Cinnamic Hydroxamic Acids

R2 HDAC NE HCT116 HI 299 in vivo MTD Xenograft dose Efficacy 

Number R R HDACI HCT116 Number Substitution -X-Y- HDAC1 WST-1 

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Giles, F., Fischer, T., Cortes, J., Garcia-Manero, G., Beck, J., Ravandi, F. et al. (2006) A phase 1 study of intravenous LBF1589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clinical Cancer Research, 12, 4628 635. 

In general, the hydroxamic acids in clinical trials are pan-active across HDAC isoforms, while the aminophenylamides show some selectivity for class I over class II isoforms. The nature of the linker and cap moieties are also important in determining isoform selectivity for example, within the cinnamic hydroxamic acids, the pyrrole-linked MC-1568 shows unusual selectivity in... 

As already mentioned, the field of hydroxamic acid HDACis is extensive, therefore the next paragraphs are divided into sections depending on the nature of the group attached to the hydroxamic acid, including aliphatic, cinnamic, phenyl and heterocyclic hydroxamic acids. 

Scheme 7.8 Synthesis of a cinnamic acid-derived hydroxamate using active esters generated with P-HBTU (25).

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