Synthesis and biological evaluation of neutral and zwitterionic 3-carboranyl thymidine analogues for boron neutron capture therapy.
Novel 3-carboranyl thymidine analogues (3CTAs) were synthesized as potential boron delivery agents for boron neutron capture therapy (BNCT). This library includes six zwitterionic NH(3)(+)-nido-m-carborane-substituted thymidine analogues (Thds) and the corresponding neutral NH(2)-closo-m-carborane-substituted counterparts. All compounds of this library were good substrates for recombinant human thymidine kinase 1 (TK1) with phosphorylation rates up to 89% relative to that of Thd. One compound out of this library, 3-[3-(7-NH(3)(+)-nido-m-carboran-1-yl)propan-1-yl]thymidine (19b), showed selective retention in TK1-expressing murine L929 wild-type tumors versus L929 TK1 (-) tumors in biodistribution studies. The biological evaluation of the zwitterionic NH(3)(+)-nido-m-carborane-substituted Thds indicated improved aqueous solubility and similar or even superior potential as BNCT agents compared with different classes of 3CTAs (Cancer Res. 2004, 64, 6280-6286 and 6287-6295). To complete previous structure-activity relationship (SAR) studies, 3-[(closo-o-carboranyl)methyl]thymidine (4) was also synthesized and evaluated.
Byun
Youngjoo
Y
Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.
Yan
Junhua
J
Al-Madhoun
Ashraf S
AS
Johnsamuel
Jayaseharan
J
Yang
Weilian
W
Barth
Rolf F
RF
Eriksson
Staffan
S
Tjarks
Werner
W
D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D001896:Boron Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016754:Boron Neutron Capture Therapy; D045744:Cell Line, Tumor; D006801:Humans; D007477:Ions; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D012995:Solubility; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013937:Thymidine Kinase / Q000737:chemistry / Q000378:metabolism; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
C498571:3-((closo-o-carboran-1-yl)methyl)thymidine; C498570:3-(3-(7-ammonium-nido-m-carboran-1-yl)propan-1-yl)thymidine; D001896:Boron Compounds; D007477:Ions; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D013936:Thymidine