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New amino acid derivatives of 6H-indolo[2,3-b]quinolines

Katarzyna Sidoryk 1Łukasz S. Kaczmarek 1Wojciech J. Szczepek 1Joanna Wietrzyk 2Marta Świtalska 2Wanda Peczyńska-Czoch 3

1. Instytut Farmaceutyczny (PRI), Rydygiera 8, Warszawa 01-793, Poland
2. Polish Academy of Sciences, Institute of Immunology and Experimental Therapy (IITD), Rudolfa Weigla 12, Wrocław 53-114, Poland
3. Wrocław University of Technology, Department of Organic Chemistry, Wybrzeże Wyspiańskiego 27, Wrocław 50-370, Poland


Some of alkyl, dialkylaminoalkyl and saccharide derivatives of 6H-indolo[2,3-b]quinoline manifest a cytotoxic activity. A wider application of these compounds is limited because of their low water solubility.

Amino acids and peptides can be used as substituents to optimize drugs. These substituents increase selectivity and bioavailability of many substances. It is well known that anthracyclines, which have a very similar structure to indolo[2,3-b]quinolines, have been successfully conjugated with L-leucine. For example, doxorubicin (Dox) has been transformed into the pro-drug N-L-leucine-doxorubicin which shows more selective biological antitumoural activity than free doxorubicin. A usage of peptide substituents as vectors (e.g. somatostatin) has been also investigated. For example, peptides were used for transporting doxorubicin through a blood-brain barrier and a peptidic vector can exert an antiproliferative effect. Another strategy to selectively deliver oncostatic drugs was coupling two peptides with doxorubicin. One peptide containing an α-integrin-binding motif, the Arg-Gly-Asp (RGD), and the other one containing an Asn-Gly-Arg (NGR) motif, enhanced the efficacy of doxorubicin against human breast cancer and also reduced the toxicity.

Continuing the search of more active in vivo compounds we undertook the investigations of amino acid conjugates with 9-amino- and 2-amino-6H-indolo[2,3-b]quinolines. This paper presents the method of synthesis of amino acid derivatives of 9-amino- and 2-amino-6H-indolo[2,3-b]quinolines with selected amino acids such as glycine, L-alanine, L-leucine, L-serine, L-methionine, L-lysine, L-proline and L-histidine. Three classical methods of coupling: DCC/HOBt, mixed anhydrides, and TBTU, were first evaluated. Finally, TBTU method was selected as it gave best yield and short reaction time, and therefore was used in all coupling reactions.

R1 = Gly-, L-Leu-, L-Met-, L-Lys-, L-Pro-, L-His-
R2 = Gly-, L-Ala-, L-Leu-, L-Ser-, L-Met-, L-Lys-, L-Pro-, L-His-

New compounds were evaluated for their cytotoxicity against KB cell lines in vitro according to a routine procedure. The biological tests showed that amino acid derivatives of 6,11-dimethyl-6H-indolo[2,3-b]quinoline possess significantly enhanced biological activity in comparison with the original 6,11-dimethyl-6H-indolo[2,3-b]quinoline.


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Presentation: Poster at VI Multidyscyplinarna Konferencja Nauki o Leku, by Joanna Wietrzyk
See On-line Journal of VI Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2008-03-03 22:05
Revised:   2009-06-07 00:48