{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/70033"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/70033","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Synthesis and Pulmonary Toxicity of Several 3-Furyl Ketones: Evidence for the Position of Metabolism by Cytochromes P-450","abstract":"Pulmonary toxicity of naturally occurring 3-furyl ketones is of increasing concern to animal science. Bioactivation of these heterocycles by pulmonary cytochromes P-450 is necessary for their toxicity, but the mechanism of this bioactivation is not clearly understood. Using a series of 3-furyl ketone congeners of perilla ketone, 1-(3-furyl)-4-methylpentan-1-one (2), it has been shown that the toxicity of these compounds in mice is dependent upon their log P and ('13)C-NMR shift characteristics. Studies were needed to further elucidate the role of the side chain of 3-furyl ketones on toxicity and the position of attack on 3-furyl ketones by cytochromes P-450. 3-Furylphenyl ketone (3), 3-furylphenethyl ketone (4), and 1-(3-furyl)-4,4-dimethylpentan-1-one (5) were synthesized to examine the first problem. The 48 h LD50 (ip) in Notre Dame Swiss mice for these analogues was greater than that of perilla ketone (2, 30 (+OR-) 5; 3, 173 (+OR-) 4; 4, 150 (+OR-) 11; 5, 81 (+OR-) 6 (mu)mol/kg). The reduced toxicity of 3, 4, and 5 cannot be explained on the basis of log P or ('13)C-NMR characteristics. Instead, it is probably due to steric hindrance of bioactivation by the bulky side chain substituents and to protective metabolism of the phenyl ring rather than the furan ring of 3 and 4. Preliminary studies indicated that 1-(2,5-dimethyl-3-furyl)-4-methylpentan-1-one (8) was non-toxic to mice. This finding was confirmed by the synthesis and toxicological testing of 8 (48 h LD50 = 2,238 (+OR-) 1,242 (mu)mol/kg). Therefore, bioactivation must occur at either the #2 or #5 carbon position of the furan ring. To determine which of these positions is involved in bioactivation, 1-(2-methyl-3-furyl)-4-methylpentan-1-one (9) and 1-(5-methyl-3-furyl)-4-methylpentan-1-one (10) were synthesized. The 2-methyl congener has a 48 h mouse LD50 (190 (+OR-) 19 (mu)mol/kg) near that predicted on the basis of chemical parameters. But, the 5-methyl congener was considerably less lethal (8,807 (+OR-) 3,710 (mu)mol/kg). Bioactivation of 3-furyl ketones must then occur at the #5 carbon position. A single sublethal administration (ip) of 10 protected against the toxicity of 2 administered (ip) 1 hr after pretreatment. This protection persisted up to 2 days after pretreatment. No significant protective effect was noted by pretreating with 8 or 9. Additive toxicity was observed with pretreatment by 2 or 9, and challenge with 2.","abstract_html":"Pulmonary toxicity of naturally occurring 3-furyl ketones is of increasing concern to animal science. Bioactivation of these heterocycles by pulmonary cytochromes P-450 is necessary for their toxicity, but the mechanism of this bioactivation is not clearly understood. Using a series of 3-furyl ketone congeners of perilla ketone, 1-(3-furyl)-4-methylpentan-1-one (2), it has been shown that the toxicity of these compounds in mice is dependent upon their log P and ('13)C-NMR shift characteristics. Studies were needed to further elucidate the role of the side chain of 3-furyl ketones on toxicity and the position of attack on 3-furyl ketones by cytochromes P-450. 