Design, synthesis, and anticancer activity of C8-substituted-4'-thionucleosides as potential HSP90 inhibitors.
A series of C8-substituted-4'-thioadenosine analogs 3a-3g, 15, and 17 and their truncated derivatives 4a-4j, 23-25, and 27 have been successfully synthesized from d-ribose and d-mannose, respectively, employing Pummerer type or Vorbrüggen condensation reactions and the functionalization at the C8-position of nucleobase via Stille coupling or nucleophilic aromatic substitution reactions as key steps. All the synthesized compounds were assayed for their HSP90 inhibitory activity, but they were found to be inactive up to 100μM. However, the 8-iodo derivatives 15, 17, and 27 exhibited potent anticancer activity, indicating that different mechanism of action might be involved in their biological activity.
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea; College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.
Shuhao
S
Qu
College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.
Varughese A
VA
Mulamoottil
College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.
Akshata
A
Nayak
College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.
Seungyeon
S
Ryu
College of Life Science, Dalian Nationalities University, Dalian 116600, China.
Xiyan
X
Hou
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
Jayoung
J
Song
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
Jinha
J
Yu
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
Pramod K
PK
Sahu
College of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116-029, China.
Long Xuan
LX
Zhao
College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.
Sun
S
Choi
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
Sang Kook
SK
Lee
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: lakjeong@snu.ac.kr.
Lak Shin
LS
Jeong
D066241:Carbon-13 Magnetic Resonance Spectroscopy; D045744:Cell Line, Tumor; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D066244:Proton Magnetic Resonance Spectroscopy; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013872:Thionucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D018841:HSP90 Heat-Shock Proteins; D013872:Thionucleosides
4′-Thionucleosides; Anticancer; HSP90; Structure–activity relationship