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Antitumor activity of bis-indole derivatives.

ABSTRACT: This paper reports the synthesis of compounds formed by two indole systems separated by a heterocycle (pyridine or piperazine). As a primary screening, the new compounds were submitted to the National Cancer Institute for evaluation of antitumor activity in the human cell line screen. The pyridine derivatives were far more active than the piperazine derivatives. For the study of the mechanism of action, the most active compounds were subjected to COMPARE analysis and to further biological tests including proteasome inhibition and inhibition of plasma membrane electron transport. The compound bearing the 5-methoxy-2-indolinone moiety was subjected to the first in vivo experiment (hollow fiber assay) and was active. It was therefore selected for the second in vivo experiment (human tumor xenograft in mice). In conclusion we demonstrated that this approach was successful, since some of the compounds described are much more active than the numerous, so far prepared and tested 3-indolylmethylene-2-indolinones.

SUBMITTER: Andreani A

PROVIDER: S-EPMC2754042 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Antitumor activity of bis-indole derivatives.

Andreani Aldo A Burnelli Silvia S Granaiola Massimiliano M Leoni Alberto A Locatelli Alessandra A Morigi Rita R Rambaldi Mirella M Varoli Lucilla L Landi Laura L Prata Cecilia C Berridge Michael V MV Grasso Carole C Fiebig Heinz-Herbert HH Kelter Gerhard G Burger Angelika M AM Kunkel Mark W MW

Journal of medicinal chemistry 20080704 15

This paper reports the synthesis of compounds formed by two indole systems separated by a heterocycle (pyridine or piperazine). As a primary screening, the new compounds were submitted to the National Cancer Institute for evaluation of antitumor activity in the human cell line screen. The pyridine derivatives were far more active than the piperazine derivatives. For the study of the mechanism of action, the most active compounds were subjected to COMPARE analysis and to further biological tests ...[more]

PMID: 18598018

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Project description:Background:In search of effective antimicrobial and cytotoxic agents, a series of indole hybridized diazenyl derivatives (DS-1 to DS-21) was efficiently prepared by condensation of diazotized p-aminoacetophenone with indole or nitroindole followed by reaction with different aromatic/heteroaromatic amines of biological significance. The synthesized derivatives were characterized by various spectroscopic techniques. Methodology:The antimicrobial evaluation of DS-1 to DS-23 was done by tube dilution method against various pathogenic bacterial and fungal strains. The active antimicrobial derivatives were further evaluated for cytotoxicity against human lung carcinoma cell line (HCT-116), breast cancer cell line (MDAMB231), leukemic cancer cell line (K562), and normal cell line (HEK293) by MTT assay using doxorubicin as the standard drug. The test derivatives were additionally docked for the B-subunit of enzyme DNA gyrase from E. coli at the ATPase binding site to study the molecular interactions using Schrodinger maestro v11.5 software. Results and discussion:Most of the synthesized derivatives have shown high activity against Gram-negative bacteria particularly E. coli and K. pneumonia with MIC ranging from 1.95 to 7.81 ?g/ml. The derivatives have demonstrated very less activity against tested Gram positive bacterial and fungal strains. The derivatives DS-14 and DS-20 have been found to active against breast cancer cell line and human colon carcinoma cell line having IC50 in the range of 19-65 µg/ml. All the derivatives were found to less potent against leukemic cancer cell line. The synthesized derivatives have revealed their safety by exhibiting very less cytotoxicity against the normal cell line (HEK-293) with IC50?>?100 µg/ml. Most of the active derivatives have shown good docking scores in comparison to the standard drugs against DNA gyrase from E. coli. Further ADME predictions by Qikprop module of the Schrodinger confirmed these molecules have drug like properties. Conclusion:The derivatives DS-14 and DS-20 have shown potential against Gram-negative bacteria and breast cancer cell line and can be used as a lead for rational drug designing of the antimicrobial and cytotoxic agents..

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Antitumor activity of bis-indole derivatives.

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Antitumor activity of bis-indole derivatives.

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