3-Furylphenyl ketone (3), 3-furylphenethyl ketone (4), and 1-(3-furyl)-4,4-dimethylpentan-1-one (5) were synthesized to examine the first problem. The 48 h LD50 (ip) in Notre Dame Swiss mice for these analogues was greater than that of perilla ketone (2, 30 (+OR-) 5; 3, 173 (+OR-) 4; 4, 150 (+OR-) 11; 5, 81 (+OR-) 6 (mu)mol/kg). The reduced toxicity of 3, 4, and 5 cannot be explained on the basis of log P or ('13)C-NMR characteristics. Instead, it is probably due to steric hindrance of bioactivation by the bulky side chain substituents and to protective metabolism of the phenyl ring rather than the furan ring of 3 and 4. Preliminary studies indicated that 1-(2,5-dimethyl-3-furyl)-4-methylpentan-1-one (8) was non-toxic to mice. This finding was confirmed by the synthesis and toxicological testing of 8 (48 h LD50 = 2,238 (+OR-) 1,242 (mu)mol/kg). Therefore, bioactivation must occur at either the #2 or #5 carbon position of the furan ring. To determine which of these positions is involved in bioactivation, 1-(2-methyl-3-furyl)-4-methylpentan-1-one (9) and 1-(5-methyl-3-furyl)-4-methylpentan-1-one (10) were synthesized. The 2-methyl congener has a 48 h mouse LD50 (190 (+OR-) 19 (mu)mol/kg) near that predicted on the basis of chemical parameters. But, the 5-methyl congener was considerably less lethal (8,807 (+OR-) 3,710 (mu)mol/kg). Bioactivation of 3-furyl ketones must then occur at the #5 carbon position. A single sublethal administration (ip) of 10 protected against the toxicity of 2 administered (ip) 1 hr after pretreatment. This protection persisted up to 2 days after pretreatment. No significant protective effect was noted by pretreating with 8 or 9. Additive toxicity was observed with pretreatment by 2 or 9, and challenge with 2.","abstract_has_math":false,"creators":["Wilson, William Chauncey"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Animal Sciences","degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-12-15T21:01:02Z","date_published":"2014-12-15T21:01:02Z","updated_at":"2026-07-22T22:26:02Z","subjects":["Health Sciences, Toxicology","Health Sciences, Pharmacology"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["(UMI)AAI8603296"],"render_values":[{"text":"(UMI)AAI8603296","href":null,"code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/2142/70033","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Wilson, William Chauncey"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2014-12-15T21:01:02Z","10000-01-01","1985"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Animal Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Health Sciences, Toxicology","Health Sciences, Pharmacology"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/70033","(UMI)AAI8603296"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Pulmonary toxicity of naturally occurring 3-furyl ketones is of increasing concern to animal science. Bioactivation of these heterocycles by pulmonary cytochromes P-450 is necessary for their toxicity, but the mechanism of this bioactivation is not clearly understood. Using a series of 3-furyl ketone congeners of perilla ketone, 1-(3-furyl)-4-methylpentan-1-one (2), it has been shown that the toxicity of these compounds in mice is dependent upon their log P and ('13)C-NMR shift characteristics. Studies were needed to further elucidate the role of the side chain of 3-furyl ketones on toxicity and the position of attack on 3-furyl ketones by cytochromes P-450. 3-Furylphenyl ketone (3), 3-furylphenethyl ketone (4), and 1-(3-furyl)-4,4-dimethylpentan-1-one (5) were synthesized to examine the first problem. The 48 h LD50 (ip) in Notre Dame Swiss mice for these analogues was greater than that of perilla ketone (2, 30 (+OR-) 5; 3, 173 (+OR-) 4; 4, 150 (+OR-) 11; 5, 81 (+OR-) 6 (mu)mol/kg). The reduced toxicity of 3, 4, and 5 cannot be explained on the basis of log P or ('13)C-NMR characteristics. Instead, it is probably due to steric hindrance of bioactivation by the bulky side chain substituents and to protective metabolism of the phenyl ring rather than the furan ring of 3 and 4. Preliminary studies indicated that 1-(2,5-dimethyl-3-furyl)-4-methylpentan-1-one (8) was non-toxic to mice. This finding was confirmed by the synthesis and toxicological testing of 8 (48 h LD50 = 2,238 (+OR-) 1,242 (mu)mol/kg). Therefore, bioactivation must occur at either the #2 or #5 carbon position of the furan ring. To determine which of these positions is involved in bioactivation, 1-(2-methyl-3-furyl)-4-methylpentan-1-one (9) and 1-(5-methyl-3-furyl)-4-methylpentan-1-one (10) were