Anticancer Properties of Amino Acid and Peptide Derivatives of Mycophenolic Acid

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Author(s): Agnieszka Siebert, Milena Deptuła, Mirosława Cichorek, Anna Ronowska, Grzegorz Cholewiński*, Janusz Rachon

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

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Background: Although Mycophenolic Acid (MPA) is applied as prodrugs in clinic as immunosuppressant, it possesses also anticancer activity. MPA acts as Inosine-5’-Monophosphate Dehydrogenase (IMPDH) inhibitor, where carboxylic group at the end of the side chain interacts with Ser 276 of the enzyme via hydrogen bonds. Therefore, MPA derivatives with other polar groups indicated high inhibition too. On the other hand, potent anticancer agents like dacarbazine and cisplatin give numerous side-effects.

Objective: Based on the literature data, MPA derivatives should be explored towards anticancer properties. Conversion of carboxylic group of MPA to amide could maintain antiproliferative activity. Therefore, we decided to investigate several amino acid and peptide derivatives of MPA against chosen cancer cell lines in vitro.

Methods: Amides of MPA hold threonine and arginine amino acid unit. These amino acid derivatives were tested as L and D enantiomers and both in free acid and methyl esters forms. Additionally, MPA was modified with tuftsin or retro-tuftsin as biologically active peptides, which could act as a drug carrier.

Results: Amino acid and peptide derivatives of MPA were investigated in vitro as potential anticancer agents on cell lines: Ab melanoma, A375 melanoma and SHSY5Y neuroblastoma. The activity of the tested compounds was compared to parent MPA and known chemotherapeutics: dacarbazine and cisplatin.

Conclusion: Amino acid moiety and sequence of amino acids in peptide part influenced observed activity. The most active amino acid MPA analogues occurred to be D and L-threonine derivatives as methyl esters, probably due to better cell membrane penetration.

Keywords: Mycophenolic acid, amino acid, peptide, anticancer, amides, conjugates

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(E-pub Ahead of Print)
DOI: 10.2174/1871520620666200516151456
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