Abstract
Improved derivatives of mycophenolic acid (MPA) are necessary to reduce the frequency of adverse effects, this drug exerts in treated patients. In this study, MPA was coupled with N-(ω-hydroxyalkyl)-9-acridone-4-carboxamides or N-(ω-hydroxyalkyl)acridine-4-carboxamides to give respective ester conjugates upon Yamaguchi protocol. This esterification required protection of phenol group in MPA. Designed conjugates revealed higher potency in vitro than parent MPA. Acridine derivatives were more active than acridone analogs and length of the alkyl linker between MPA and heterocyclic units influenced the observed cytotoxicity. Derivatives 2b, 2d, 3a, 3b displayed the most promising immunosuppressive activity.
Keywords:
Acridines; IMPDH inhibitors; acridones; esterification; mycophenolic acid.
MeSH terms
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Acridines / chemistry
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Acridines / pharmacology*
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Acridones / chemistry
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Acridones / pharmacology*
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Esters / chemical synthesis
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Esters / chemistry
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Esters / pharmacology*
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Healthy Volunteers
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Humans
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Immunosuppressive Agents / chemical synthesis*
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Immunosuppressive Agents / chemistry
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Immunosuppressive Agents / pharmacology*
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Jurkat Cells
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / immunology
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Molecular Structure
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Mycophenolic Acid / analogs & derivatives*
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Mycophenolic Acid / chemical synthesis
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Mycophenolic Acid / chemistry
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Mycophenolic Acid / pharmacology*
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Structure-Activity Relationship
Substances
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Acridines
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Acridones
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Esters
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Immunosuppressive Agents
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Mycophenolic Acid