of folded RNA using small molecules -- Design, synthesis and screening of 15 individual tetrapeptide libraries targeting binding pockets in folded RNA -- Summary and conclusions of RNA recognition projec

COMMON FIXED POINT THEOREM FOR OCCASIONALLY WEAKLY COMPATIBLE MAPPINGS IN FUZZY METRIC SPACE

The present paper deals with common fixed point theorem in fuzzy metric space by employing the notion of occasionally weakly compatible mappings. Our result generalizes the recent result of Singh et. al. [16].Keywords : Common fixed points, fuzzy metric space, compatible maps, occasionally weakly compatible mappings and weak compatible mappings.Â

Pregabalin Addiction: Case Report of a Young Adult

Pregabalin has been used widely for the treatment of neuropathic pain, generalized anxiety disorders and epilepsy. Data is scarce and much is not known about the addictive potential of pregabalin. Herein, we report details of a young adult who got addicted to pregabalin and approached for a smooth withdrawal. The subject had a successful outcome. Literature suggests a growing concern for the abuse of pregabalin. Risk factors associated with the development of addictive behavior with pregabalin need to be assessed

Use of intramedullary implants in adult diaphyseal fracture both bone forearm

Background: Fractures of the forearm bones are very common. The most common form of stabilization is plate and screw fixation. The role of Intramedullary nailing of fractures of the shafts of the adult radius and ulna is still to be defined. This study was perform to analyze anatomical and function outcome of the patients treated by Talwarkar square nail.Methods: We evaluated 46 patients (29 males and 17 females) had fracture both bone forearm treated by intramedullary nail. We analyzed patients in two broad group one with close fracture or grade I, II open fracture (34 patients) and other have open fracture grade IIIA or IIIB (12 patients). First group patients further analyzed weather close (22 patients) or open reduction (8 patients) required. Functional outcome was calculated by Grace and Eversman system.Results: Out of 32 patients of close fracture or open grade 1 or 2 fracture, 29 (90.62%) have excellent or acceptable result. All the patients (100%) in whom close reduction succeeds achieved excellent result. 22 (64.70%) patients close nailing possible.12 patients in whom open reduction required 9 (75%) goes into union. Close nailing have overall success rate is 90.62% where it fail and open nailing require success rate bring down to 75%.. Conclusions: IM nailing gives satisfactory results. Advantages of close nailing are- early union, low incidence of infection, small scars, less blood loss, short operating time with minimal surgical trauma, easier implant removal. Even though plate and screw fixation is the gold standard for stabilization of both bone forearm fracture but intramedullay implant can be used in selected cases with good result. To achieve acceptable result – early surgery, proper selection of the case, pre-operative planning, proper assessment of diameter, length and radial bowing of the nail, is required

Modeling Driver\u27s Route Choice Behavior Under the Influence of Advanced Traveler Information Systems (Vol. 2; Vol. 1: 96/10)

This research consisted of two parts; this report is volume 2 of 2 volumes; Volume 1 is Report No. FHWA/IN/JHRP-96/10. The first part developed a set of incident clearance time prediction models for the Borman Expressway. The second part consisted of modeling driver’s route choice behavior under the influence of advanced traveler information systems. Volume 2 of this report describes the modeling driver\u27s route choice behavior under the iinfluence of Advanced Traveler Information Systems. These models can help in understanding the behavior and response of travelers under the influeince of Advanced Traveler Information Systmes.r The products of this research project will be incorpored in the Advanced Traffic Managment System that is being implemented on the Morman Expressway, a 16-mile segment of *-80 n northwest Indiana