Synthesis of 5-(Carboranylalkylmercapto)-2‘-deoxyuridines and 3-(Carboranylalkyl)thymidines and Their Evaluation as Substrates for Human Thymidine Kinases 1 and 2

• Published in: Journal of medicinal chemistry Vol. 42; no. 17; pp. 3378 - 3389
• Main Authors: Lunato, Anthony J, Wang, Jianghai, Woollard, Jeffrey E, Anisuzzaman, Abul K. M, Ji, Weihua, Rong, Feng-Guang, Ikeda, Seiichiro, Soloway, Albert H, Eriksson, Staffan, Ives, David H, Blue, Thomas E, Tjarks, Werner
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.08.1999; Amer Chemical Soc
• Subjects: 3-(carboranylalkyl)thymidine; 5-(carboranylalkylmercapto)-2'-deoxyuridine; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antineoplastic agents; Antiviral agents; Biological and medical sciences; Boron Compounds - chemical synthesis; Boron Compounds - chemistry; Boron Compounds - metabolism; Chemistry, Medicinal; Deoxyuridine - analogs & derivatives; Deoxyuridine - chemical synthesis; Deoxyuridine - chemistry; Deoxyuridine - metabolism; General aspects; Humans; Life Sciences & Biomedicine; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phosphorylation; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Science & Technology; Structure-Activity Relationship; Substrate Specificity; Thymidine - analogs & derivatives; Thymidine - chemical synthesis; Thymidine - chemistry; Thymidine - metabolism; Thymidine Kinase - biosynthesis; Thymidine Kinase - chemistry; Thymidine Kinase - metabolism; Tumor Cells, Cultured; CELLS; POTENTIAL AGENTS; ENZYME; NEUTRON-CAPTURE THERAPY; CONTAINING PYRIMIDINE NUCLEOSIDES; DNA INCORPORATION; AFFINITY-CHROMATOGRAPHY; DERIVATIVES; BIOCHEMICAL-ACTIVITY; OLIGONUCLEOTIDES; Substrate; Thymidine kinase; Enzyme; Transferases; Boron Organic compounds; Carborane; Thymidine; Deoxyribonucleoside; Chemical synthesis; Pyrimidine nucleoside; Biological activity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990125i

Derivatives of thymidine containing o-carboranylalkyl groups at the N-3 position and derivatives of 2‘-deoxyuridine containing o-carboranylalkylmercapto groups at the C-5 position were synthesized. The alkyl spacers consist of 4−8 methylene units. The synthesis of the former compounds required 3−4 reaction steps in up to 75% overall yield and that of the latter 9−10 reaction steps with significantly lower overall yield. Derivatives of thymidine substituted with carboranylalkyl substituents at the N-3 position and short spacers were phosphorylated by both recombinant and purified cytosolic thymidine kinase (TK1) to a relatively high degree. None of the tested 2‘-deoxyuridine derivatives possessing carboranyl substituents at the C-5 position were phosphorylated by either recombinant or purified TK1. The amounts of phosphorylation product detected for some of the C-5-substituted nucleosides with recombinant mitochondrial thymidine kinase (TK2) were low but significant and decreased with increasing lengths of the alkyl spacer. The data obtained in this study do not seem to support the tether concept applied in the synthesis of the new C-5- and N-3-substituted carboranyl nucleosides intended to reduce possible steric interference in the binding of carboranyl nucleosides with deoxynucleoside kinases. Instead, it appeared that a closer proximity of the bulky carborane moiety to the nucleoside scaffold resulted in better substrate characteristics.