Giampaolo Primofiore

Synthesis, in vitro antiproliferative activity and DNA-interaction of benzimidazoquinazoline derivatives as potential anti-tumor agents

The synthesis of benzimidazoquinazoline derivatives bearing different alkylamino side chains is reported. All new compounds tested by means of an in vitro assay exhibit antiproliferative activity toward human tumor cell lines. The cytotoxic effect depends on the type of side chain inserted in the planar nucleus and in some cases it is comparable to that of the well-known drug ellipticine. In order to understand the mechanism of action of these compounds, the interaction with DNA has been investigated. Linear flow dichroism measurements allowed us to verify the formation of a molecular complex with DNA and the corresponding geometry of interaction. Intrinsic binding constants have also been evaluated by performing fluorimetric titrations.

Synthesis, DNA binding and in vitro antiproliferative activity of purinoquinazoline, pyridopyrimidopurine and pyridopyrimidobenzimidazole derivatives as potential antitumor agents

Abstract In the search for new antitumor agents, 8,10-dimethylpurino[7,8-a]quinazoline-5,9, 11(6H,8H,10H)-triones 1 , 8,10-dimethylpyrido [2′,3′:4,5]pyrimido[1,2-f]purine-5,9,11 (6H,8H, 10H)-triones 2 , and 5,7-dihydro-5-oxopyrido[3′,2′:5,6]pyrimido[1,2-a]benzimidazoles 3 , a series of new planar heteropolycyclic compounds, were synthesized. The approach to understanding their structure-activity relationship involved a physico-chemical investigation of the binding process of these molecules to DNA, considered to be an important target for drug action, and an examination of their biological activity. Thermodynamic parameters of the DNA binding process, intrinsic binding constant and exclusion parameter were determined. The mode of interaction was additionally investigated by means of linear flow dichroism studies. Evaluation of the biological activity included cell growth inhibition in human tumoral cell lines and the ability to induce DNA cleavage in the presence of eukaryotic topoisomerase II. Only compounds of the purinoquinazoline series 1 , which are able to form a complex with DNA and to inhibit the topoisomerase II, show antiproliferative activity.

Indole amide derivatives: synthesis, structure–activity relationships and molecular modelling studies of a new series of histamine H1-receptor antagonists

A number of indole amide derivatives bearing a basic side chain, in which the indole ring replaces the isoster benzimidazole nucleus typical of some well-known antihistamines, were prepared and tested for their H1-antihistaminic activity. The 1-benzyl-3- indolecarboxamides 32-42 showed antihistaminic (H1) activity (pA2 6-8); the 3-indolylglyoxylylamides 7-16 and the 2-indolecarboxamides 48-56 showed little or no activity. Insertion of the basic side chain of the active 3-indolecarboxamide derivatives into a piperazine ring (compounds 57-59) led to a dramatic loss of activity. All the active compounds proved to be competitive antagonists, since the values of the regression slope were not statistically different from 1. The most active compounds, 32, 33, 38-41, were also tested both in vitro for their anticholinergic activity and in vivo for their ability to antagonize histamine-induced cutaneous vascular permeability in rats. The biological results and the structure-activity relationships of the novel compounds are discussed in the light of molecular modelling studies, taking the molecule of astemizole as a model, and referring to proposed H1-receptor pharmacophore models.

Dialkylaminoalkylindolonaphthyridines as potential antitumour agents: Synthesis, cytotoxicity and DNA binding properties

The synthesis of new planar derivatives characterised by the presence of an indolonaphthyridine nucleus, carrying a dimethylaminoethyl or a dimethylaminopropyl side chain is reported. The antiproliferative activity of the new products was tested by means of an in vitro assay on human tumour cell lines (HL-60 and HeLa). A number of compounds (1a-d, 1h) showed IC(50) values comparable to that obtained with the well-known drug ellipticine on the HL-60 cell line. The interaction with DNA was also investigated. Linear flow dichroism measurements allowed us to understand the interaction geometry. The thermodynamic parameters of the binding process, i.e. intrinsic binding constant and exclusion parameter, were determined by fluorimetric titration.

Reinvestigation of reductive butylation of aminophthalimides: new compounds with local anesthetic activity

A careful reinvestigation on reductive butylation of N-β-diethylaminoethyl aminophthalimides showed that this reaction yields the corresponding butylaminophthalimides together with the 1-hydroxy butylaminophthalimidines. The same reaction carried out on N-β-diethylaminoethyl aminophthalimides hydrochlorides gave the corresponding butylamino phthalimidines. The 1-hydroxy butylaminophthalimidines 5 and 6, tested for their local anesthetic properties, exhibited interesting activity comparable to that of Novesine, showing hence a potential therapeutic efficacy.

Synthesis of Purinobenzodiazepine and Purinobenzotriazocine derivatives, two new heterocyclic ring systems.

The preparation of two new heterocyclic ring systems, purinobenzodiazepine and purinobenzotriazocine derivatives by the condensation of 8-aminotheophylline or 8-hydrazinotheophylline with o-carboxybenzaldehyde or o-carboxyacetophenone is described.

N-(Indol-3-ylglyoxylyl) methionine derivatives: preparation and gastric anti-secretory activity

Abstract The authors describe the synthesis of several N -(indol-3-ylglyoxylyl)methionine derivatives. The target compounds were prepared starting from substituted indoleglyoxylyl chlorides and methionine ethyl ester. Some of them were tested for their gastric anti-secretory activity. Among these compounds, the N -(5-chloroindol-3-ylglyoxylyl)methionine Ve was the most active, being quite comparable to cimetidine.

N-(Indol-3-ylglyoxylyl)dopamine derivatives: preparation and anti-depressant activity

Abstract The synthesis of several N -(indol-3-ylglyoxylyl)dopamine derivatives is described. The target compounds were prepared starting from substituted indoleglyoxylyl chlorides and dopamine hydrochloride. An analogous compound derived from 2-aminobenzimidazole is reported. All the products were tested for their anti-depressant activity. The N -(5-chloroindol-3-ylglyoxylyl)dopamine 3c proved to be of particular interest and exhibited a good activity in all the tests performed.

Synthesis and local anesthetic activity of some n-beta-diethylaminoethylnaphthalimides.

Some N-beta-diethylaminoethylnaphthalimides substituted in the 3 or 3 and 4 positions with alkoxy or butylamino groups or with alkoxy and amino groups (III) have been synthesized by reaction of the appropriate naphthalic anhydride with N,N-diethylethylenediamine. Some compounds (III) were tested to evaluate their anesthetic activity: compounds (III e) and (III f) have been shown to have a greater activity than lidocaine.

Synthesis and antiinflammatory activity of some N-(5-substituted indole-3-ylglyoxyl)amine derivatives.

The synthesis of some amidic derivatives, obtained by condensation of various 5-substituted indoleglyoxylchlorides with physiologically important amines as tyramine, tryptamine and 5-aminouracil, is described. The preparation of one glycolyl derivative is also reported. Study of analgesic and antiinflammatory properties has shown only a feeble activity of these compounds.