Expedient Total Synthesis of Triciribine and Its Prodrugs |
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Authors: | Wei Shen Jae-Seung Kim John Hilfinger |
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Institution: | 1. TSRL Inc. , Ann Arbor , Michigan , USA wshen@tsrlinc.com;4. weiweishen@yahoo.com;5. TSRL Inc. , Ann Arbor , Michigan , USA |
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Abstract: | Triciribine (TCN, 1) and its monophosphate (TCNP, 2) are tricyclic nucleotide derivatives that have potential antineoplastic activity. Triciribine inhibits the phosphorylation, activation, and signaling of Akt-1, -2, and -3, which may result in the inhibition of Akt-expressing tumor cell proliferation. Both TCN and TCNP have very low bioavailability, and the development of both drugs as intravenous (IV) treatments was halted because of the toxicity induced by the high doses needed for their use as general cytotoxic agents. This publication describes an expedient and straightforward total synthesis of amino acid prodrugs (3, 4) of TCN and TCNP. In our study, both the prodrugs significant improved the plasma exposure of the parent drugs and the prodrugs. |
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Keywords: | Amino acid prodrugs antitumor bioavailability phosphoramidate prodrug triciribine triciribine monophosphate |
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