Paula M. T. Ferreira

Nanoliposomes for encapsulation and delivery of the potential antitumoral methyl 6-methoxy-3-(4-methoxyphenyl)-1H

A potential antitumoral fluorescent indole derivative, methyl 6-methoxy-3-(4-methoxyphenyl)-1H-indole-2-carboxylate, was evaluated for the in vitro cell growth inhibition on three human tumor cell lines, MCF-7 (breast adenocarcinoma), A375-C5 (melanoma), and NCI-H460 (non-small cell lung cancer), after a continuous exposure of 48 h, exhibiting very low GI50 values for all the cell lines tested (0.25 to 0.33 μM). This compound was encapsulated in different nanosized liposome formulations, containing egg lecithin (Egg-PC), dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylglycerol (DPPG), DSPC, cholesterol, dihexadecyl phosphate, and DSPE-PEG. Dynamic light scattering measurements showed that nanoliposomes with the encapsulated compound are generally monodisperse and with hydrodynamic diameters lower than 120 nm, good stability and zeta potential values lower than -18 mV. Dialysis experiments allowed to monitor compound diffusion through the lipid membrane, from DPPC/DPPG donor liposomes to NBD-labelled lipid/DPPC/DPPG acceptor liposomes.

Synthesis of new heteroaryl and heteroannulated indoles from dehydrophenylalanines: Antitumor evaluation

A 3-(dibenzothien-4-yl)indole and a phenylbenzothienoindole or a 3-(dibenzofur-4-yl)indole and a phenylbenzofuroindole were prepared by a metal-assisted C-N intramolecular cyclization of the methyl esters of N-Boc-(E) or (Z)-beta-dibenzothien-4-yl or beta-dibenzofur-4-yl dehydrophenylalanines. The latter were obtained by Suzuki cross-coupling of the methyl esters of N-Boc-(E) or (Z)-beta-bromodehydrophenylalanines with dibenzothien-4-yl or dibenzofur-4-yl boronic acids, in high yields. The intramolecular cyclization from E or Z pure Suzuki-coupling products gave the corresponding heteroaryl and heteroannulated indoles, in different ratios, by either direct cyclization or cyclization after isomerisation. Three of the cyclized compounds, the two heteroarylindoles and the phenylbenzothienoindole, were evaluated for their capacity to inhibit the in vitro growth of three human tumor cell lines, MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), and SF-268 (CNS cancer). The methyl 3-(dibenzothien-4-yl)indole-2-carboxylate was the most potent compound with GI(50) values ranging from 11 to 17microM.

Gold nanoparticles functionalised with stable, fast water exchanging Gd3+ chelates as high relaxivity contrast agents for MRI

Gold nanoparticles functionalized with Gd(3+) chelates displaying fast water exchange, superb pH stability and inertness towards transmetalation with Zn(2+) have been prepared and characterized as a new high relaxivity (29 mM(-1) s(-1), 30 MHz, 25 °C) contrast agent potentially safe for in vivo MRI applications. The Lipari-Szabo treatment for internal rotation was used to evaluate the effect of linker flexibility on the relaxivity of the gold nanoparticles. The effect of fast water exchange on the relaxivity of gold nanoparticles functionalized with Gd(3+) chelates is also addressed in this communication.

Efficient synthesis of dehydroamino acid derivatives

By using a DMAP catalysed reaction of β-hydroxyamino acid derivatives with tert-butylpyrocarbonate, the corresponding dehydroamino acid derivatives were obtained in high yields.

Synthesis and intramolecular cyclization of novel β, β-bis-(benzo[b]thienyl)dehydroalanine derivatives

Abstract The methyl ester of tert -butyloxycarbonyl-β,β-dibromodehydroalanine was obtained in a one-pot procedure from bis-( N - tert -butyloxycarbonyl)dehydroalanine. The former was reacted with several boronic benzo[ b ]thiophene acids under Suzuki cross coupling conditions, to give new β,β-bis-(benzo[ b ]thienyl)dehydroalanines in high yields. These compounds were cyclized to pyrrole derivatives by treatment with Pd(OAc) 2 and Cu(OAc) 2 in DMF.

