NAD-based inhibitors with anticancer potential

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• 作者：Krzysztof Felczak ; Robert Vince ; Krzysztof W. Pankiewicz
• 关键词：Nicotinamide adenine dinucleotide ; Mycophenolic acid ; Inosine monophosphate dehydrogenase ; Mycophenolic adenine dinucleotides ; Novel IMPDH inhibitors
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：1 January, 2014
• 年：2014
• 卷：24
• 期：1
• 页码：332-336
• 全文大小：965 K

文摘

Three classes of novel inhibitors of inosine monophosphate dehydrogenase have been prepared and their anti-proliferative properties were evaluated against several cancer cell lines.

(1) Mycophenolic adenine dinucleotide analogues (8-13) containing a substituent at the C2 of adenine ring were found to be potent inhibitors of IMPDH (K_i鈥檚 in range of 0.6-82 nM) and sub-渭M inhibitors of leukemic K562 cell proliferation. (2) Mycophenolic adenosine (d and l) esters (20 and 21) showed a potent inhibition of IMPDH2 (K_i = 102 and K_i = 231 nM, respectively) and inhibition of K562 cell growth (IC₅₀ = 0.5 and IC₅₀ = 1.6 渭M). These compounds serve both as inhibitors of the enzyme and as a depot form of mycophenolic acid. The corresponding amide analogue 22, also a potent inhibitor of IMPDH (K_i = 84 nM), did not inhibit cancer cell proliferation. (3) Mycophenolic-(l)- and (d)-valine adenine di-amide derivatives 25 (K_i = 9 nM) and 28 (K_i = 3 nM) were found to be very potent enzymatically, but did not inhibit proliferation of cancer cells.