The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.

Inhibitors of histone deacetylase

A growing solid tumor relies on a developing vasculature to meet its needs in terms of oxygen, nutrients, depuration, etc. This implies that if the vascular bed that has developed within the tumoral mass can be made to collapse, tumoral growth can be significantly hampered. Indeed, the first proof of principle that this could be achieved was provided more than 10 years ago when a ricin-conjugated antibody directed against an endothelial protein was able to eradicate the tumoral mass in mice.1-4 Therapeutically, two pharmacological strategies can be foreseen that stand on this observation: (1) the development of the growing tumoral vasculature can be arrested by drugs; (2) the established vasculature perfusing the tumoral mass can be destroyed by drugs. Among the crucial questions in the field is how to specifically target the endothelial cells participating in the tumoral neovasculature without causing damage to vasculature elsewhere. A wide body of data has emerged over this issue. 3 It has now been shown that the developing vasculature and the tumoral vasculature express unique proteins and that this uniqueness can be used for selective pharmacological targeting. Indeed, if we consider a plasma membrane protein expressed solely on the undesired vasculature, we could envisage the use of specific antibodies conjugated with toxins, vaccines, etc.3 Yet it is also possible that the neovasculature is more sensitive over normal tissues to more traditional small-molecule drugs. Indeed, this strategy has also been exploited, and a number of compounds have entered or are entering clinical trials (these drugs are cumulatively referred to as low molecular weight vasculature-disrupting agents). 4 For example, the growth of the neovasculature is dependent on activation of the vascular endothelial growth factor receptor, and therefore, a number of receptor antagonists have been devised and are currently tested or employed. 5 Disruption of tubulin polymerization also disrupts the formation of tumoral vasculature, and it is therefore no surprise that a number of agents have been brought forward into the drug pipeline that share this mechanism of action. The present review will concentrate primarily on the medicinal chemistry of one of these drugs, combretastatin A4 (CA-4 a

Medicinal chemistry of combretastatin A4: present and future directions.

A series of combretastatin A-4 (CA-4) analogues were synthesized, and their cytotoxic effects against murine Colon 26 adenocarcinoma and inhibitory activity on tubulin polymerization were evaluated. Since CA-4 has limited aqueous solubility, the target compounds were designed to improve solubility by introduction of a nitrogen-containing group. Among the compounds synthesized, those with an amino moiety in place of the phenolic OH of CA-4 showed potent antitubulin activity and cytotoxicity against murine Colon 26 adenocarcinoma in vitro. Some of the compounds which were potent in vitro were evaluated in the murine tumor model Colon 26 in vivo. Among these, 13bHCl, 21aHCl, and 21bHCl showed significant antitumor activity in the animal model, while CA-4 was ineffective. 13bHCl and 21aHCl were further evaluated in two murine tumor models (Colon 38 and 3LL) and human xenografts HCT-15. These compounds showed potent antitumor activity comparable or superior to that of CDDP. The structure−activity relationships...

Novel Combretastatin Analogues Effective against Murine Solid Tumors: Design and Structure−Activity Relationships

A structure-activity relationship (SAR) study of the South African willow tree (Combretum caffrum) antineoplastic constituent combretastatin A-4 (1b) directed at maintaining the (Z)-stilbene relationship of the olefin diphenyl substituents led to synthesis of a potent cancer cell growth inhibitor designated phenstatin (3b). Initially phenstatin silyl ether (3a) was unexpectedly obtained by Jacobsen oxidation of combretastatin A-4 silyl ether (1c --> 3a), and the parent phenstatin (3b) was later synthesized (6a --> 3a --> 3b) in quantity. Phenstatin was converted to the sodium phosphate prodrug (3d) by a dibenzyl phosphite phosphorylation and subsequent hydrogenolysis sequence (3b --> 3c --> 3d). Phenstatin (3b) inhibited growth of the pathogenic bacterium Neisseriagonorrhoeae and was a potent inhibitor of tubulin polymerization and the binding of colchicine to tubulin comparable to combretastatin A-4 (1b). Interestingly, the prodrugs were found to have reduced activity in these biochemical assays. While no significant tubulin activity was observed with the phosphorylated derivative of combretastatin A-4 (1d), phosphate 3d retained detectable inhibitory effects in both assays.

Antineoplastic agents. 379. Synthesis of phenstatin phosphate.

Resveratrol (3,4',5-trihydroxy-trans-stilbene), an antioxidant from grapes, and five other polyhydroxystilbenes were synthesized. Their antioxidative properties were evaluated in two model systems [pure lipid oxidation using the Rancimat method and 2, 2-diphenyl-1-picryhydrazyl (DPPH) free radical scavenging model.] 3, 3',4,5'-Tetrahydroxystilbene, 3,3',4,5,5'-pentahydroxystilbene, and 3,4,4',5-tetrahydroxystilbene were found to be more active than resveratrol in both models. A dimer of resveratrol was identified as the major radical reaction product when resveratrol was reacted with DPPH radicals.

