In an effort to more fully understand the chemical basis for carcinogenic/mutagenic activity in several classes of environmentally ubiquitous PAHs, the major thrust of the proposal is to generate their carbocations directly under stable ion conditions and to derive charge delocalization pathways based on NMR studies (at 500 MHz), in order to search for correlations between charge delocalization mode(s) and magnitude of carcinogenic activity. Charge delocalization mapping enables the most likely sites for nucleophile attachment to be identified. Previous studies supported under the AREA program emphasized cyclopenta[a]phenanthrenes, benzo[a]anthracenes, chrysenes, methylene bridged-PAHs and fluoranthene-PAHs, having varied degrees of carcinogenic, mutagenic and tumorigenic activities. In continuation, structure-reactivity studies on a series of strategically substituted benzo[a]anthracenes, a series of alkylated benzo[c]phenanthrenes and their methoxy/hydroxy derivatives, dibenzoanthracenes, their alkyl and dihydrodiols, and several other classes of polyarenes are planned. Parallel DNA-binding studies on representative covalent precursors (alcohols and halides) with MCF-7 cells and mutagenicity studies will be performed to correlate carbocation-based studies with carcinogenic/mutagenic activity. To mimic PAH-DNA adduct formation, quenching experiments with model bases will be performed with the aim to compare product distribution and regio selectitivities with the PAH-DNA adducts obtained from mammalian cell cultures. Other studies focus on heterocations and carbocations derived from aza-PAHs in relation to their dual carcinogenic/anti-cancer functions. Nitro-PAHs will be used to synthesize novel DNA-intercalating agents. A unique feature of this work is that reactive intermediates are examined directly. The results should provide a clearer mechanistic picture, bridging metabolic studies with mechanism and theory as a basis for predictability of cancer induction. DNA binding and mammalian cell mutagenicity studies on the substituted and derivatized-PAHs proposed for stable ion work will enhance the available literature data on structure/reactivity relationships. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
2R15CA078235-02A1
Application #
6701256
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Zaika, Ellen
Project Start
1999-07-01
Project End
2008-03-31
Budget Start
2004-04-01
Budget End
2008-03-31
Support Year
2
Fiscal Year
2004
Total Cost
$216,750
Indirect Cost
Name
Kent State University at Kent
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041071101
City
Kent
State
OH
Country
United States
Zip Code
44242
Laali, Kenneth K; Chun, Joong-Hyun; Okazaki, Takao et al. (2007) Electrophilic chemistry of thia-PAHs: stable carbocations (NMR and DFT), S-alkylated onium salts, model electrophilic substitutions (nitration and bromination), and mutagenicity assay. J Org Chem 72:8383-93
Borosky, Gabriela L; Laali, Kenneth K (2007) Oxidized metabolites from benzo[a]pyrene, benzo[e]pyrene, and aza-benzo[a]pyrenes. A computational study of their carbocations formed by epoxide ring opening reactions. Org Biomol Chem 5:2234-42
Brule, Cedric; Laali, Kenneth K; Okazaki, Takao et al. (2007) Structure/reactivity relationships in the benzo[c]phenanthrene skeleton: stable ion and electrophilic substitution (nitration, bromination) study of substituted analogues, novel carbocations and substituted derivatives. J Org Chem 72:3232-41
Bae, Suyeal; Mah, Heduck; Chaturvedi, Surendrakumar et al. (2007) Synthetic, crystallographic, computational, and biological studies of 1,4-difluorobenzo[c]phenanthrene and its metabolites. J Org Chem 72:7625-33
Laali, Kenneth K; Arrica, Maria A; Okazaki, Takao et al. (2007) Substituent effects in benz[a]anthracene carbocations: a stable ion, electrophilic substitution (nitration, bromination), and DFT study. J Org Chem 72:6768-75
Borosky, Gabriela L; Laali, Kenneth K (2006) Carbocations from oxidized metabolites of benzo[a]anthracene: a computational study of their methylated and fluorinated derivatives and guanine adducts. Chem Res Toxicol 19:899-907
Brule, Cedric; Holmer, Stephanie; Krechanin, Seth et al. (2006) Sterically crowded azulene-based dication salts as novel guests: synthesis and complexation studies with crown ethers and calixarenes in solution and in the gas phase. Org Biomol Chem 4:3077-84
Borosky, Gabriela L; Laali, Kenneth K (2005) A computational study of carbocations from oxidized metabolites of dibenzo[a,h]acridine and their fluorinated and methylated derivatives. Chem Res Toxicol 18:1876-86
Borosky, Gabriela L; Laali, Kenneth K (2005) Theoretical study of aza-polycyclic aromatic hydrocarbons (aza-PAHs), modelling carbocations from oxidized metabolites and their covalent adducts with representative nucleophiles. Org Biomol Chem 3:1180-8
Laali, Kenneth K; Sarca, Viorel D; Okazaki, Takao et al. (2005) Triflic acid-catalyzed adamantylation of aromatics in [BMIM][OTf] ionic liquid; synthetic scope and mechanistic insight. Org Biomol Chem 3:1034-42

Showing the most recent 10 out of 20 publications