Interaction of derivatives of 7-amino-1,5-benzo-diazepin-2-ones with α,β-unsaturated ketones

Derivatives of new condensed heterosystems, the tetracyclic [1,4]diazepino[3,2,1-hi]pyrido-[4,3,2-cd]indoles and tricyclic [1,4]diazepino[2,3-g]- and -[2,3-f]quinolines have been synthesized by the interaction of 7-amino-4-phenyl(or methyl)-1,3,4,5-tetrahydro(or 1,3-dihydro)-2H-1,5-benzodiazepin- 2-ones with dimethyl 2-oxoglutaconate and methyl 4-oxo-2-pentenoate. The corresponding carboxylic acids of the new derivatives were synthesized by alkaline hydrolysis of the methyl esters. The direction of the cyclocondensation reaction was determined by both the structure of the diazepine ring of the initial amines and also by the structure of the α,β-unsaturated ketones. Quantum-chemical calculations have been carried out of the minimal values of the local energy of ionization and of the resonance stabilization energy on specific atoms of the initial amines.     

Theoretical studies on the methylsulfenyl chloride addition to propene

Thiiranium heterocycles play an important role in biocatalytic processes of cells. Usually formation of thiiranium ions is known to proceed by the electrophilic additions of sulfenylhalides to substituted olefins, subsequently undergoing the regioselective and stereoselective nucleophilic attack of the halide atom on either C‐1 or C‐2 carbon atom of the thiiranium intermediate to gave two isomeric adducts. The detailed sequence of the reaction mechanism, the nature of intermediates, and transition states that occur in this electrophilic addition reaction are not well understood. In our work, this reaction has been modeled using Ab initio methods at the MP2/6‐31+G(d,f) level of theory to look into the mechanism of the reaction and to explain how the regioselectivity of the reaction is controlled. We focused on the electrophilic addition reaction of the methylsulfenyl chloride to propene. Our calculations show that the reaction is predicted to proceed via two distinct directions. The first direction proceeds when the starting reacting molecules formed the cis‐methyl‐oriented thiiranium intermediate, and the second direction is when the starting reactants resulted in the trans‐methyl‐oriented thiiranium intermediate. The calculated reaction potential energy surface profile suggests that the minimum energy pathway via the first direction is energetically more preferred than that via trans one. Moreover, calculation of the intrinsic reaction coordinate on the minimum energy pathway revealed the stepwise mechanism for the addition reaction. Thus the energetically preferred first reaction direction consists of the addition of methylsulfenyl chloride to the double bond of propene undergoing synchronous concerted transition state leading to the thiiranium intermediate formation (the rate‐limiting step in the electrophilic addition reaction); regioselective thiiranium intermediate ring‐opening process by the chloride anion attack on the C‐2 carbon of the thiiranium intermediate forming 2‐chloro adduct of kinetically controlled addition reaction; the isomerization reaction of 2‐chloro adduct to more energetically favorable thermodynamically stable 1‐chloro product. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:1–13, 2010; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20571     

Functionalization of 2,3,4,5-Tetrahydro-1,5-benzodiazepin-2(1<Emphasis Type="Italic">H</Emphasis>)-ones by Electrophilic Aromatic Substitution

Summary. Highly substituted, novel, 8- and 9-nitro-2,3,4,5-tetrahydro-1,5-benzodiazepin-2(1H)-ones were obtained by direct nitration of the 7-bromo-5-trifluoroacetyl (or formyl)-substituted tetrahydrobenzodiazepinones. Alkaline and acidic hydrolysis of the novel mononitro derivatives was examined. Semiempirical AM1 calculations of aromatic substituents orientation in the nitration products are presented.     

mTHPC-mediated photodynamic treatment up-regulates the cytokines VEGF and IL-1alpha

Photodynamic therapy (PDT) of cancer induces oxidative stress, which intervenes in the expression of cytokines by tumor cells. The cytokines might have either a positive or a negative impact on tumor eradication. Here, we studied the expression of cytokines vascular endothelial growth factor (VEGF) and interleukin-1alpha (IL-1alpha) in the human epidermoid carcinoma A-431 cells following m-tetra(3-hydroxyphenyl)-chlorin (mTHPC)-mediated PDT in vitro and assessed the IL-1alpha effect on VEGF expression. Quantitative polymerase chain reaction and enzyme-linked immunosorbent assay revealed the enhanced production of VEGF and IL-1alpha both on mRNA and protein levels by mTHPC-loaded cells after light exposure. The silencing of IL1A by small interfering RNA resulted in decreased production of IL-1alpha and a reduced amount of VEGF. Furthermore, exogenous recombinant IL-1alpha stimulated the VEGF expression after PDT. Thus, in addition to the cytotoxic action on the A-431 cells, mTHPC-mediated PDT stimulated the production of VEGF and IL-1alpha, and IL-1alpha contributed to the VEGF overexpression. These data establish IL-1alpha as a possible target of combined cancer treatment.     

Quantum chemical estimation of reactivity of 2,3,4,5-tetrahydro-1,5-benzodiazepin-2(1H)-ones in electrophilic aromatic substitution

DFT B3LYP calculation study was employed to estimate the regioselectivity of an electrophilic aromatic substitution in functionalized 2,3,4,5-tetrahydro-1,5-benzodiazepin-2(1H)-ones. Charge density, frontier molecular orbital study, energetics of σ-complex intermediates of electrophilic substitution reactions in the 2,3,4,5-tetrahydro-1,5-benzodiazepin-2(1H)-ones yield information on different reactivity of aromatic sites. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:263–270, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20015