This invention comprises the novel compounds of formula (I) ##STR00001## wherein n, m, t, R.sup.1, R.sup.2, L, Q, X, Y, Z and ##STR00002## have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.

One aspect of the invention relates to HDAC inhibitors. Methods of sensitizing a cancer cell to the cytotoxic effects of radiotherapy are also provided. The invention also provides methods for treating cancer and methods for treating neurological diseases. Additionally, the invention further provides pharmaceutical compositions comprising an HDAC inhibitor of the invention, and kits comprising a container containing an HDAC inhibitor of the invention.

This invention comprises the novel compounds of formula (I) wherein n, R.sup.1, R.sup.2, R.sup.3, R.sup.4, L, Q, X, Y, Z and have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine. ##STR00001##

Compounds represented by formula (1) have strong inhibitory activity that is selective towards HDAC1 and HDAC4. Therefore, the compounds of the present invention are useful as pharmaceutical agents for treating or preventing diseases caused by HDAC1 and HDAC4. ##STR00001##

A process for producing deacetylase which comprises incubating a deacetylase-producing bacterium belonging to Vibrio cholerae in a IFO 15429 culture medium containing a carbon source, a nitrogen source, an inorganic salt and an inducer for producing the deacetylase and isolating the deacetylase from cells separated from said culture medium.

The present invention provides methods for identifying agents that modulate a level or an activity of a mitochondrial NAD-dependent deacetylase polypeptide, as well as agents identified by the methods. The invention further provides methods of modulating mitochondrial NAD-dependent deacetylase activity in a cell. The invention further provides methods of modulating mitochondrial function by modulating the activity of mitochondrial NAD-dependent deacetylase.

The present invention relates to the use of the drug valproic acid and derivatives thereof as inhibitors of enzymes having histone deacetylase activity. The invention also relates to the use of those compounds for the manufacture of a medicament for the treatment of diseases which are associated with hypoacetylation of histones or in which induction of hyperacetylation has a beneficial effect for example by induction of differentiation and/or apoptosis in transformed cells.

Disclosed herein are carbonyl compounds of Formula I, II, or III, and others as described herein. ##STR00001## Also disclosed are methods of treating disease, such as cancer, neurological disorders, including polyglutamine-repeat disorders, anemias, thalassemias, inflammatory conditions, autoimmune diseases and cardiovascular conditions, using the compounds of the invention. In addition, methods of modulating the activity of histone deacetylase (HDAC) are also disclosed.

A process for preparing unsaturated esters useful as intermediates for HDAC inhibitors, by reacting an aldehyde or ketone having the following formula I: ##STR00001## wherein R.sub.1 is an aromatic group or a combined aliphatic and aromatic group; X is --O--, --S--, --COO--, --OOC--, --CONR.sub.7--, or --R.sub.7NCO--; L.sub.1 an aliphatic linking group, an aromatic linking group, or a combined aliphatic and aromatic linking group; R.sub.2 and R.sub.3 are each independently hydrogen, a hydroxy gr...

Histone deacetylase is a metallo-enzyme with zinc at the active site. Compounds having a zinc-binding moiety, for example, an alpha-chalcogenmethylcarbonyl group, such as an alpha-ketothio group, can inhibit histone deacetylase. Histone deacetylase inhibition can repress gene expression, including expression of genes related to tumor suppression. Accordingly, inhibition of histone deacetylase can provide an alternate route for treating cancer, hematological disorders, e.g., hemoglobinopathies, a...