synthesized. The 2-methyl congener has a 48 h mouse LD50 (190 (+OR-) 19 (mu)mol/kg) near that predicted on the basis of chemical parameters. But, the 5-methyl congener was considerably less lethal (8,807 (+OR-) 3,710 (mu)mol/kg). Bioactivation of 3-furyl ketones must then occur at the #5 carbon position. A single sublethal administration (ip) of 10 protected against the toxicity of 2 administered (ip) 1 hr after pretreatment. This protection persisted up to 2 days after pretreatment. No significant protective effect was noted by pretreating with 8 or 9. Additive toxicity was observed with pretreatment by 2 or 9, and challenge with 2.","Made available in DSpace on 2014-12-15T21:01:02Z (GMT). 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Bioactivation of these heterocycles by pulmonary cytochromes P-450 is necessary for their toxicity, but the mechanism of this bioactivation is not clearly understood. Using a series of 3-furyl ketone congeners of perilla ketone, 1-(3-furyl)-4-methylpentan-1-one (2), it has been shown that the toxicity of these compounds in mice is dependent upon their log P and ('13)C-NMR shift characteristics. Studies were needed to further elucidate the role of the side chain of 3-furyl ketones on toxicity and the position of attack on 3-furyl ketones by cytochromes P-450. 3-Furylphenyl ketone (3), 3-furylphenethyl ketone (4), and 1-(3-furyl)-4,4-dimethylpentan-1-one (5) were synthesized to examine the first problem. The 48 h LD50 (ip) in Notre Dame Swiss mice for these analogues was greater than that of perilla ketone (2, 30 (+OR-) 5; 3, 173 (+OR-) 4; 4, 150 (+OR-) 11; 5, 81 (+OR-) 6 (mu)mol/kg). The reduced toxicity of 3, 4, and 5 cannot be explained on the basis of log P or ('13)C-NMR characteristics. Instead, it is probably due to steric hindrance of bioactivation by the bulky side chain substituents and to protective metabolism of the phenyl ring rather than the furan ring of 3 and 4. Preliminary studies indicated that 1-(2,5-dimethyl-3-furyl)-4-methylpentan-1-one (8) was non-toxic to mice. This finding was confirmed by the synthesis and toxicological testing of 8 (48 h LD50 = 2,238 (+OR-) 1,242 (mu)mol/kg). Therefore, bioactivation must occur at either the #2 or #5 carbon position of the furan ring. To determine which of these positions is involved in bioactivation, 1-(2-methyl-3-furyl)-4-methylpentan-1-one (9) and 1-(5-methyl-3-furyl)-4-methylpentan-1-one (10) were synthesized. The 2-methyl congener has a 48 h mouse LD50 (190 (+OR-) 19 (mu)mol/kg) near that predicted on the basis of chemical parameters. But, the 5-methyl congener was considerably less lethal (8,807 (+OR-) 3,710 (mu)mol/kg). Bioactivation of 3-furyl ketones must then occur at the #5 carbon position. A single sublethal administration (ip) of 10 protected against the toxicity of 2 administered (ip) 1 hr after pretreatment. This protection persisted up to 2 days after pretreatment. No significant protective effect was noted by pretreating with 8 or 9. Additive toxicity was observed with pretreatment by 2 or 9, and challenge with 2.","Made available in DSpace on 2014-12-15T21:01:02Z (GMT). No. of bitstreams: 1 8603296.pdf: 3479223 bytes, checksum: cea3c247749c2449fa1df4ea7748e3db (MD5) Previous issue date: 1985","Embargo set by: Seth Robbins for item 70199 Lift date: Forever Reason: Restricted to the U of I community idenfinitely during batch ingest of legacy ETDs","Restricted to the U of I community idenfinitely during batch ingest of legacy ETDs","U of I Only","103 p.","Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1985."],"dc:identifier":["http://hdl.handle.net/2142/70033","(UMI)AAI8603296"],"dc:subject":["Health Sciences, Toxicology","Health Sciences, Pharmacology"],"dc:title":["Synthesis and Pulmonary Toxicity of Several 3-Furyl Ketones: Evidence for the Position of Metabolism by Cytochromes P-450"],"dc:type":["text"],"thesis:degree_discipline":["Animal Sciences"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:26:02Z"}