Synthesis of hdac inhibitors: trichostatin a and analogues
AssigneeUniversity of Notre Dame du Lac
InventorsPaul Helquist, Douglas Schauer, Casey C. Cosner, Vijaya B.R. Iska, Anamitra Chatterjee, Olaf Wiest
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Abstract
Embodiments herein relate to histone deacetylaces (HDACs) and HDAC inhibitors, such as trichostatin A (TSA) and TSA analogues. Embodiments provide simple methods of synthesizing TSA and TSA analogues. These methods provide routes of synthesis of TSA and TSA analogues that enable the production of the HDAC inhibitors at lower cost and in greater quantities than previously were available.
Claims20
A method of synthesizing TSA or a TSA analogue, the method comprising:
- providing (2E,4E)-methyl 7-methoxy-4,6-dimethyl-7-(4-dimethylaminophenyl)hepta-2,4-dienoate:
- wherein R′=Me;
- reacting the (2E,4E)-methyl 7-methoxy-4,6-dimethyl-7-(4-dimethylaminophenyl)hepta-2,4-dienoate with LiOH/H2O to replace the Me at R′ with H to form (2E,4E)-methyl 7-methoxy-4,6-dimethyl-7-(4-dimethylaminophenyl)hepta-2,4-dienoic acid;
- performing an oxidation reaction on the (2E,4E)-methyl 7-methoxy-4,6-dimethyl-7-(4-dimethylaminophenyl)hepta-2,4-dienoic acid with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and dichloromethane (DCM) to form trichostatic acid;
- and
- reacting the trichostatic acid with hydroxylamine or a hydroxylamine derivative to form the TSA or TSA analogue.
A method of synthesizing a TSA analogue, the method comprising:
- providing compound B, wherein R═H, Et, Ph, or Bn:
- reacting compound B with CICOOEt, TEA, and NH2OTBS to form compound C:
- wherein R″═NHOTBS;
- and
- reacting compound C with CsF and MeOH to convert the NHOTBS at R″ with NHOH, thereby synthesizing the TSA analogue.
A method of synthesizing TSA or a TSA analogue, the method comprising:
- providing (2E,4E,6R)-methyl 4,6-dimethyl-7-(4-dimethylaminophenyl)-7-oxohepta-2,4-dienoate;
- reacting the (2E,4E,6R)-methyl 4,6-dimethyl-7-(4-dimethylaminophenyl)-7-oxohepta-2,4-dienoate with Me3SnOH or pig liver esterase to form trichostatic acid;
- and
- reacting the trichostatic acid with hydroxylamine or a hydroxylamine derivative to form the TSA or TSA analogue.
A method of synthesizing TSA or a TSA analogue, the method comprising:
- providing 4-(dimethylamino)propiophenone and methyl (2E,4E)-5-bromo-4-methylpenta-2,4-dienoate;
- and
- coupling the 4-(dimethylamino)propiophenone and the methyl (2E,4E)-5-bromo-4-methylpenta-2,4-dienoate under modified Negishi cross-coupling conditions, wherein the coupling reaction employs a nickel catalyst and ligand G:
- wherein the coupling reaction produces racemic (2E,4E)-methyl 4,6-dimethyl-7-(4-dimethylaminophenyl)-7-oxohepta-2,4-dienoate, and
- reacting the racemic (2E,4E)-methyl 4,6-dimethyl-7-(4-dimethylaminophenyl)-7-oxohepta-2,4-dienoate with hydroxylamine or a hydroxylamine derivative to form the TSA or TSA analogue.
A method of synthesizing a trichostatic acid analogue, the method comprising:
- providing compound H having the structure:
- and
- reacting the compound H with compound I having the structure:
- wherein R=iodide, bromide, tosylate, or para-toluenesulfonate.
Dependencies are inferred from the claim text.