A synthetic strategy for regio- and stereoselective site specific modification of oligonucleotides by hydrocarbon diol epoxides

Thesis/Dissertation · Fri Jan 01 04:00:00 EST 1993

OSTI ID:7296656

Chaturvedi, S

The primary metabolites formed by the oxidative metabolism of polycyclic aromatic hydrocarbons (PAHs) are phenols, quinones, bay region diol epoxides and their corresponding trans-dihydrodiols. These electrophilic diol epoxides intercalate and bind covalently to cellular DNA. Existing evidence suggests that covalent binding of carcinogen diol epoxides to DNA causes cell transformation either due to improper lesion repair or due to base mismatch in the vicinity of the adducted nucleoside during DNA replication which lead to point mutations. The mechanism of cell transformation and the mechanism of carcinogenesis at the molecular level is not yet understood. This has therefore encouraged the author to synthesize PAH adducted deoxyadensosines followed by their rational site specific incorporation into a defined DNA sequence of biological importance. This method developed by the author provides oligonucleotides containing both the (+) and ([minus]) PAH diol epoxide adducts in significant amounts. The adducted oligonucleotides are characterized by UV, CD and negative ion FAB spectroscopy. This dissertation describes the synthesis of model adducts and their incorporation into a pentamer (TpGpA*pGpT). The synthesis of activated phosphoramidite derivatives of B[a]P followed by their incorporation into oligonucleotides comprising codons 60-62 of the human K-ras b proto-oncogene d(5[prime]-GGTCA*CGAG) (where A* is the modified base) has been performed. These oligonucleosides having both (+) or ([minus]) isomer of diol epoxides could be used for site-directed mutagenesis. The solution structure of oligonucleotides containing the (+) and ([minus]) isomers of PAH diol epoxide could also be performed by NMR. The action of repair enzymes and their activity on oligonucleotides containing (+) and ([minus]) isomer of PAH diol epoxide could also be probed.

• Research Organization: Oklahoma Univ., Norman, OK (United States)
• OSTI ID: 7296656
• Country of Publication: United States
• Language: English

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
400201 -- Chemical & Physicochemical Properties
550200* -- Biochemistry
59 BASIC BIOLOGICAL SCIENCES
ADDUCTS
ADENOSINE
ALCOHOLS
AROMATICS
BIOLOGICAL PATHWAYS
DNA
DNA ADDUCTS
EPOXIDES
GLYCOLS
HYDROCARBONS
HYDROXY COMPOUNDS
MOLECULAR STRUCTURE
MUTAGENESIS
NUCLEIC ACIDS
NUCLEOSIDES
NUCLEOTIDES
OLIGONUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
POLYCYCLIC AROMATIC HYDROCARBONS
RIBOSIDES
STEREOCHEMISTRY
SYNTHESIS