TY - JOUR
T1 - Synthesis and biological evaluation of neutral and zwitterionic 3-carboranyl thymidine analogues for boron neutron capture therapy
AU - Byun, Youngjoo
AU - Yan, Junhua
AU - Al-Madhoun, Ashraf S.
AU - Johnsamuel, Jayaseharan
AU - Yang, Weilian
AU - Barth, Rolf F.
AU - Eriksson, Staffan
AU - Tjarks, Werner
PY - 2005/2/24
Y1 - 2005/2/24
N2 - Novel 3-carboranyl thymidine analogues (3CTAs) were synthesized as potential boron delivery agents for boron neutron capture therapy (BNCT). This library includes six zwitterionic NH3+-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-NH3+-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 NH3+-nido-/n- 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.
AB - Novel 3-carboranyl thymidine analogues (3CTAs) were synthesized as potential boron delivery agents for boron neutron capture therapy (BNCT). This library includes six zwitterionic NH3+-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-NH3+-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 NH3+-nido-/n- 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.
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U2 - 10.1021/jm0491896
DO - 10.1021/jm0491896
M3 - Article
C2 - 15715485
AN - SCOPUS:13944281680
SN - 0022-2623
VL - 48
SP - 1188
EP - 1198
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 4
ER -