- Structure-based drug design and potent anti-cancer activity of tricyclic 5:7:5-fused diimidazo[4,5-d:4′,5′-f][1,3]diazepines
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Judicial structural modifications of 5:7-fused ring-expanded nucleosides (RENs), based on molecular modeling studies with one of its known targets, human RNA helicase (hDDX3), led to the lead, novel, 5:7-5-fused tricyclic heterocycle (1). The latter exhibited promising broad-spectrum in vitro anti-cancer activity against a number of cancer cell lines screened. This paper describes our systematic, albeit limited, structure-activity relationship (SAR) studies on this lead compound, which produced a number of analogs with broad-spectrum in vitro anti-cancer activities against lung, breast, prostate, and ovarian cancer cell lines, in particular compounds 15i, 15j, 15m and 15n which showed IC 50 values in submicromolar to micromolar range, and are worthy of further explorations. The SAR data also enabled us to propose a tentative SAR model for future SAR efforts for ultimate realization of optimally active and minimally toxic anti-cancer compounds based on the diimidazo[4,5-d:4′, 5′-f][1,3]diazepine structural skeleton of the lead compound 1.
- Kondaskar, Atul,Kondaskar, Shilpi,Fishbein, James C.,Carter-Cooper, Brandon A.,Lapidus, Rena G.,Sadowska, Mariola,Edelman, Martin J.,Hosmane, Ramachandra S.
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p. 618 - 631
(2013/02/25)
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- Fluorescent derivatives of AC-42 to probe bitopic orthosteric/allosteric binding mechanisms on muscarinic M1 receptors
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Two fluorescent derivatives of the M1 muscarinic selective agonist AC-42 were synthesized by coupling the lissamine rhodamine B fluorophore (in ortho and para positions) to AC42-NH2. This precursor, prepared according to an original seven-step procedure, was included in the study together with the LRB fluorophore (alone or linked to an alkyl chain). All these compounds are antagonists, but examination of their ability to inhibit or modulate orthosteric [3H]NMS binding revealed that para-LRB-AC42 shared several properties with AC-42. Carefully designed experiments allowed para-LRB-AC42 to be used as a FRET tracer on EGFP-fused M1 receptors. Under equilibrium binding conditions, orthosteric ligands, AC-42, and the allosteric modulator gallamine behaved as competitors of para-LRB-AC42 binding whereas other allosteric compounds such as WIN 51,708 and N-desmethylclozapine were noncompetitive inhibitors. Finally, molecular modeling studies focused on putative orthosteric/allosteric bitopic poses for AC-42 and para-LRB-AC42 in a 3D model of the human M1 receptor.
- Daval, Sandrine B.,Valant, Céline,Bonnet, Dominique,Kellenberger, Esther,Hibert, Marcel,Galzi, Jean-Luc,Ilien, Brigitte
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experimental part
p. 2125 - 2143
(2012/06/01)
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- Trifluoroacetic anhydride-catalyzed oxidation of isonitriles by DMSO: A rapid, convenient synthesis of isocyanates
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A smooth and efficient oxidation of isonitriles to isocyanates by sulfoxides is catalyzed by trifluoroacetic anhydride. With use of DMSO as the oxidant and 5 mol·% TFAA (dichloromethane, -60 to 0 °C), the process is complete in a few minutes, forming dimethyl sulfide as the only byproduct. The newly formed isocyanates may be used directly or isolated in high purity by solvent evaporation.
- Le, Hoang V.,Ganem, Bruce
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supporting information; experimental part
p. 2584 - 2585
(2011/06/25)
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- Organosilicon synthesis of isocyanates: III. Synthesis of aliphatic, carbocyclic, aromatic, and alkylaromatic isocyanatocatboxylic acid esters
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A series of aminoacid esters was prepared by treating the aminoacid suspensions in ethanol with thionyl chloride. Best conversion of aminoacid esters to corresponding isocyanates was achieved in the case of aromatic and carbocyclic aminoesters by phosgeneation of their N-silyl derivatives, and in the case of aliphatic and alkylaromatic aminoesters by phosgeneation of O-silyl or N,O-bissilylurethanes on their basis. In the last case additional step of esterification of the by-products isocyanatoalkylcarboxylic acid chlorides is required after phosgeneation. Unusual generation of cynnamates and intramolecular N→O-migration of trimethylsilyl group in the solutions of silylated alkylaromatic β-aminoacid esters were found. Pleiades Publishing, Inc., 2006.
- Lebedev,Lebedeva,Sheludyakov,Ovcharuk,Kovaleva,Ustinova
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p. 1069 - 1080
(2008/02/05)
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- A convenient and efficient synthesis of novel 1-ethoxycarbonylmethyl-3-ethyl-1,2,3,4-tetrahydro-4-oxo- 1,3,2-benzodiazaphosphorin-2-carboxamide 2-oxides
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Some novel 1-ethoxycarbonylmethyl-3-ethyl-1,2,3,4-tetra- hydro-4-oxo-1,3,2-benzodiazaphosphorin-2-carboxamide 2-oxides containing α-amino acid ester or α -aminophosphonate groups have been designed incorporating the proximate carbonyl and phosphoryl groups into the benzoannulated phosphidiamide heterocycle and synthesized by a convenient one-pot procedure in good yields, in which the hydrochlorides of α-amino acid esters or hydrobromides of α -aminophosphonates reacted smoothly with bis(trichloromethyl) carbonate with the help of four molar equivalents of triethylamine to give the corresponding isocyanates that then formed the products by the addition with the phosphorus reagent containing a P-H bond.
- Huang, Jun-Min,Chen, Hui,Chen, Ru-Yu
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p. 1357 - 1363
(2007/10/03)
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- Inhibition of serine proteases: Activity of 1,3-diazetidine-2,4-diones
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The present work demonstrates that the 1,3-diazetidine-2,4-dione nucleus is effective as a scaffold of serine protease inhibitors. Compound 1 displayed high activity against human cathepsin G and α-chymotrypsin (0.39, 0.69 nM). Compound 6 exhibited 0.85 nM inhibition of human chymase. Compound 10 was a selective inhibitor against human neutrophil elastase.
- Aoyama, Yasunori,Uenaka, Masaaki,Konoike, Toshiro,Hayasaki-Kajiwara, Yoko,Naya, Noriyuki,Nakajima, Masatoshi
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p. 1691 - 1694
(2007/10/03)
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- Condensation between isocyanates and carboxylic acids in the presence of 4-dimethylaminopyridine (DMAP), a mild and efficient synthesis of amides
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A mild and convenient method for the preparation of amides from carboxylic acids and isocyanates is described. By using DMAP as a catalyst milder reaction conditions are realised which also allow the conversion of α-chiral isocyanates, as well as α-chiral carboxylic acids without racemisation.
- Schuemacher,Hoffmann
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p. 243 - 246
(2007/10/03)
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