1,1-enediamines and β-substituted enamines in heterocyclic synthesis

The work in this thesis mainly deals with l,l-enediamines and ~ -substituted enamines (push-pull olefines) and their reactions, leading to the formation of a number of heterocycles. Various ~-substituted enamines were prepared by a 'one pot synthesis' in which a l,l-enediamine presumably acts as an intermediate. These enamines, various substituted crotonamides and propenamides, were made by using two different orthoesters, various secondary and primary amines and cyanoacetamide. Their structures, mechanism of formation and geometry are discussed. A synthetic route to various unsymmetrically substituted pyridines was examined. Two substituted pyridinones were obtained by using two different ~-substituted enamines and cyanoacetamide. In one case a dihydropyridine was isolated. This dihydropyridine, on heating in acidic conditions, gave a pyridinone, which confirmed this dihydropyridine as an intermediate in this pyridine synthesis. A new synthetic method was used to make highly substituted pyridinones, which involved the reaction of l,l-enediamines with the ~-substituted enamines. A one pot synthesis and an interrupted one pot synthesis were used to make these pyridinones. Two different orthoesters and three different secondary amines were used. Serendipitous formation of a pyrimidinone was observed when pyrrolidine was used as the secondary amine and triethyl orthopropionate was used as the orthoester. In all cases cyanoacetamide was used as the carbon acid. This pyridine synthesis was designed with aI, l-enediamine as the Michael donor and the ~ -substituted enamines as Michael acceptors. Substituted ureas were obtained in two cases, which was a surprise. Some pyrimidines were made by reacting two substituted enamines with two different amidines. When benzamidine was used, the expected pyrimidines were obtained. But, when 2-benzyl-2-thiopseudourea (which is also an amidine) was used, of the two expected pyrimidines, only one was obtained. In the other case, an additional substitution reaction took place in which the S-benzyl group was lost. An approach to quinazolone and benzothiadiazine synthesis is discussed. Two compounds were made from 1, I-dimorpholinoethen

The novel anti-androgen candidate galeterone targets deubiquitinating enzymes, USP12 and USP46, to control prostate cancer growth and survival

Metastatic castration resistant prostate cancer is one of the main causes of male cancer associated deaths worldwide. Development of resistance is inevitable in patients treated with anti-androgen therapies. This highlights a need for novel therapeutic strategies that would be aimed upstream of the androgen receptor (AR). Here we report that the novel small molecule anti-androgen, galeterone targets USP12 and USP46, two highly homologous deubiquitinating enzymes that control the AR-AKT-MDM2-P53 signalling pathway. Consequently, galeterone is effective in multiple models of prostate cancer including both castrate resistant and AR-negative prostate cancer. However, we have observed that USP12 and USP46 selectively regulate full length AR protein but not the AR variants. This is the first report of deubiquitinating enzyme targeting as a strategy in prostate cancer treatment which we show to be effective in multiple, currently incurable models of this disease

Enantioselective syntheses of aldohexoses using macrocyclic stereocontrol

A general method for enantioselective syntheses of aldohexoses using macrocyclic stereocontrol is described. The strategy employs simultaneous bis-dihydroxylation of chiral macrocyclic dienes to install the four contiguous stereogenic centers of aldohexoses. Conformational searches have been performed on two different macrocyclic precursors to the desired aldohexose using molecular mechanics calculations. Qualitative analysis of the low energy conformers obtained from these searches predicts L-gulose and D-idose, respectively, to be formed as major products in high enantiomeric ratios. The synthesis of the macrocyclic precursor to L-gulose was carried out in 5 steps from l-menthol. Key steps in this synthesis include a one-pot oxidation-Baeyer Villiger rearrangement of l-menthol and an intramolecular Horner-Wadsworth olefination to form a 14-membered ring in high yield. A broad survey of dihydroxylation conditions for osmylation of the diene was conducted. Although the majority of conditions resulted in complex mixtures of diastereomeric tetraols, catalytic OsO\sb4 and Me\sb3NO afforded two diastereomeric tetraols cleanly. Enantiomeric purity of the dihydroxylation products was determined through conversion of the macrocyclic tetraol to the corresponding hexitol hexaacetate and correlation with authentic material. The generality of this method was demonstrated by the synthesis of D-galactose from a related macrocycle using identical osmylation conditions

Discovery of 3‑(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl‑3<i>H</i>‑imidazo[4,5‑<i>b</i>]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor

The work in this paper describes the optimization of the 3-(3-phenyl-3<i>H</i>-imidazo­[4,5-<i>b</i>]­pyridin-2-yl)­pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (<b>21a</b>). The cocrystal structure of compound <b>21a</b> bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound <b>21a</b> demonstrated high enzymatic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound <b>21a</b> also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma