Synthesis of functionalized new conjugates of batracylin with tuftsin/retro-tuftsin derivatives and their biological evaluation

• A series of batracylin conjugates with tuftsin/retro-tuftsin have been synthesized.
• The in vitro cytotoxic activity of the new conjugates and their precursors was evaluated using a series of human and murine tumor cells.
• BAT conjugates containing retro-tuftsin with leucine 5k or isoleucine 5l, were about 10-fold more cytotoxic toward two human tumor cell lines: HL-60 and A549.
• The high biological activity of the most active BAT conjugates may be a result of their greatly increased intracellular accumulation.

New batracylin conjugates with tuftsin/retro-tuftsin derivatives were designed and synthesized using T3P as a coupling agent. The conjugates possess an amide bond formed between the carboxyl group of heterocyclic molecule and the N-termini of the tuftsin/retro-tuftsin chain. The in vitro cytotoxic activity of the new analogues and their precursors was evaluated using a series of human and murine tumor cells. BAT conjugates containing retro-tuftsin with branched side aminoacid chain, in particular with leucine or isoleucine, were about 10-fold more cytotoxic toward two human tumor cell lines (lung adenocarcinoma (A549) and myeloblastic leukemia (HL-60)). These compounds showed about 10-fold increased cytotoxicity against the two types of tumor cells compared to parent BAT. We have not observed important differences in the mechanism of action between BAT and its cytotoxic tuftsin/retro-tuftsin conjugates. We propose that high biological activity of the most active BAT conjugates is a result of their greatly increased intracellular accumulation.

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