Uniform TitleSynthesis of dinucleoside tetraphosphates and their analogs
NameHan, Qianwei (author), Jones, Roger (chair), Uhrich, Kathryn (internal member), Williams, Lawrence (internal member), MacCoss, Malcolm (outside member), Rutgers University, Graduate School - New Brunswick,
SubjectChemistry and Chemical Biology,
DescriptionDinucleoside polyphosphates, NpnN' (n = 2 - 7), are observed in many biological processes and are recognized as playing important regulatory functions. Ap4A is a particularly important signaling molecule. AZTp4A is the product of excision of AZT by HIV-1 RT from a growing chain of viral DNA, and can be used to study details of the excision process. Its hydrolysis-resistant analogs can be used to study the inhibition of AZT excision. Current methods to prepare dinucleoside tetraphosphates, enzymatic or chemical, are not satisfactory.
A convenient and high-yield method was developed to prepare dinucleoside tetra- and pentaphosphates. The method was based on a mixture of P(III) and P(V) chemistry and involved a trimetaphosphate intermediate. Six dinucleoside tetraphosphates and two pentaphosphates were prepared. In addition, the method was modified to prepare thio, seleno, borano, methylene and difluoromethylene analogs of Ap4A and AZTp4A. These analogs are good model compounds for their unmodified versions. Ap4A analogs can be used to study the mechanisms of its molecular signaling processes. The AZTp4A analogs are currently being used in HIV-1 RT drug resistance studies. The configurations of the diastereomers of the thio, seleno and borano analogs were assigned based on the elution order on reverse-phase HPLC. Enzymatic degradation of the Ap4A analogs was done with snake venom phosphodiesterase in order to confirm the configuration assignments.
Furthermore, this method was extended to prepare multimodified hydrolysis-resistant AZTpSpCX2ppSA and AZTpSpCX2ppSAZT (X = H or F) as potential inhibitors of the AZT excision reaction by HIV-1 RT. The reactions were carried out by the coupling of adenosine or AZT H-phosphonate with trimetaphosphate analogs, taking advantage of the differential power of elemental sulfur to sulfurize H-phosphonate diesters but not monoesters. Enzymatic degradation was performed in order to assign configurations of the diastereomers and compare their enzymatic stabilities.
NoteIncludes bibliographical references.
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.