Evaluation of resveratrol derivatives as potential antioxidants and identification of a reaction product of resveratrol and 2, 2-diphenyl-1-picryhydrazyl radical.

Structural modifications of the potassium channel activator cromakalim (1) are described in which the amide moiety at C-4 has been replaced by carboxamide and thiocarboxamide functions. Analogues in which the hydroxyl group at C-3 has been oxidized or removed are also disclosed. Such analogues display an interesting profile of smooth muscle relaxant activity in the guinea pig isolated trachea, not all of which appears to result from the opening of potassium channels, but few compounds retain useful in vivo activity. However, one compound in particular, 6-cyano-2,2-dimethyl-N-methyl-2H-1-benzopyran-4-thiocarboxamide (13) was shown to be a potent potassium channel activator in vitro and to provide prolonged protection to guinea pigs from the respiratory effects of inhaled histamine.

Relaxant activity of 6-cyano-2,2-dimethyl-2H-1-benzopyran-4-carboxamides and -thiocarboxamides and their analogues in guinea pig trachealis.

Compounds of formula (I) wherein: R is hydroxy, hydrogen, alkyl, alkenyl, alkynyl or aryl; R1 is arylmethyl or heterocyclylmethyl; R2 is alkyl, alkenyl, aryl, cycloalkyl or cycloalkenyl; and R3 is hydrogen, alkyl, alkenyl, alkynyl or aryl; with the provisio that: if R1 is phenylmethyl or naphtylmethyl, wherein the phenyl or naphthyl group is unsubstituted or substituted by up to five substituents selected from the group consisting of halogen, (C?1-6?)alkyl, aryl(C1-6)alkyl, (C1-6)alkoxy, (C1-6)alkoxy(C1-6)alkyl, halo(C1-6)alkyl, hydroxy, nitro, amino, mono- and di-N-(C1-6)alkylamino, acylamino, acyloxy, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-(C1-6)alkylcarbamoyl, (C1-6)alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino, sulphonylamino, aminosulphonyl, (C1-6)alkylthio, (C1-6)alkyl sulphinyl (C1-6)alkylsulphonyl, heterocyclyl, heterocyclyl (C1-6)alkyl, and a (C3-5)alkylene chain linking two adjacent ring carbon atoms to form a carbocyclic ring; then R is hydroxy; are useful in the treatment of disorders mediated by s-CD23.

INHIBITORS OF THE PRODUCTION OF s-CD23 AND THE SECRETION OF TNF

In an endeavour to develop isoenzyme selective inhibitors of the cyclic nucleotide phosphodiesterases, structural modifications of 8-amino-1,3-bis(cyclopropylmethyl)xanthine (BRL 61063) have been investigated. Particularly significant was the observation that certain 7-aralkyl derivatives incorporating chlorine or bromine in place of the 8-amino substituent afforded selective inhibitors of the PDE 4 isoenzyme. The 7-(2-naphthylmethyl) derivatives of 8-chloroxanthine 16 and 8-bromoxanthine 17 in particular showed sub-micromolar IC 50 values against PDE 4 while eliciting some 10 and 100-fold or greater selectivity, respectively, against the 1b, 1c, 2, 3, and 5a isoenzymes

Inhibition of Type 4 Cyclic Nucleotide Phosphodiesterase by 8‐Chloroxanthines

An unusual base-mediated ring contraction reaction of benzopyrans to benzofurans

The reaction of 2-(trifluoroacetyl)pyrrole with trans-3-bromo-3,4-dihydro-4-hydroxy-2,2-dimethyl-2H-chromene-6-carbonitrile under basic conditions has been shown to afford high yields of (4R*, 5aS*,11 bS*)-5a-hydroxy-6,6-dimethyl-4-trifluoromethyl-5a,11 b-dihydro-4H,6H-pyrrolo[1′,2′:4,5]-oxazino[2,3-c]chromene-10-carbonitrile rather than the anticipated amino alcohol. The unequivocal structural assignment of this unusual tetracyclic product by spectroscopic and X-ray crystallographic techniques is described and possible mechanistic explanations for its formation are discussed. Analogous reactions of pyrroles substituted in the 2-position by formyl, acetyl and benzoyl moieties have been shown to behave in an essentially similar manner, suggesting that the reaction is general for 2-acylpyrroles.

Andrew Faller

Papers

Relaxant activity of 6-cyano-2,2-dimethyl-2H-1-benzopyran-4-carboxamides and -thiocarboxamides and their analogues in guinea pig trachealis.

INHIBITORS OF THE PRODUCTION OF s-CD23 AND THE SECRETION OF TNF

Inhibition of Type 4 Cyclic Nucleotide Phosphodiesterase by 8‐Chloroxanthines

An unusual base-mediated ring contraction reaction of benzopyrans to benzofurans

Novel redox cyclisation products derived from 2-acylpyrroles and trans-3-bromo-3,4-dihydro-4-hydroxy-2,2-dimethyl-2H-chromene-6-carbonitrile