Biodegradable polymers or oligopeptides, which are recognized by cell-surface receptors, have been shown to increase specificity and lower systemic toxicity of cytotoxic drugs. The goal of the present study was to evaluate biological properties of several bioconjugates based on tuftsin and its branched analogs combined with 1-nitro-acridines, through a series of different linkers, using the solid phase chemistry. Tuftsin is a natural TKPR tetrapeptide, that has a wide spectrum of biological activities, including stimulation of immune response, phagocytosis, and growth inhibitory activity against bacteria, fungi and tumor cells.

We determined cytotoxic activity and biological effects induced by studied conjugates in two human in vitro tumor models, lung adenocarcinoma A549 and myeloblastic leukemia HL-60. We observed very divergent effects induced by studied tuftsin-acridine conjugates in tumor cells. Two studied conjugates showed comparable cytotoxicity  toward both tumor cell types (compounds M8 and M9) or did not produce any cytotoxic effect  (compounds M2 and M5). However, conjugate M39 was about 6-fold more cytotoxic toward A549 cells than its corresponding precursor 1-nitroacridine, compound P6. Interestingly, close structural analog of M39, conjugate M29, that differs in only one methylene group in the linker, was about 4-fold less cytotoxic than its acridine precursor, compound P5. We also followed changes in the progression through the cell cycle induced by studied compounds. Exposure of tumor cells to both conjugates and their acridine procursors led to growth arrest in early S and G2/M phases. At longer incubation times, increased fractions of cells undergoing mitotic catastrophe and apoptosis were observed. None of the studied tuftsin-acridine conjugates and their parent acridine precursors showed any effect on DNA topoisomerase I and II activity in vitro.

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