1,2,3,19-Tetrahydroxy-12-ursen-28-oic acid

Acid-promoted cyclization of 2,4-diaryl-1,1,1-trifluorobut-3-en-2-oles and their TMS-ethers into CF3-indenes.[Pubmed:28261737]

Org Biomol Chem. 2017 Mar 22;15(12):2541-2550.

2,4-Diaryl-1,1,1-trifluorobut-3-en-2-oles and their TMS-ethers in H2SO4 at room temperature in just 2 min are quantitatively cyclized into 1-aryl-3-trifluoromethyl-1H-indenes. The reaction proceeds through an intermediate formation of the corresponding CF3-allyl cations, which are cyclized regioselectively at the allyl carbon atom most remote from the CF3-group. The obtained CF3-indenes in solution of EtOAc in the presence of silica gel at room temperature over 4 h are quantitatively isomerized into 3-aryl-1-trifluoromethyl-1H-indenes.

Discovery of 4-((3'R,4'S,5'R)-6''-Chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2''-oxodispiro[ cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamido)bicyclo[2.2.2]octane -1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development.[Pubmed:28339198]

J Med Chem. 2017 Apr 13;60(7):2819-2839.

We previously reported the design of spirooxindoles with two identical substituents at the carbon-2 of the pyrrolidine core as potent MDM2 inhibitors. In this paper we describe an extensive structure-activity relationship study of this class of MDM2 inhibitors, which led to the discovery of 60 (AA-115/APG-115). Compound 60 has a very high affinity to MDM2 (Ki < 1 nM), potent cellular activity, and an excellent oral pharmacokinetic profile. Compound 60 is capable of achieving complete and long-lasting tumor regression in vivo and is currently in phase I clinical trials for cancer treatment.

2-[(4-Chlorobenzyl) amino]-4-methyl-1,3-thiazole-5-carboxylic acid exhibits antidiabetic potential and raises insulin sensitivity via amelioration of oxidative enzymes and inflammatory cytokines in streptozotocin-induced diabetic rats.[Pubmed:28262618]

Biomed Pharmacother. 2017 May;89:651-659.

Thiazole derivatives are potential candidates for drug development. They can be efficiently synthesized and are extremely active against several diseases, including diabetes. In our present study, we investigated the anti-diabetic, anti-oxidant and anti-inflammatory properties of 2-[(4-Chlorobenzyl) amino]-4-methyl-1,3-thiazole-5-carboxylic acid (BAC) a new thiazole derivative, in a streptozotocin (STZ) induced neonatal model of non-insulin dependent diabetes mellitus (NIDDM) rats. Diabetes was induced by injecting STZ (100mg/kg) intraperitoneally to two days old pups. BAC administration for 3 weeks significantly decreased blood glucose and raised insulin level and improves insulin sensitivity (KITT) level. Additionally, BAC also suppressed several inflammatory cytokines generation as evidenced by decreased levels of serum tumor necrosis factor-alpha and interleukin-6. In addition, BAC also protects against hyperlipidemia and liver injury. Furthermore, BAC significantly restored pancreatic lipid peroxidation, catalase, superoxide dismutase, and reduced glutathione content. Histological studies of pancreatic tissues showed normal architecture after BAC administration to diabetic rats. Altogether, our results suggest that BAC successfully reduces the blood glucose level and possesses anti-oxidant as well as anti-inflammatory activity. This leads to decreased histological damage in diabetic pancreatic tissues suggesting the possibility of future diabetes treatments.

Direct Functionalization of an Acid-Terminated Nanodiamond with Azide: Enabling Access to 4-Substituted-1,2,3-Triazole-Functionalized Particles.[Pubmed:28248516]

Langmuir. 2017 Mar 21;33(11):2790-2798.

Azides on the periphery of nanodiamond materials (ND) are of great utility because they have been shown to undergo Cu-catalyzed and Cu-free cycloaddition reactions with structurally diverse alkynes, affording particles tailored for applications in biology and materials science. However, current methods employed to access ND featuring azide groups typically require either harsh pretreatment procedures or multiple synthesis steps and use surface linking groups that may be susceptible to undesirable cleavage. Here we demonstrate an alternative single-step approach to producing linker-free, azide-functionalized ND. Our method was applied to low-cost, detonation-derived ND powders where surface carbonyl groups undergo silver-mediated decarboxylation and radical substitution with azide. ND with directly grafted azide groups were then treated with a variety of aliphatic, aromatic, and fluorescent alkynes to afford 1-(ND)-4-substituted-1,2,3-triazole materials under standard copper-catalyzed cycloaddition conditions. Surface modification steps were verified by characteristic infrared absorptions and elemental analyses. High loadings of triazole surface groups (up to 0.85 mmol g(-1)) were obtained as determined from thermogravimetric analysis. The azidation procedure disclosed is envisioned to become a valuable initial transformation in numerous future applications of ND.