Topoisomerase I-mediated DNA cleavage as a guide to the development of antitumor agents derived from the marine alkaloid lamellarin D: triester derivatives incorporating amino acid residues
| Autor: | José A Jiménez, Alfredo Pastor, Andrés Francesch, Ignacio Manzanares, Brigitte Baldeyrou, Cristina Mateo, Carmen Cuevas, Christian Bailly, William Laine, Dolores Garcı́a-Gravalos, Michael Facompré, Christelle Tardy |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Cell Survival
Stereochemistry Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Topoisomerase-I Inhibitor Cleavage (embryo) Heterocyclic Compounds 4 or More Rings Biochemistry Structure-Activity Relationship chemistry.chemical_compound Alkaloids Coumarins Cell Line Tumor Drug Discovery medicine Animals Humans Amino Acids Molecular Biology Alanine chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure biology Topoisomerase Organic Chemistry Esters DNA Isoquinolines Amino acid DNA Topoisomerases Type I chemistry Drug Design Lamellarin D biology.protein Molecular Medicine Drug Screening Assays Antitumor Topoisomerase I Inhibitors Camptothecin medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 12:1697-1712 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2004.01.020 |
| Popis: | The marine alkaloid lamellarin D (LAM-D) has been recently characterized as a potent poison of human topoisomerase I endowed with remarkable cytotoxic activities against tumor cells. We report here the first structure-activity relationship study in the LAM-D series. Two groups of triester compounds incorporating various substituents on the three phenolic OH at positions 8, 14 and 20 of 6H-[1]benzopyrano[4',3':4,5]pyrrolo[2,1-a]isoquinolin-6-one pentacyclic planar chromophore typical of the parent alkaloid were tested as topoisomerase I inhibitors. The non-amino compounds in group A showed no activity against topoisomerase I and were essentially non cytotoxic. In sharp contrast, compounds in group B incorporating amino acid residues strongly promoted DNA cleavage by human topoisomerase I. LAM-D derivatives tri-substituted with leucine, valine, proline, phenylalanine or alanine residues, or a related amino side chain, stabilize topoisomerase I-DNA complexes. The DNA cleavage sites detected at T downward arrow G or C downward arrow G dinucleotides with these molecules were identical to that of LAM-D but slightly different from those seen with camptothecin which stimulates topoisomerase I-mediated cleavage at T downward arrow G only. In the DNA relaxation and cleavage assays, the corresponding Boc-protected compounds and the analogues of the non-planar LAM-501 derivative lacking the 5-6 double bond in the quinoline B-ring showed no effect on topoisomerase I and were considerably less cytotoxic than the corresponding cationic compounds in the LAM-D series. The presence of positive charges on the molecules enhances DNA interaction but melting temperature studies indicate that DNA binding is not correlated with topoisomerase I inhibition or cytotoxicity. Cell growth inhibition by the 41 lamellarin derivatives was evaluated with a panel of tumor cells lines. With prostate (DU-145 and LN-CaP), ovarian (IGROV and IGROV-ET resistant to ecteinascidin-743) and colon (LoVo and LoVo-Dox cells resistant to doxorubicin) cancer cells (but not with HT29 colon carcinoma cells), the most cytotoxic compounds correspond to the most potent topoisomerase I poisons. The observed correlation between cytotoxicity and topoisomerase I inhibition strongly suggests that topoisomerase I-mediated DNA cleavage assays can be used as a guide to the development of superior analogues in this series. LAM-D is the lead compound of a new promising family of antitumor agents targeting topoisomerase I and the amino acid derivatives appear to be excellent candidates for a preclinical development. |
| Databáze: | OpenAIRE |
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