Dissertation/Thesis Abstract

Small molecule control of biological function
by Ballard, Thomas Eric, Jr., Ph.D., North Carolina State University, 2008, 445; 3329203
Abstract (Summary)

Attracted by the novel homodimeric glycosylated diazobenzo[b ]fluorene natural product lomaiviticin A and its monomeric cousins the kinamycins, we investigated the ability of simplified diazofluorenes to recapitulate DNA cleaving activity of kinamycin D. Under DTT mediated conditions, we obtained high percentages of DNA nicking by kinamycin D, 1-methoxydiazofluorene and 4-aminodiazofluorene. Upon further examination, the concentrations of both DTT and kinamycin D could be lowered significantly and still retain high DNA cleavage activity. This culminated in the identification that kinamycin D effectively cleaved DNA in a concentration, temperature, and time-dependent fashion by both DTT and glutathione under mild biomimetic conditions.

The virulence and persistence of bacterial biofilm infections is responsible for many chronic illnesses as well as increased morbidity and mortality rates in a plethora of infectious diseases. Using the marine natural product oroidin as molecular inspiration, a library of reverse amide (RA) 2-aminoimidazole analogues were synthesized and assayed for anti-biofilm activity. A thorough and detailed structure-activity-relationship (SAR) culminated in the identification of a long linear aliphatic tridecyl RA analogue with sub-micromolar anti-biofilm activity against Pseudomonas aeruginosa and low micromolar activity against Acinetobacter baumannii. Additionally, a sub-class of aliphatic analogues lacking the amide moiety were synthesized that were very active at inhibiting and dispersing both P. aeruginosa and A. baumannii biofilms.

SDC-1721, a fragment of the potent HIV inhibitor TAK-779, was synthesized and conjugated to 2.0 nm diameter gold nanoparticles. Free SDC-1721 had no inhibitory effect on HIV infection; however, the (SDC-1721)-gold nanoparticle conjugates displayed activity comparable to that of TAK-779. This result suggests that multivalent presentation of small molecules on gold nanoparticle surfaces can convert inactive drugs into potent therapeutics.

Indexing (document details)
Advisor: Melander, Christian
School: North Carolina State University
School Location: United States -- North Carolina
Source: DAI-B 69/09, Dissertation Abstracts International
Subjects: Organic chemistry
Keywords: Aminoimidazoles, Biofilms, DNA cleavage, Kinamycins
Publication Number: 3329203
ISBN: 978-0-549-82060-4
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