A direct alkylation route to branched derivatives of suberoylanilide hydroxamic acid (SAHA), a potent non-selective inhibitor of histone deacetylases

Alkylation of malonamic esters provides a direct approach to derivatives of suberoylanilide hydroxamic acid (SAHA) that are branched at the amide carbon atom, a location pivotal for enhancing biological and therapeutic activity. Alkylations use NaH in THF followed by addition of the ester of 6-bromohexanoic acid; no protection of the amidic NH group is necessary. By this means, carboxylic acid, ester, amide, hydroxymethyl and 2-benzimidazolyl branching units have been appended to the SAHA backbone. Routes to vary one of the branching units at a time have been developed

A stepwise lactol carbocyclisation to bridged ethers via a keto–acetal cascade

Lactol carbocyclisations provide a succinct method of constructing the oxabicyclo[3.2.1]octane scaffold, a motif present in various natural products of medicinal interest. Lactols containing an unsaturated ketone or ester were prepared by olefin cross-metathesis; an electrophilic alkene derived from methyl vinyl ketone underwent concomitant terminal α-methylenation and oxa-Michael addition to give a bridged lactol which then underwent oxygen-to-carbon transposition in the presence of titanium (IV) chloride giving the desired unsaturated carbocyclic seven-membered bridged ether via a novel dehydrative cascade considered to involve titanium enolates

Domino Michael-aldol annulations for the stereocontrolled synthesis of bicyclo[3.3.1]nonane and bicyclo[3.2.1]octane derivatives

Domino Michael-aldol annulation of cycloalkane-1,3-diones with enals affords a general route to 6-hydroxybicyclo[3.3.1]nonane-2,9-diones and 2-hydroxybicyclo[3.2.1]octane-6,8-diones, notably in one-pot procedures under convenient conditions. The annulation is shown to be compatible with one or more substituents at six positions of the bicyclo[3.3.1]nonane-2,9-dione scaffold. In some cases, the relative configuration of the product can be controlled by the appropriate choice of solvent, base and temperature for the annulation. In contrast to the chair–chair conformations usually adopted, the bicyclo compounds derived from 2,4,4-trimethylcyclohexane-1,3-dione possessed boat-chair conformations. Oxidation of the annulation products gave the corresponding bicyclo triketones

Potent non-hydroxamate inhibitors of histone deacetylase-8: Role and scope of an isoindolin-2-yl linker with an α-amino amide as the zinc-binding unit

A series of potent inhibitors of histone deacetylase-8 (HDAC8) is described that contains an α-amino amide zinc-binding unit and a substituted isoindolinyl capping group. The presence of a 2,4-dichlorophenyl unit located in the acetate-release cavity was shown to confer a gain of approx. 4.3 kJ mol−1 in binding energy compared to a phenyl group, and the isoindoline linker has approx. 5.8 kJ mol−1 greater binding energy than the corresponding tetrahydroisoquinoline ring system. In a series of 5-substituted isoindolin-2-yl inhibitors, a 5-acetylamino derivative was found to be more potent than the 5-unsubstituted lead HDAC8 inhibitor (increase in binding energy of 2.0 kJ mol−1, ascribed to additional binding interactions within the Nε-acetyl-l-lysine binding tunnel in HDAC8, including hydrogen bonding to Asp101. Tolerance of a 5-substituent (capping group) on the isoindoline ring has been demonstrated, and which in some cases confers improved enzyme inhibition, the HDAC8 substrate-binding region providing a platform for additional interactions

Regioselective synthesis of substituted piperidine-2,4-diones and their derivatives via Dieckmann cyclisations

A flexible route to piperidine-2,4-diones variously substituted at the 6-, 5,6- and 2,6-positions, both with and without 1-substitution, is described; no N-protective group is required. A related regioselective Dieckmann cyclisation is also described that uses Davies' α-methylbenzylamine auxiliary and affords 6-substituted piperidine-2,4-diones enantioselectively

Potent and selective inhibitors of histone deacetylase-3 containing chiral oxazoline capping groups and a N-(2-Aminophenyl)-benzamide binding unit

A novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contains an oxazoline capping group and a N-(2-aminophenyl)-benzamide unit. Among several new inhibitors of this type exhibiting Class I selectivity and potent inhibition of HDAC3-NCoR2, in vitro assays for the inhibition of HDAC1, HDAC2, and HDAC3-NCoR2 by N-(2-aminophenyl)-benzamide 15k gave respective IC50 values of 80, 110, and 6 nM. Weak inhibition of all other HDAC isoforms (HDAC4, 5, 6, 7, and 9: IC50 > 100 000 nM; HDAC8: IC50 = 25 000 nM; HDAC10: IC50 > 4000 nM; HDAC11: IC50 > 2000 nM) confirmed the Class I selectivity of 15k. 2-Aminoimidazolinyl, 2-thioimidazolinyl, and 2-aminooxazolinyl units were shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)-benzamides previously reported, but the 2-aminooxazolinyl unit was the most potent in inhibiting HDAC3-NCoR2. Many of the new HDAC inhibitors showed higher solubilities and lower binding to human serum albumin than that of Mocetinostat. Increases in histone H3K9 acetylation in the human cell lines U937 and PC-3 was observed for all three oxazolinyl inhibitors evaluated; those HDAC inhibitors also lowered cyclin E expression in U937 cells but not in PC-3 cells, indicating underlying differences in the mechanisms of action of the inhibitors on those two cell lines

Pteridine-2,4-diamine derivatives as radical scavengers and inhibitors of lipoxygenase that can possess anti-inflammatory properties

BACKGROUND: Reactive oxygen species are associated with inflammation implicated in cancer, atherosclerosis and autoimmune diseases. The complex nature of inflammation and of oxidative stress suggests that dual-target agents may be effective in combating diseases involving reactive oxygen species. RESULTS: A novel series of N-substituted 2,4-diaminopteridines has been synthesized and evaluated as antioxidants in several assays. Many exhibited potent lipid antioxidant properties, and some are inhibitors of soybean lipoxygenase, IC50 values extending down to 100 nM for both targets. Several pteridine derivatives showed efficacy at 0.01 mmol/kg with little tissue damage in a rat model of colitis. 2-(4-methylpiperazin-1-yl)-N-(thiophen-2-ylmethyl)pteridin-4-amine (18f) at 0.01 mmol/kg exhibited potent anti-inflammatory activity (reduction by 41%). CONCLUSION: The 2,4-diaminopteridine core represents a new scaffold for lipoxygenase inhibition as well as sustaining anti-inflammatory properties

Late-stage fluorination of bridged scaffolds: chemoselective generation of a CHF group at three positions of the bicyclo[3.3.1]nonane system

Monofluorobicyclo[3.3.1]nonane derivatives were prepared by late-stage fluorination, often proceeding with control of stereochemistry. Introduction of fluorine at the 3-, 6- or 7-position was achieved chemoselectively, the bicyclo system being constructed by a tandem one-pot Michael-aldol annulation. The major conformer was deduced for each of the fluorobicyclo compounds prepared, each possessing a unique CF orientation on a common rigid bridged scaffold that can be polysubstituted

Targeting TAO kinases using a new inhibitor compound delays mitosis and induces mitotic cell death in centrosome amplified breast cells

Thousand-and-one amino acid kinases (TAOKs) 1 and 2 are activated catalytically during mitosis and can contribute to mitotic cell rounding and spindle positioning. Here, we characterize a compound that inhibits TAOK1 and TAOK2 activity with IC50 values of 11-15 nM, is ATP-competitive and targets these kinases selectively. TAOK inhibition or depletion in centrosome amplified SKBR3 or BT549 breast cancer cell models increases the mitotic population, the percentages of mitotic cells displaying amplified centrosomes and multipolar spindles, induces cell death and inhibits cell growth. In contrast, non-tumorigenic and dividing bipolar MCF-10A breast cells appear less dependent on TAOK activity and can complete mitosis and proliferate in the presence of the TAOK inhibitor. We demonstrate that TAOK1 and TAOK2 localize to the cytoplasm and centrosomes respectively during mitosis. Live cell imaging shows that the TAOK inhibitor prolongs the duration of mitosis in SKBR3 cells, increases mitotic cell death and reduces the percentages of cells exiting mitosis, whereas MCF-10A cells continue to divide and proliferate. Over 80% of breast cancer tissues display supernumerary centrosomes and tumor cells frequently cluster extra centrosomes to avoid multipolar mitoses and associated cell death. Consequently, drugs that stimulate centrosome declustering and induce multipolarity are likely to target dividing centrosome amplified cancer cells preferentially, whilst sparing normal bipolar cells. Our results demonstrate that TAOK inhibition can enhance centrosome declustering and mitotic catastrophe in cancer cells and these proteins may therefore offer novel therapeutic targets suitable for drug inhibition and the potential treatment of breast cancers, where supernumerary centrosomes occur

Multiple treatment comparisons in epilepsy monotherapy trials

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