Various 2-arylideneindanones 1, 2-arylidenetetralones 2, and 2-arylidenebenzosuberones 3 were synthesized with the aim of determining the relative orientations of the two aryl rings which favored cytotoxicity. Molecular modeling of the unsubstituted compound in each series revealed differences in the spatial arrangements of the two aryl rings, and evaluation of these compounds against P388, L1210, Molt 4/C8, and CEM cells as well as a panel of human tumor cell lines indicated that in general the order of cytotoxicity was 3 > 2 > 1. In particular 2-(4methoxyphenylmethylene)-1-benzosuberone (3k) had the greatest cytotoxicity, possessing 11 times the potency of the reference drug melphalan when all five screens were considered. Series 3 was considered in further detail. First, excision of the aryl ring fused to the cycloheptanone moiety in series 3 led to some 2-arylidene-1-cycloheptanones 4 which had approximately onethird of the bioactivity of the analogues 3. Second, in some screens cytotoxicity was correlated negatively with the U values and positively with the MR constants of the substituents in the arylidene aryl ring of 3. Third, X-ray crystallography of five representative compounds (3i,kn) revealed differences in the locations of the aryl rings which may have contributed to the variations in cytotoxicity. Finally three members of series 3 inhibited RNA and protein syntheses and induced apoptosis in human Jurkat T cells. This study has revealed that 2-arylidene-1benzosuberones are a group of useful cytotoxic agents, and in particular 3k serves as a prototypic molecule for subsequent structural modifications.

Conformational and quantitative structure-activity relationship study of cytotoxic 2-arylidenebenzocycloalkanones.

A series of substituted pyridine and pyrimidine derivatives were synthesized as analgesic, anti convulsant, and antiparkinsonian agents by using compounds 1, 2, and 9 as starting materials. Pyr idino-imide derivative 3 was prepared by condensation of 1 with tetrachlorophthalic anhydride and compounds 4 and 5 were also obtained by reaction of compound 1 with 1,2,4,5-benzene-tetra carboxylic dianhydride and 1,4,5,8-naphthalenetetracarboxylic dianhydride, respectively. Similarly, compound 2 was reacted with previous anhydrides to afford the corresponding imide 6 and bis-imide derivatives 7 and 8, respectively. Bis-arylmethylene derivatives 9 were treated with hydrogen peroxide to afford the corresponding bis-oxiranocycloalkanone derivatives 10, which condensed with thiourea to give the corresponding thioxopyrimidine derivatives 11. Treatment of compound 11 with chloroacetic acid in the presence of anhydrous sodium acetate afforded the corresponding thiazolopyrim idine derivative 12 which condensed with aromatic aldehydes in acetic acid/acetic anhydride to give arylmethylene derivative 13. Also, compounds 13 could be prepared by reaction of compounds 11 with chloroacetic acid, aromatic aldehydes, and sodium acetate in a mixture of acetic acid and acetic anhydride. The pharmacological screening showed that many of these obtained compounds have good analgesic, anticonvulsant, and antiparkinsonian activities comparable to Valdecoxib, Carbamazepine, and Benzatropine as reference drugs.

Synthesis and reactions of some new substituted pyridine and pyrimidine derivatives as analgesic, anticonvulsant and antiparkinsonian agents

An ‘aldol’ reaction is the reaction of one carbonyl compound, acting as a nucleophile in the form of its enol or enolate derivative, with another, acting as an electrophile. The two carbonyl compounds may or may not be the same. The general reaction is subject to either acid or base catalysis. The initial product is a β-hydroxycarbonyl compound. Under some conditions, this primary product undergoes dehydration, resulting in an α,β-unsaturated carbonyl compound. In this chapter, we summarize the aldol reaction from a historical perspective and point out the limitations of the reaction as it was generally used prior to about 15 years ago.1 Succeeding chapters treat the aldol reaction as it is usually practiced today, in a ‘directed’ manner, using ‘preformed’ enolates.2 As will be seen in the sequel, an understanding of the factors regulating the stereochemistry of the aldol reaction has been largely responsible for the rebirth of this venerable reaction in the last 15 years.3

1.5 – The Aldol Reaction: Acid and General Base Catalysis

Quantitative investigations of E,Z-photoisomerization of chiral dopants (−)-2-arylidene-p-menthanones were carried out using solvents of different nature and various liquid crystalline matrices.

T.C. Mead

Papers

The stereochemistry of 2-benzalcyclohexanones and 2-benzalcyclopentanones☆

Stereoisomerism in 2-benzalcyclanones☆