Nanoliposomes for encapsulation and delivery of the potential antitumoral methyl 6-methoxy-3-(4-methoxyphenyl)-1H-indole-2-carboxylate

A potential antitumoral fluorescent indole derivative, methyl 6-methoxy-3-(4-methoxyphenyl)-1H-indole-2-carboxylate, was evaluated for the in vitro cell growth inhibition on three human tumor cell lines, MCF-7 (breast adenocarcinoma), A375-C5 (melanoma), and NCI-H460 (non-small cell lung cancer), after a continuous exposure of 48 h, exhibiting very low GI50 values for all the cell lines tested (0.25 to 0.33 μM). This compound was encapsulated in different nanosized liposome formulations, containing egg lecithin (Egg-PC), dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylglycerol (DPPG), DSPC, cholesterol, dihexadecyl phosphate, and DSPE-PEG. Dynamic light scattering measurements showed that nanoliposomes with the encapsulated compound are generally monodisperse and with hydrodynamic diameters lower than 120 nm, good stability and zeta potential values lower than -18 mV. Dialysis experiments allowed to monitor compound diffusion through the lipid membrane, from DPPC/DPPG donor liposomes to NBD-labelled lipid/DPPC/DPPG acceptor liposomes.

Synthesis Using Suzuki Cross Couplings of Sulfur Analogues of Dehydrotryptophan with a Definite Stereochemistry

Sulfur analogues of dehydrotryptophan (5−7) were prepared in moderate to good yields (40−80%) by Suzuki cross coupling [Pd(PPh3)4, Na2CO3 or NaHCO3, DME/H2O, 90 °C] of several benzo[b]thiophene boronic acids with the methyl esters of N-tert-butyloxycarbonyl-β-bromodehydroalanine [Boc-ΔAla(β-Br)-OMe] or N-tert-butyloxycarbonyl-β-bromodehydroaminobutyric acid [Boc-ΔAbu(β-Br)-OMe]. The β-bromodehydroamino acid precursors 2 were, in turn, synthesized in high yields from the corresponding N,N-diacyldehydroamino acids 1 by treatment with trifluoroacetic acid (TFA) and N-bromosuccinimide (NBS) in two steps or in a one-pot procedure. Both procedures were stereoselective for the E-isomer of Boc-ΔAla(β-Br)-OMe. However, for Boc-ΔAbu(β-Br)-OMe, different ratios of E/Z isomers were obtained in each procedure. The stereoselectivity for the Z-isomer was increased greatly with the one-pot procedure. Pure isomers were used in the coupling reactions and the stereochemistry of the starting material was generally maintained. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

High yielding synthesis of heterocyclic β-substituted alanine derivatives

Heterocyclic β-substituted alanine derivatives such as β-(pyrazol-1-yl) and β-(1,2,4-triazol-1-yl)-alanine are synthesized in high yields by a Michael addition of heterocyclic nucleophiles to N,N-bis(tert-butyloxycarbonyl)-dehydroalanine methyl ester, using mild reaction conditions and simple work-up procedures.

Gallium labeled NOTA-based conjugates for peptide receptor-mediated medical imaging.

We report a straightforward and efficient synthetic strategy for the synthesis of three model glycine-arginine-glycine-aspartic acid-glycine (GRGDG) conjugates based on derivatives of NOTA and of their Ga(III) complexes targeted to the integrin α(ν)β(3) receptor. (71)Ga NMR spectroscopy showed that the Ga(III)-labeled conjugates are highly stable in aqueous solution. The (67)Ga-labeled conjugates proved to have high kinetic stability and showed a weak but specific binding to the receptors in a U87MG-glioblastoma cell line.

Synthesis of novel β-substituted α,β-dehydroamino acid derivatives

Abstract β-Substituted α,β-dehydroamino acids are synthesised in high yields by a Michael addition of heterocyclic nucleophiles to the methyl esters of N-tert -butyloxycarbonyl, N -(4-toluenesulfonyl)dehydroamino acids, followed by a base-induced elimination of the 4-toluenesulfonyl group with regeneration of the α,β-double bond.