Ashraf A. Aly

New cycloaddition reactions of some ethenyl and ethinyl[2.2]paracyclophanes with some dienophiles

Abstract 4-Ethenyl[2.2]paracyclophane ( 1 ), 4,12-, ( 13 ), 4,15-, ( 16 ) and 4,16-diethenyl[2.2]paracyclophane ( 18 ) as well as, 4-ethinyl-[2.2]paracyclophane ( 20 ) undergo[2+2]cycloaddition reactions with tetracyanoethylene (TCNE). These reactions involve the formation of a charge-transfer complex as an initial step. With 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), bromanil (BRL) as well as 4-phenyl-1,2,4-triazoline-3,5-dione and 4-ethenyl[2.2]paracyclophane ( 1 ) as the diene, [2+4]cycloadditions took place. The reaction between 4,12-, ( 13 ), 4,15-, ( 16 ) and 4,16-, diethenyl[2.2]paracyclophane ( 18 ) and TCNE are influenced by the transannular electronic interactions.

REACTIONS OF BENZIMIDAZOLYL-ACETONITRILE AND METHANETHIOL WITH ELECTRON DEFICIENT COMPOUNDS

Addition of l//-benzimidazole-2-acetonitrile I and benziimidazole-2-ylmethanethiol 2 to some π-acceptors such as tetracyanoethylene (TCNE), £-chloranil (CHL-g). o-chloranil (CHL-o), 2,3-dichloro-5.6-dicyano-l,4-benzoquinone (DDQ). 2,3dichloroand 2.3-dicvano-1,4-naphthoquinones (DCHNQ and DCNQ) and dicynomethyleneindane-1.3-dione (CNIND) gave pyrido-, indolo-, naphthoquinopyrrolo-, thiazino-. naphthoquinothiazino[1.2-o]benzimidazole as well as pyridazino[l,2ojdibenzimidazole derivatives.

NOVEL HETEROCYCLES FROM CREATININE

Creatinine 1 interacts with some π-deficient compounds such as tetracvanoethylene. 2.3dichioro-5.6-dicyano-1.4-benzoquinone. 2.3.5.6-tetrachloro-l .4-benzoquinone. 2.3-dichloro-l .4naphthoquinone and 2.3-dicyano-1.4-naphthoquinone to give imidazolidinone. imidazolinyl-azomethine. furobisimidazolidine. naphthoimidazoimidazolidine and benzobisimidazoimidazo-lidines derivatives.

Chapter Five - Heterocycles from the Reaction of Thione Groups with Acetylenic Bonds

Abstract This chapter discusses reactions between the thione and alkyne functional groups, subdivided into internal (intramolecular) and external (intermolecular) reactions. Many such reactions are intramolecular; surprisingly, few involve addition of thione groups to benzyne. Selectivity of additions varies from one substrate to another, and is affected by solvent polarity. The synthesized heterocycles range from four- to eight-membered ring systems with one to three heteroatoms.

Reaction of amidrazones with 2,3-diphenylcyclopropenone: Synthesis of 3-(aryl)-2,5,6-triphenylpyrimidin-4(3 H )-ones

Amidrazones react with 2,3-diphenylcyclopropenone to give 3-aryl-2,5,6-triphenylpyrimidin-4(3H)-one derivatives in good yields. The synthesised compounds were characterised by spectroscopic tools and their structures confirmed by X-ray crystallography. A rational mechanism of formation of the products is presented.

Design, Synthesis and Biological Evaluation of Fused naphthofuro[3,2-c] quinoline-6,7,12-triones and pyrano[3,2-c]quinoline6,7,8,13-tetraones derivatives as ERK inhibitors with Efficacy in BRAF-mutant Melanoma

Approximately 60% of human cancers exhibit enhanced activity of ERK1 and ERK2, reflecting their multiple roles in tumor initiation and progression. Acquired drug resistance, especially mechanisms associated with the reactivation of the MAPK (RAF/MEK/ERK) pathway represent a major challenge to current treatments of melanoma and several other cancers. Recently, targeting ERK has evolved as a potentially attractive strategy to overcome this resistance. Herein, we report the design and synthesis of novel series of fused naphthofuro[3,2-c]quinoline-6,7,12-triones 3a-f and pyrano[3,2-c]quinoline-6,7,8,13-tetraones 5a,b and 6, as potential ERK inhibitors. New inhibitors were synthesized and identified by different spectroscopic techniques and X-ray crystallography. They were evaluated for their ability to inhibit ERK1/2 in an in vitro radioactive kinase assay. 3b and 6 inhibited ERK1 with IC50s of 0.5 and 0.19 µM, and inhibited ERK2 with IC50s of 0.6 and 0.16 µM respectively. Kinetic mechanism studies revealed that the inhibitors are ATP-competitive inhibitors where 6 inhibited ERK2 with a Ki of 0.09 µM. Six of the new inhibitors were tested for their in vitro anticancer activity against the NCI-60 panel of tumor cell lines. Compound 3b and 6 were the most potent against most of the human tumor cell lines tested. Moreover, 3b and 6 inhibited the proliferation of the BRAF mutant A375 melanoma cells with IC50s of 3.7 and 0.13 µM, respectively. In addition, they suppressed anchorage-dependent colony formation. Treatment of the A375 cell line with 3b and 6 inhibited the phosphorylation of ERK substrates p-90RSK and ELK-1 and induced apoptosis in a dose dependent manner. Finally, a molecular docking study showed the potential binding mode of 3b and 6 within the ATP catalytic binding site of ERK2.

Syntheses of New Pyridoxazines, Benzoxa(thia)azines, and Benzoxa(thia)azepines via Cyclocondensation and Elimination Reactions between Donors and Acceptors

Reaction of 3-amino-2-hydroxypyridine and 2-amino(thio)phenols with various selected π-acceptors are herein reported. Different modes of cyclization via elimination and/or condensation reactions were observed during the reaction of the donors with 3,4,5,6-tetrachloro-1,2-benzoquinone (CHLo), 2,3,5,6-tetrachloro-1,4-benzoquinone (CHL-p), 2,3-dicyano-1,4-naphthoquinone (DCNQ) and 2- dicyanomethyleneindane-1,3-dione (CNIND). A series of pyridoxazines, benzoxa(thia)azines, benzoxa( thia)azepines has been synthesized in good yields.