Lewis Acid‐Catalyzed or Base‐Promoted Regioselective Cycloisomerization of N‐Imidoyl‐o‐alkynylanilines for Synthesis of N‐Imidoyl‐(1 H)‐indoles and 4‐Alkylidene‐3,4‐dihydroquinazolines

Product selectivity control for the synthesis of imidoylindoles and 4‐alkylidenedihydroquinazolines from N‐imidoyl‐o‐alkynylanilines via silver triflate‐catalyzed cycloisomerization or tetrabutylammonium fluoride‐promoted cyclization is described. The product selectivity depends mainly on the catalyst/promoter used, and on the substituents on the alkyne and amidine functions of the substrates.

     

Synthesis of Diverse Azolo[c]quinazolines by Palladium(II)‐ Catalyzed Aerobic Oxidative Insertion of Isocyanides

We report the palladium(II)‐catalyzed aerobic oxidative coupling of isocyanides with various (2‐aminophenyl)azoles using air as the stoichiometric oxidant. A diverse range of medicinally valuable azolo[c]quinazolines was obtained by this new approach.

     

Allene as an alternative functional group for drug design: effect of C--C multiple bonds conjugated with quinazolines on the inhibition of EGFR tyrosine kinase

A series of allenic quinazolines were synthesized as receptor tyrosine kinase inhibitors by using a simple protocol for palladium-catalyzed allene transformation. Among the compounds synthesized, two allenic 4-anilinoquinazolines selectively suppressed epidermal growth factor receptor (EGFR) tyrosine kinase activity in vitro. According to immunoblot analysis, the allenic quinazolines inhibited the EGF-mediated phosphorylation of EGFR and its downstream kinases in A431 cells. Furthermore, one of these allenic quinazolines decreased the proliferation of A431 cells through the induction of cell-cycle arrest and apoptosis.     

A Cooperative Catalytic System of Platinum/Iridium Alloyed Nanoclusters and a Dimeric Catechol Derivative: An Efficient Synthesis of Quinazolines Through a Sequential Aerobic Oxidative Process

A cooperative catalytic system of heterogeneous polymer‐supported bi‐metallic platinum/iridium (Pt/Ir) alloyed nanoclusters and 5,5′,6,6′‐tetrahydroxy‐3,3,3′,3′‐tetramethyl‐1,1′‐spiro‐bisindane (TTSBI) enabled the facile preparation of quinazoline derivatives with low catalyst loadings and broad substrate scope under mild aerobic oxidative conditions. The ability to perform the reaction in gram‐scale and under open‐air conditions highlights the synthetic application of this cooperative catalytic system.     

A 2,6-disubstituted 4-anilinoquinazoline derivative facilitates cardiomyogenesis of embryonic stem cells

Chemical approaches are widely used in directed differentiation of embryonic stem (ES) cells. In our search for novel lead compounds that could facilitate cardiomyogenesis of ES cells, we designed a two-step screening system based on P19 embryonic carcinoma and mouse ES cells. Application of this system to a quinazoline compound library including 2,3-disubstituted 8-arylamino-3H-imidazo[4,5-g]quinazolines and 2,6-disubstituted 4-anilinoquinazoline led us to the discovery of compound 62, which exhibits a stable cardiomyogenic effect on both P19 and mouse ES cells at a concentration of 0.1 μM. An EGFR inhibition assay and molecular docking studies confirmed 62 as a potent EGFR inhibitor with a tyrosine kinase IC(50) value of 101 nM. However, major differences in cardiomyogenic activity were observed between iressa and 62, indicating that other molecular events are also involved in compound 62-induced cardiomyogenesis of ES cells.     

Effects of the Tumor‐Vasculature‐Disrupting Agent Verubulin and Two Heteroaryl Analogues on Cancer Cells,Endothelial Cells,and Blood Vessels

Two analogues of the discontinued tumor vascular‐disrupting agent verubulin (Azixa®, MPC‐6827, 1 ) featuring benzo‐1,4‐dioxan‐6‐yl (compound 5 a ) and N‐methylindol‐5‐yl (compound 10 ) residues instead of the para‐anisyl group on the 4‐(methylamino)‐2‐methylquinazoline pharmacophore, were prepared and found to exceed the antitumor efficacy of the lead compound. They were antiproliferative with single‐digit nanomolar IC₅₀ values against a panel of nine tumor cell lines, while not affecting nonmalignant fibroblasts. Indole 10 surpassed verubulin in seven tumor cell lines including colon, breast, ovarian, and germ cell cancer cell lines. In line with docking studies indicating that compound 10 may bind the colchicine binding site of tubulin more tightly (E_bind=?9.8 kcal mol^?1) than verubulin (E_bind=?8.3 kcal mol^?1), 10 suppressed the formation of vessel‐like tubes in endothelial cells and destroyed the blood vessels in the chorioallantoic membrane of fertilized chicken eggs at nanomolar concentrations. When applied to nude mice bearing a highly vascularized 1411HP germ cell xenograft tumor, compound 10 displayed pronounced vascular‐disrupting effects that led to hemorrhages and extensive central necrosis in the tumor.     

