Maria Dolors Pujol

Synthesis, anti-inflammatory activity, and in vitro antitumor effect of a novel class of cyclooxygenase inhibitors: 4-(aryloyl)phenyl methyl sulfones.

Following our previous research on anti-inflammatory drugs (NSAIDs), we report on the design and synthesis of 4-(aryloyl)phenyl methyl sulfones. These substances were characterized for their capacity to inhibit cyclooxygenase (COX-1 and COX-2) isoenzymes. Molecular modeling studies showed that the methylsulfone group of these compounds was inserted deep in the pocket of the human COX-2 binding site, in an orientation that precludes hydrogen bonding with Arg120, Ser353, and Tyr355 through their oxygen atoms. The N-arylindole 33 was the most potent inhibitor of COX-2 and also the most selective (COX-1/COX-2 IC(50) ratio was 262). The indole derivative 33 was further tested in vivo for its anti-inflammatory activity in rats. This compound showed greater inhibitory activity than ibuprofen. Other compounds (20, 26, 9, and 30) showed strong activity against carrageenan-induced inflammation. The latter compounds showed a weak capacity to inhibit the proliferation of human cell lines K562, NCI-H460, and HT-29 in vitro.

Synthesis of isoquinolines and tetrahydroisoquinolines as potential antitumour agents

Abstract The isoquinoline 17 and the tetrahydroisoquinoline 16 were synthesized from 2,3-dihydro-1,4-benzodioxin (1) by different synthetic strategies. Preparation of arylethylamines and their cyclization in Bischler–Napieralski conditions have been studied. Another approach to isoquinolines was based on the amination of the ketone 13 followed by cyclization in acidic media. The route via the amide 15 was found to be more successful with respect to both yield and ease of reaction.

A convenient synthesis of pyrrolo[2,1-c][1,4] benzoxazines

Abstract The pyrrolo[2,1- c ][1,4]benzoxazine system was synthesized from 2-fluoroaniline involving an intramolecular nucleophilic displacement of the fluoride atom. The intermediate alcohols 7a and 10 were treated in basic media under strictly controlled conditions which led to the desired tricyclic structure. The unsubstituted alcohol 10 was more stable than the substituted one.

Antitumor agents. Synthesis and biological evaluation of new compounds related to podophyllotoxin, containing the 2,3-dihydro-1,4-benzodioxin system

New compounds with naphtho-fused systems were synthesized and evaluated as antitumor agents. The naphtho-fused systems 6 and 7, synthesized from the hydroxy-acetal, exhibit antitumor activity. The bis(phenylthio) derivatives were considered as possible precursors for lignan lactones (11). The hydroxy-naphthalen 6 showed a significant antineoplastic activity.

Cyclin-dependent kinases 4 and 6 control tumor progression and direct glucose oxidation in the pentose cycle.

Cyclin-dependent kinases CDK4 and CDK6 are essential for the control of the cell cycle through the G1 phase. Aberrant expression of CDK4 and CDK6 is a hallmark of cancer, which would suggest that CDK4 and CDK6 are attractive targets for cancer therapy. Herein, we report that calcein AM (the calcein acetoxymethyl-ester) is a potent specific inhibitor of CDK4 and CDK6 in HCT116 human colon adenocarcinoma cells, inhibiting retinoblastoma protein (pRb) phosphorylation and inducing cell cycle arrest in the G1 phase. The metabolic effects of calcein AM on HCT116 cells were also evaluated and the flux between the oxidative and non-oxidative branches of the pentose phosphate pathway was significantly altered. To elucidate whether these metabolic changes were due to the inhibition of CDK4 and CDK6, we also characterized the metabolic profile of a CDK4, CDK6 and CDK2 triple knockout of mouse embryonic fibroblasts. The results show that the metabolic profile associated with the depletion of CDK4, CDK6 and CDK2 coincides with the metabolic changes induced by calcein AM on HCT116 cells, thus confirming that the inhibition of CDK4 and CDK6 disrupts the balance between the oxidative and non-oxidative branches of the pentose phosphate pathway. Taken together, these results indicate that low doses of calcein can halt cell division and kill tumor cells. Thus, selective inhibition of CDK4 and CDK6 may be of greater pharmacological interest, since inhibitors of these kinases affect both cell cycle progression and the robust metabolic profile of tumors.

