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Mammalian target of rapamycin (mTOR) is essential in controlling several cellular functions. This pathway is dysregulated in keloid disease (KD). KD is a common fibroproliferative dermal lesion with an ill-defined treatment strategy. KD demonstrates excessive matrix deposition, angiogenesis, and inflammatory cell infiltration. In KD, both total and phosphorylated forms of mTOR and p70(S6K)(Thr421/Ser424) are upregulated. Therefore, the aim of this study was to investigate adenosine triphosphate-competitive inhibitors of mTOR kinase previously unreported in keloid and their comparative efficacy with Rapamycin. Here, we present two mTOR kinase inhibitors, KU-0063794 and KU-0068650, that target both mTORC1 and mTORC2 signaling. Treatment with either KU-0063794 or KU-0068650 resulted in complete suppression of Akt, mTORC1, and mTORC2, and inhibition of keloid cell spreading, proliferation, migration, and invasive properties at a very low concentration (2.5 μmol l(-1)). Both KU-0063794 and KU-0068650 significantly (P0.05) inhibited cell cycle regulation and HIF1-α expression compared with that achieved with Rapamycin alone. In addition, both compounds induced shrinkage and growth arrest in KD, associated with the inhibition of angiogenesis, induction of apoptosis, and reduction in keloid phenotype-associated markers. In contrast, Rapamycin induced minimal antitumor activity. In conclusion, potent dual mTORC1 and mTORC2 inhibitors display therapeutic potential for the treatment of KD.

Homochiral (E)- and (Z)-enamides derived from SuperQuat (S)-4-phenyl-5,5-dimethyl-oxazolidin-2-one undergo highly diastereoselective epoxidation upon treatment with dimethyldioxirane. Subsequent epoxide opening with meta-chlorobenzoic acid proceeds via a stereoselective SN1-type process, with retention of configuration, to give the corresponding 1′-m-chlorobenzoyl-2′-hydroxy derivatives. Treatment of the SuperQuat enamides with mCPBA effects this two-step transformation in one pot. Reductive cleavage of the isolated 1′-m-chlorobenzoyl-2′-hydroxy derivatives (≥96% de) generates homochiral 1,2-diols in ≥96% ee. Alternatively, regioselective lithiation of the enamide at C(1′) with tBuLi followed by reaction with an aromatic aldehyde and in situ O-benzylation generates a 1′-(benzyloxy-aryl-methyl) substituted enamide with high diastereoselectivity. Subsequent oxidative cleavage of the enamide C{double bond, long}C bond with NaIO4/RuCl3 followed by methanolysis of the resultant N-acyl fragment furnishes an O-benzyl protected α-hydroxy methyl ester in high ee. © 2008 Elsevier Ltd. All rights reserved.

(R)-4-Phenyl-5,5-dimethyl-oxazolidin-2-one, readily available from d -phenylglycine, is shown to be an effective chiral auxiliary for stereoselective conjugate additions to attached α,β-unsaturated N-acyl moieties. Its utility is demonstrated by the asymmetric synthesis of the antifungal, antibacterial (−)-Aplysillamide B.

N -acyl-5,5-dimethyl-oxazolidin-2-ones can function as versatile latent aldehyde equivalents - reductive cleavage with DIBAL-H affords aldehydes in good yield, while tandem DIBAL-H/Wittig methodology affords α,β-unsaturated esters.

The synthesis of a series of chiral auxiliaries, 5-substituted-3,3-dimethyl-2-pyrrolidinones, “quats”, from L-glutamic acid is described. Efficient regeneration of the chiral auxiliaries from their N-pivaloyl derivatives is readily achieved with LiOH in THF-water at 20°C.

The highly enantioselective preparation of synthetically useful tetrahydropyridine derivatives employing a one-pot nitro-Mannich/hydroamination cascade is reported. This approach utilizes an asymmetric organocatalytic nitro-Mannich reaction followed by a gold-catalyzed alkyne hydroamination/isomerization sequence that yields the desired tetrahydropyridines in good yields and high diastereo- and enantioselectivities.

2,4-Disubstituted-5-fluoropyrimidine is a biologically active molecular core seen in various anticancer agents such as 5-fluorouracil (5-FU). As part of a programme aimed at discovering kinase inhibitors, routes to two series of novel compounds (5-fluoropyrimidine-2-carboxamides and 5-fluoropyrimidine-4-carboxamides) were successfully executed. For the first series, regioselective substitution at the 4-position of the pyrimidine with an amine (HNR 1 R 2 ) was achieved, followed by preparation of the amide at the 2-position. The route to the second series involved introduction of the methoxy protecting group at the 4-position, which allowed subsequent amine substitution to occur at the 2-position. The 4-amide substituent was finally introduced by direct conversion of the 4-methoxy into a 4-chloro group followed by transformation into an amide by palladium catalysis.

Novel indole-3-thio-, 3-sulfonyl- and 3-oxy-aryl-1-acetic acids are reported which are potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). Optimization required maintenance of high CRTh2 potency whilst achieving a concomitant reduction in rates of metabolism, removal of cyp p450 inhibition and minimization of aldose reductase and aldehyde reductase activity. High quality compounds suitable for in vivo studies are highlighted, culminating in the discovery of AZD1981 (22).

