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1.
J Med Chem ; 67(7): 5259-5271, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38530741

RESUMO

A series of activators of GCN2 (general control nonderepressible 2) kinase have been developed, leading to HC-7366, which has entered the clinic as an antitumor therapy. Optimization resulted in improved permeability compared to that of the original indazole hinge binding scaffold, while maintaining potency at GCN2 and selectivity over PERK (protein kinase RNA-like endoplasmic reticulum kinase). The improved ADME properties of this series led to robust in vivo compound exposure in both rats and mice, allowing HC-7366 to be dosed in xenograft models, demonstrating that activation of the GCN2 pathway by this compound leads to tumor growth inhibition.


Assuntos
Proteínas Serina-Treonina Quinases , eIF-2 Quinase , Humanos , Camundongos , Ratos , Animais , Proteínas Serina-Treonina Quinases/metabolismo , eIF-2 Quinase/metabolismo , Camundongos Endogâmicos C57BL , RNA , Retículo Endoplasmático/metabolismo
2.
Org Lett ; 25(3): 461-465, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36638117

RESUMO

The synthesis of fully substituted fused pyrroles through a multicomponent reaction between a thioamide, an aldehyde, and ammonium acetate is described. This process improves on a route commonly employed in the patent literature by avoiding the use of potentially hazardous oxidants, which cause the formation of side products and require a stringent process of derisking to be utilized on scale. The reaction proceeds under mild conditions, displays excellent functional group tolerance, and facilitates diversification through multiple vectors.

3.
Chemistry ; 24(70): 18658-18662, 2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30341926

RESUMO

Hydrogen atom transfer-mediated intramolecular C-C coupling reactions between alkenes and nitriles, using PhSiH3 and catalytic Fe(acac)3 , are described. This introduces a new strategic bond disconnection for ring-closing reactions, forming ketones via imine intermediates. Of note is the scope of the reaction, including formation of sterically hindered ketones, spirocycles and fused cyclic systems.

4.
Org Lett ; 20(17): 5493-5496, 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-30152703

RESUMO

The synthesis of pentafluorophenyl (PFP) sulfonate esters based on the Pd-catalyzed sulfination of aryl and heteroaryl boronic acids is reported. The sulfinate intermediates are converted in situ to the corresponding sulfonate esters using a copper-catalyzed oxidative process, providing a broad range of PFP esters in good yields.

5.
Org Lett ; 19(14): 3891-3894, 2017 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-28682080

RESUMO

Simple propargylic silyl ethers can be converted to complex cyclopropylboronic acid pinacol esters in an efficient one-pot procedure. Terminal acetylenes undergo a Schwartz's reagent catalyzed hydroboration; subsequent addition of further Schwartz's reagent and Lewis acid-mediated activation of neighboring silyl ether allows cyclization to access a range of cyclopropylboronic acid pinacol esters. The scope includes aromatic, aliphatic, quaternary, and spiro substituted cyclopropyl rings, which can be transformed via Suzuki coupling into a range of lead-like substituted cyclopropyl aryl products.

6.
Chem Sci ; 8(4): 2890-2897, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28451354

RESUMO

A mild palladium-catalyzed ligand-controlled regioselective 1,3-arylfluorination of 2[H]-chromenes has been developed. The products with a syn-1,3 substitution pattern were obtained with high enantiomeric excess using a PyrOx ligand, wherein the utility of these pyranyl-fluorides was further demonstrated through their participation in a diastereoselective C-C bond forming reaction. Ligand dependent divergent formation of both the 1,3- and 1,2- alkene difunctionalization products was observed. The nature of this bifurcation was investigated through experimental studies in combination with computational and statistical analysis tools. Ultimately, the site selectivity was found to rely on ligand denticity and metal electrophilicity, the electronics of the boronic acid, and the donor ability of the directing group in the substrate.

7.
Org Lett ; 19(4): 870-873, 2017 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-28177642

RESUMO

A metal-free strategy for the formation of lactams via selective oxidation of cyclic secondary and tertiary amines is described. Molecular iodine facilitates both chemoselective and regioselective oxidation of C-H bonds directly adjacent to a cyclic amine. The mild conditions, functional group tolerance, and substrate scope are demonstrated using a suite of diverse small molecule cyclic amines, including clinically approved drug scaffolds.

8.
Adv Synth Catal ; 356(4): 687-691, 2014 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-24839436

RESUMO

A mild, catalytic, atom economical synthesis of imidazo[1,2-a]pyridines has been developed: catalytic PicAuCl2 in the presence of an acid produces a range imidazo[1,2-a]pyridines in good yield. This strategy is mild and forseen to be of particular use for the installation of stereogenic centers adjacent to the imidazo[1,2-a]pyridine ring without loss of enantiomeric excess.

9.
J Am Chem Soc ; 136(11): 4101-4, 2014 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-24617344

RESUMO

A mild catalytic asymmetric direct fluoro-arylation of styrenes has been developed. The palladium-catalyzed three-component coupling of Selectfluor, a styrene and a boronic acid, provides chiral monofluorinated compounds in good yield and in high enantiomeric excess. A mechanism proceeding through a Pd(IV)-fluoride intermediate is proposed for the transformation and synthesis of an sp(3) C-F bond.


Assuntos
Hidrocarbonetos Fluorados/síntese química , Paládio/química , Estirenos/química , Catálise , Hidrocarbonetos Fluorados/química , Estrutura Molecular
10.
Chem Commun (Camb) ; 2012 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-22614128

RESUMO

The first synthesis of the bioactive sesquiterpene lactone hydroxyanthecotulide is achieved in 7 steps, involving a stereocontrolled Cr(ii)-catalysed reaction of 3-(bromomethyl)furan-2(5H)-one with enynal 9 and a mild Au(i)-catalysed Meyer-Schuster rearrangement.

11.
Org Lett ; 13(21): 5751-3, 2011 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-21981361

RESUMO

The bioactive sesquiterpene lactone (+)-anthecotulide (1) is synthesized for the first time, in a six-step sequence devoid of protecting groups. The key transformations are a novel Rh(I)-catalyzed asymmetric enyne rearrangement of a terminal alkynyl ester (4), to form the α-methylene-γ-butyrolactone core, and a final-step mild Au(I)-catalyzed Meyer-Schuster rearrangement.


Assuntos
Cetonas/química , Lactonas/síntese química , Sesquiterpenos/síntese química , Catálise , Ciclização , Estrutura Molecular , Estereoisomerismo
12.
Org Lett ; 13(10): 2594-7, 2011 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-21488628

RESUMO

Zinc or a chromium(II) source with 3-(bromomethyl)furan-2(5H)-one (3) and an aldehyde gives ß-(hydroxymethylaryl/alkyl)-α-methylene-γ-butyrolactones 5 in good yields and high diastereoselectivities. The methodology is demonstrated in concise syntheses of (±)-hydroxymatairesinol (8) and (±)-methylenolactocin (10) by subsequent arylboronate conjugate addition and translactonization, respectively.


Assuntos
4-Butirolactona/análogos & derivados , Furanos/química , Lactonas/síntese química , Lignanas/síntese química , 4-Butirolactona/síntese química , 4-Butirolactona/química , Catálise , Cromo/química , Lactonas/química , Lignanas/química , Estereoisomerismo , Zinco/química
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