Synthesis and Biological Activity of New Class of Dioxygenated Anticancer Agents

This paper describes extensive research on the activity of more of 100 cytotoxic compounds containing an oxygenated ring in their structure and isolated from natural plants or prepared by semisynthesis or synthesis from available intermediates. Anticancer drugs have been classified according to the chemical structure of the natural products that are considered to lead the series. The origin and mechanism of action involved in each case have been considered. This new family of natural, semisynthetic and synthetic products includes compounds with interesting antitumor activity such as podophyllotoxin derivatives, NK-611 (15), TOP-53 (16), NPF (24) and Tafluposide (28); camptothecin analogs such as 45 with a considerable cytotoxicity against beta-cell chronic lymphocytic leukemia (CLL), and 52 (new piperazinyl-CPT analog). New dioxygenated ellipticine analogs showed more activity and stability than the natural pattern when the structure incorporated a lactone function instead of the pyridine ring. In the acridine series the new tetracyclic derivatives 75 and 76 containing ethylenedioxy groups at the 2- and 3-positions of the acridine system exhibited the same activity as m-AMSA in vivo against murine P-388 leukemia. Other isolated compounds containing a dioxygenated ring in their structure such as 100 and 101 showed antitumor activities related to kinase inhibition, and are attractive candidates for development of new synthetic antitumor agents.

Synthesis of New Compounds Containing the 2,3-dihydro-1, 4-dioxino[2,3-b]pyridine Heterocyclic System as a Substructure:

2,3-Dihydro-spiro[1,4]dioxino[2,3-b]pyridine-3,3′-pyrrolidine (8A) and 2,3-dihydro-spiro[1,4]dioxino[2,3-b]pyridine-3,4′-piperidine (9A) have been synthesized from 2-chloro-3-pyridinol. The corresponding 2,3′ (8B) and 2,4′ (9B) isomers were obtained via the Smiles rearrangement, while 9B was also selectively synthesized from 2-nitro-3-pyridinol. The separation of the isomers A and B under the sulfamide form was carried out by flash column chromatography. Subsequent transformations of the corresponding dioxinopyridine derivatives were described.

Synthesis of 6,7-ethylenedioxyquinoxalines and pyrido[2,3-b]pyrazines as intermediates in the preparation of antineoplastic agents

Abstract A convenient procedure for the synthesis of quinoxalines and pyridopyrazines has been developed from aryldiamines. The condensation of aminocarbamates such as 12 with ethyl 2,3-dibromopropionate provide the quinoxaline 14 directly, in a one-step operation. The methodology reported herein represents an alternative to condensation of o -phenylenediamines with α-dicarbonyl compounds for the quinoxalines formation. The same procedure was applied to the 2,3-diaminopyridine to obtain the corresponding pyridopyrazines.

B-Adrenergic antagonists: N-alkyl and N-amidoethyl (arylalkoxy)propanolamines related to propranolol☆

The synthesis and β-blocking activity of a new series of (arylalkoxy)propanolamines is described. These compounds are structural analogues of the aryloxypropanolamine β-blockers, in which different bridging moieties have been interposed between the aromatic ring and the ethereal oxygen atom. Although all compounds showed a considerable degree of β1- or β2-blockade, the (arylalkoxy) derivatives were 10–100 times less potent than the corresponding phenoxy-propanolamines, thus suggesting that a spreading of the charge in the ethereal oxygen atom could enhance binding to the β-adrenoceptor. Cardioselectivity in the new series seems to be associated with a low pKa value for the amine nitrogen. Thus, derivatives 5d, 6d, and 7d are potent β1-blockers with low β3-activity.Abstract The synthesis and β-blocking activity of a new series of (arylalkoxy)propanolamines is described. These compounds are structural analogues of the aryloxypropanolamine β-blockers, in which different bridging moieties have been interposed between the aromatic ring and the ethereal oxygen atom. Although all compounds showed a considerable degree of β1- or β2-blockade, the (arylalkoxy) derivatives were 10–100 times less potent than the corresponding phenoxy-propanolamines, thus suggesting that a spreading of the charge in the ethereal oxygen atom could enhance binding to the β-adrenoceptor. Cardioselectivity in the new series seems to be associated with a low pKa value for the amine nitrogen. Thus, derivatives 5d, 6d, and 7d are potent β1-blockers with low β3-activity.

Preparation of Diarylamines and Arylhydrazines Using Palladium Catalysts

Aryl halides and aryl triflates (triflate = trifluoromethanesulfonyl) are coupled with N-compounds to give the corresponding arylamines or arylhydrazines in the presence of a palladium catalyst, a suitable ligand, and a base. Catalyst systems consisting of palladium (II) and BINAP or triphenylphos phine are generally effective for the amination of a wide range of aryl halides and aryl triflates with anilines and hydrazines.