A novel series of small molecule C5a antagonists is reported. In particular, in vitro metabolic studies and solution based combinatorial synthesis are demonstrated as useful tools for the rapid identification of antagonists with low in vitro clearance. Members of this series specifically inhibited the binding of (125)I-labeled C5a to human recombinant C5a receptor (C5aR). In functional cell assays these compounds displayed surmountable antagonism against C5a and did not demonstrate any detectable agonist activity.

Starting with the weak agonist indomethacin, a series of potent, selective CRTh2 (DP(2)) antagonists have been discovered as potential treatments for asthma, allergic rhinitis and other inflammatory diseases.

A lead generation and optimization program delivered the highly selective and potent CatC inhibitor 10 as an in vivo tool compound and potential development candidate. Structural studies were undertaken to generate SAR understanding.

A series of dual CCR3/H1 antagonists based on a bispiperidine scaffold were discovered. Introduction of an acidic group overcame hERG liability. Bioavailability was optimised by modulation of physico-chemical properties and physical form to deliver a compound suitable for clinical evaluation.

Enolates derived from the N -propionoyl derivative of the “quat” chiral auxiliary ( R )-(−)-5-methyl-3,3-dimethyl-2-pyrrolidinone undergo highly stereoselective aldol and alkylation reactions. Removal of the auxiliary has been demonstrated with LiOH, PhCH 2 OLi, MeOMgBr and LiAlH 4 to generate respectively (2 R ,3 R )-3-hydroxy-2-methyl-3-phenylpropionic acid in homochiral form, and with 96% e.e. ( S )-2-methyl-3-phenylpropionic acid and derived methyl and benzyl esters and with >94% e.e. ( S )-2-methyl-3-phenylpropanol.

The proclivity of alpha-branched N-2'-benzyl-3'-phenylpropionyl derivatives of (S)-4-benzyl-5,5-dimethyl-, (S)-4-phenyl-5,5-dimethyl-, (S)-4-isopropyl-5,5-dimethyl-, (S)-4-benzyl- and (S)-4-benzyl-5,5-diphenyl-oxazolidin-2-ones to generate directly 2-benzyl-3-phenylpropionaldehyde upon hydride reduction with DIBAL is investigated. The (S)-4-benzyl-5,5-dimethyl-derivative proved optimal for inhibition of endocyclic nucleophilic attack, giving 2-benzyl-3-phenylpropionaldehyde in good yield upon reduction. Application of this methodology for the asymmetric synthesis of chiral aldehydes via diastereoselective enolate alkylation of a range of (S)-N-acyl-4-benzyl-5,5-dimethyloxazolidin-2-ones to afford and array of alpha-substituted-N-acyl-5,5-dimethyloxazolidin- 2-ones (85-94% de) and subsequent reduction with DIBAL afforded directly non-racemic alpha-substituted aldehydes without loss of stereochemical integrity (87-94% ee). The extension of this protocol for the asymmetric synthesis of beta-substituted aldehydes is demonstrated, via the diastereoselective conjugate addition of a range of organocuprates to (S)-N-acyl-4-phenyl-5,5-dimethyloxazolidin-2-ones which proceeds with high diastereoselectivity (generally > 95% de). Reduction of the conjugate addition products with DIBAL gives non-racemic beta-substituted aldehydes in high yields and in high ee (generally > 95% ee). This methodology is exemplified by the asymmetric synthesis of (R)-3-isopropenylhept-6-enal, which has previously been used in the synthesis of (3Z,6R)-3-methyl-6-isopropenyl-3,9-decadien-1-yl acetate, a component of the sex pheromones of the California red scale.

A study of the properties of N-hydrocinnamoyl- derivatives of 5,5-dimethyloxazolidin-2-one, 4,4-dimethyloxazolidin-2-one and oxazolidin-2-one upon hydride reduction with DIBAL-H demonstrates that the 5,5-dimethyl-group is essential for inhibition of endocyclic nucleophilic attack. For instance, treatment of N-hydrocinnamoyl-5,5-dimethyloxazolidin-2-one with DIBAL-H results in the selective formation of the stable N-1'-hydroxyalkyl derivative which may be regarded as a masked hydrocinnamaldehyde equivalent, as treatment under basic conditions affords the parent aldehyde in excellent yield. Treatment of N-hydrocinnamoyl-4,4-dimethyloxazolidin-2-one with DIBAL-H under identical conditions affords a complex mixture of products, including the formate ester product of endocyclic cleavage. As an alternate strategy, DIBAL-H reduction of straight chain and branched N-acyl-5,5-dimethyloxazolidin-2-one derivatives, followed by a Horner-Wadsworth-Emmons reaction affords alpha,beta-unsaturated esters in good yields. Branching alpha- to the exocyclic carbonyl in N-acyl-oxazolidinones inhibits DIBAL-H reduction, but this can be overcome by precomplexation with ZnCl2, with subsequent fragmentation generating either the corresponding aldehyde or alpha,beta-unsaturated esters. The addition of ZnCl2 has been shown to increase the diastereoselectivity observed in Wadsworth-Horner-Emmons reactions of lithiated phosphonates.