Fluorine‐Containing 6,7‐Dialkoxybiaryl‐Based Inhibitors for Phosphodiesterase 10 A: Synthesis and in vitro Evaluation of Inhibitory Potency,Selectivity, and Metabolism

Based on the potent phosphodiesterase 10 A (PDE10A) inhibitor PQ‐10, we synthesized 32 derivatives to determine relationships between their molecular structure and binding properties. Their roles as potential positron emission tomography (PET) ligands were evaluated, as well as their inhibitory potency toward PDE10A and other PDEs, and their metabolic stability was determined in vitro. According to our findings, halo‐alkyl substituents at position 2 of the quinazoline moiety and/or halo‐alkyloxy substituents at positions 6 or 7 affect not only the compounds′ affinity, but also their selectivity toward PDE10A. As a result of substituting the methoxy group for a monofluoroethoxy or difluoroethoxy group at position 6 of the quinazoline ring, the selectivity for PDE10A over PDE3A increased. The same result was obtained by 6,7‐difluoride substitution on the quinoxaline moiety. Finally, fluorinated compounds (R)‐7‐(fluoromethoxy)‐6‐methoxy‐4‐(3‐(quinoxaline‐2‐yloxy)pyrrolidine‐1‐yl)quinazoline ( 16 a ), 19 a – d , (R)‐tert‐butyl‐3‐(6‐fluoroquinoxalin‐2‐yloxy)pyrrolidine‐1‐carboxylate ( 29 ), and 35 (IC₅₀ PDE10A 11–65 nM ) showed the highest inhibitory potential. Further, fluoroethoxy substitution at position 7 of the quinazoline ring improved metabolic stability over that of the lead structure PQ‐10.     

Chemical investigation of aggregation behavior ofTriatoma bugs (Hemiptera: Reduviidae)

Nymphs ofTriatoma infestans andTriatoma mazzottii are weakly attracted to their feces and to extracts of feces in polar solvents, but not to nonpolar solvent extracts. The major volatile compounds identified in feces by solvent extraction and thermal desorption wereo-aminoacetophenone, 4-methylquinazoline, and 2,4-dimethylquinazoline, but these showed no attractant activity at a range of concentrations. Choice tests with a moving current of air gave no positive reaction to feces, extracts, or pure compounds.     

IsoCombretaQuinazolines: Potent Cytotoxic Agents with Antitubulin Activity

A series of novel isocombretaquinazolines (isoCoQ) 4 were quickly prepared by coupling N‐toluenesulfonylhydrazones with 4‐chloroquinazolines under palladium catalysis. These compounds, which can be regarded as isocombretastatin A‐4 (isoCA‐4) analogues that lack the 3,4,5‐trimethoxyphenyl ring, displayed nanomolar‐level cytotoxicity against various human cancer cell lines and were observed to effectively inhibit tubulin polymerization. The isoCoQ compounds 2‐methoxy‐5‐(1‐(2‐methylquinazolin‐4‐yl)vinyl)phenol ( 4 b ), 4‐[1‐(3‐fluoro‐4‐methoxyphenyl)vinyl]‐2‐methylquinazoline ( 4 c ), and 2‐methoxy‐5‐(1‐(2‐methylquinazolin‐4‐yl)vinyl)aniline ( 4 d ), which respectively bear the greatest resemblance to isoCA‐4, isoFCA‐4, and isoNH₂CA‐4, are able to arrest HCT116 cancer cells in the G₂/M cell‐cycle phase at very low concentrations. Preliminary in vitro antivascular assay results show that 4 d is able to disrupt a network of capillary‐like structures formed by human umbilical vein endothelial cells on Matrigel. All these results clearly demonstrate that replacement of the 3,4,5‐trimethoxyphenyl ring of isoCA‐4 with a quinazoline nucleus is a feasible approach toward new and highly promising derivatives with the potential for further development as antitubulin agents.     

One‐Pot Synthesis of 2‐Arylquinazolines and Tetracyclic Isoindolo[1,2‐a]quinazolines via Cyanation Followed by Rearrangement of ortho‐Substituted 2‐Halo‐N‐arylbenzamides

The one‐pot synthesis of substituted 2‐arylquinazoline derivatives and tetracylic isoindolo[1,2‐a]quinazoline via cyanation followed by rearrangement of ortho‐substituted 2‐halo‐N‐arylbenzamides is described. Using dimethyl sulfoxide (DMSO) as the solvent, the cleavage of the tetracyclic isoindole fused quinazoline leads to the formation of 2‐arylquinazoline derivatives. When 1,4‐dioxane is used as the solvent, tetracyclic isoindole fused quinazolines are produced in good yield. A wide range of products, including 2‐phenylquinazolin‐4‐amine, 4‐methyl‐2‐phenylquinazoline and long‐chain 2‐phenyl‐4‐styrylquinazoline derivatives were produced in moderate to good yields using DMSO as the solvent. However, various tetracyclic isoindole fused quinazoline derivatives were obtained in good yields when 1,4‐dioxane was used as the solvent.