M. Solange D. Carvalho

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.

Fluorescence Studies on Potential Antitumoral Heteroaryl and Heteroannulated Indoles in Solution and in Lipid Membranes

Fluorescence properties of three potential antitumoral compounds, a 3-(dibenzothien-4-yl)indole 1, a phenylbenzothienoindole 2 and a 3-(dibenzofur-4-yl)indole 3, were studied in solution and in lipid aggregates of dipalmitoyl phosphatidylcholine (DPPC), dioleoyl phosphatidylethanolamine (DOPE) and egg yolk phosphatidylcholine (Egg-PC). The 3-(dibenzofur-4-yl)indole 3 exhibits the higher fluorescence quantum yields in all solvents studied (0.32 ≤ ΦF ≤ 0.51). All the compounds present a solvent sensitive emission, with significant red shifts in alcohols. The results point to an ICT character of the excited state, more pronounced for compound 1. Fluorescence (steady-state) anisotropy measurements of the compounds incorporated in lipid aggregates of DPPC, DOPE and Egg-PC indicate that the three compounds are deeply located in the lipid bilayer, feeling the difference between the rigid gel phase and fluid phases.

Fluorescence Studies on New Potential Antitumoral Benzothienopyran-1-ones in Solution and in Liposomes

Fluorescence properties of four new potential antitumoral compounds, 3-arylbenzothieno[2,3-c]pyran-1-ones, were studied in solution and in lipid membranes of dipalmitoyl phosphatidylcholine (DPPC), egg yolk phosphatidylcholine (Egg-PC) and dioctadecyldimethylammonium bromide (DODAB). The 3-(4-methoxyphenyl)benzothieno[2,3-c]pyran-1-one (1c) exhibits the higher fluorescence quantum yields in all solvents studied. All compounds present a solvent sensitive emission, with significant red shifts in polar solvents for the methoxylated compounds. The results point to an ICT character of the excited state, more pronounced for compound 1c. Fluorescence (steady-state) anisotropy measurements of the compounds incorporated in liposomes of DPPC, DODAB and Egg-PC indicate that all compounds have two different locations, one due to a deep penetration in the lipid membrane and another corresponding to a more hydrated environment. In general, the methoxylated compounds prefer hydrated environments inside the liposomes. The 3-(4-fluorophenyl)benzothieno[2,3-c]pyran-1-one (1a) clearly prefers a hydrated environment, with some molecules located at the outer part of the liposome interface. On the contrary, the preferential location of 3-(2-fluorophenyl)benzothieno[2,3-c]pyran-1-one (1b) is in the region of lipid hydrophobic tails. Compounds with a planar geometry (1a and 1c) have higher mobility in the lipid membranes when phase transition occurs.