title: Preparation and biological evaluation of 10B-enriched 3-[5-{2-(2,3-dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl]thymidine (N5-2OH), a new boron delivery agent for boron neutron capture therapy of brain tumors.
abstract: 3-[5-{2-(2,3-Dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl]thymidine (compound 1, N5-2OH) belongs to a novel class of boron delivery agents for neutron capture therapy, which was designated 3-carboranylthymidine analogue (3CTAs). Two shorter and more convenient synthetic routes were developed for the synthesis of 1 in the 10B-enriched form, which is necessary for its preclinical and clinical evaluation in neutron irradiation studies. For more insight on structure-activity relationships, various stereochemical and geometrical isomers of 1 were synthesized and their specificities as substrate for human thymidine kinase 1 (hTK1) were evaluated. A computational model for the binding of various isomers of 1 to the active site of hTK1 was developed. Preliminary studies carried out in F98 glioma bearing rats that had received a 10B-enriched form of 1 followed by neutron irradiation demonstrated a significant prolongation in survival times compared to control animals, suggesting that further studies are warranted to evaluate the therapeutic potential of 1.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, OH, USA. byun.12@osu.edu
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Byun
authors.forename: B T S
authors.initials: BT
authors.lastname: Thirumamagal
authors.forename: Weilian
authors.initials: W
authors.lastname: Yang
authors.forename: Staffan
authors.initials: S
authors.lastname: Eriksson
authors.forename: Rolf F
authors.initials: RF
authors.lastname: Barth
authors.forename: Werner
authors.initials: W
authors.lastname: Tjarks
mesh_terms: D000818:Animals; D001665:Binding Sites; D001896:Boron Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016754:Boron Neutron Capture Therapy; D001932:Brain Neoplasms / Q000532:radiotherapy*; D002118:Calcium / Q000378:metabolism; D005910:Glioma / Q000532:radiotherapy*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013937:Thymidine Kinase / Q000737:chemistry
chemical_list: C514063:3-(5-(2-(2,3-dihydroxyprop-1-yl)-o-carboran-1-yl)pentan-1-yl)thymidine; D001896:Boron Compounds; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D002118:Calcium; D013936:Thymidine