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Bisinterkalatory jako potencjalne leki przeciwnowotworowe

Stańczak A., Szumilak M.

Wiadomości Chemiczne

2009

[Z] 63, 9-10

847-875

Intercalators constitute a group of compounds which interact reversibly with DNA double helix. The insertion of planar, polycyclic aromatic systems between adjacent base pairs leads to topological changes in the double helix (lengthening, unwinding) and disrupts replication, transcription and repair processes [1–4]. Some of the monointercalators e.g. doxorubicin are valuable drugs, but their clinical effectiveness is limited by their undesirable side effects, and development of multidrug resistance [12]. In order to overcome these limitations bisintercalators have been designed. Dimerization of monointercalating compounds was supposed to enhance their anticancer activity and minimize side effects [1,7]. Many research groups have been interested in designing various groups of bisintercalating agents of diverse chemical structure and biological properties, such as echinomycin antibiotics [5, 7–10], 7H-pyridocarbazole derivatives [19–21], bisanthracyclines [7, 12, 16], bisnaphthalimides [7, 22–37], bisacridines [38–48] and bisimidazoacridones [50–52]. There have been a number of modifications undertaken on polyaromatic rings, and linker chains in an attempt to improve the compounds’ activity. The structure-activity relationships have been suggested. It has been discovered that introduction of small lipophilic substituents or additional heterocycles into ring systems may lead to significant changes in binding affinity and cytotoxic activity of the compounds. It was discovered that many tumor types contained elevated polyamine levels and an active polyamine transporter for importing exogenous polyamines. Designing bisintercalators with aminoalkyl chains similar to polyamines has given a chance to improve selectivity in drug delivery to rapidly proliferating cells by utilizing the polyamine transporter. More extensive SAR studies revealed significant influence of length and rigidity of a linker binding two intercalating moieties on binding affinity and antiproliferative activity of bisintercalators. Intercalation and topoisomerases inhibition are not the only possible modes of action of the compounds. Some of them exert cytotoxic effect through induction of apoptosis e. g. bisnaphthalimidopropylspermidine (BNIPSpd, (29) Fig. 9) or disrupting repair process of DNA double helix (WMC -26, (55) Fig. 18). In this work we presented enormous chemical diversity of bisintercalators and depicted multiplicity of structural modification of dimeric molecules which may lead to enhanced cytotoxic activity becoming valuable anticancer drugs.

Antybiotyki antracyklinowe

Grynkiewicz G.

Przemysł Chemiczny

2002

T. 81, nr 5

294-299