Design and Synthesis of HDACi Derivatives for Cancer Treatment

Lead Author Affiliation

Biological Sciences

Lead Author Status

Undergraduate - Senior

Second Author Affiliation

Biological Sciences

Second Author Status

Undergraduate - Senior

Third Author Affiliation

Department of Chemistry

Third Author Status

Faculty Mentor

Research or Creativity Area

Pharmacy

Abstract

Cancer, the second leading cause of death worldwide, entails the unregulated growth and proliferation of abnormal human cells anywhere in the body with the ability to infiltrate and destroy healthy tissue. Histone deacetylase enzymes (HDAC) are widely overexpressed in a number of cancers, likely contributing to the silencing of various anti-cancer regulatory factors, including tumor suppressor genes, cell-cycle inhibitor genes, and apoptosis inducer genes, by condensing the chromatin through deacetylation of histones in nucleosomes. HDAC inhibitors (HDACi) bind to the zinc active site of the HDAC to prevent catalysis of deacetylase activity, thereby allowing expression of tumor suppressive genes and leading to apoptosis of cancer cells. These inhibitors consist of a protein recognition surface domain (cap), a linker scaffold, and a zinc-binding group,. By conjugating a HDAC inhibitor to a platinum core through the coordination site on the cap and fine tuning its structure, selectivity of the resulting bifunctional platinum drug may increase while mitigating negative side effects of treatment.

One HDACi, derivative L18, was synthesized, purified, and subsequently characterized by mass spectrometry and 1H NMR. Derivative L18 with a pyridine cap was based on FDA-approved HDACi panobinostat. By modifying the cap group of the HDACi derivative, specificity of Pt-HDACi conjugates toward cancer cells may be enhanced when the HDACi ligand could target the overexpressed HDAC enzymes in resistant cancer cell lines.

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Design and Synthesis of HDACi Derivatives for Cancer Treatment

Cancer, the second leading cause of death worldwide, entails the unregulated growth and proliferation of abnormal human cells anywhere in the body with the ability to infiltrate and destroy healthy tissue. Histone deacetylase enzymes (HDAC) are widely overexpressed in a number of cancers, likely contributing to the silencing of various anti-cancer regulatory factors, including tumor suppressor genes, cell-cycle inhibitor genes, and apoptosis inducer genes, by condensing the chromatin through deacetylation of histones in nucleosomes. HDAC inhibitors (HDACi) bind to the zinc active site of the HDAC to prevent catalysis of deacetylase activity, thereby allowing expression of tumor suppressive genes and leading to apoptosis of cancer cells. These inhibitors consist of a protein recognition surface domain (cap), a linker scaffold, and a zinc-binding group,. By conjugating a HDAC inhibitor to a platinum core through the coordination site on the cap and fine tuning its structure, selectivity of the resulting bifunctional platinum drug may increase while mitigating negative side effects of treatment.

One HDACi, derivative L18, was synthesized, purified, and subsequently characterized by mass spectrometry and 1H NMR. Derivative L18 with a pyridine cap was based on FDA-approved HDACi panobinostat. By modifying the cap group of the HDACi derivative, specificity of Pt-HDACi conjugates toward cancer cells may be enhanced when the HDACi ligand could target the overexpressed HDAC enzymes in resistant cancer cell lines.