title: Synthesis of functionalized new conjugates of batracylin with tuftsin/retro-tuftsin derivatives and their biological evaluation.
abstract: 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.
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, Gdansk University of Technology, 11/12 G. Narutowicza Street, 80-233 Gdansk, Poland.
authors.forename: Wioleta
authors.initials: W
authors.lastname: Januchta
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, 11/12 G. Narutowicza Street, 80-233 Gdansk, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Serocki
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, Gdansk University of Technology, 11/12 G. Narutowicza Street, 80-233 Gdansk, Poland. Electronic address: krydzier@pg.gda.pl.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Dzierzbicka
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, Gdansk University of Technology, 11/12 G. Narutowicza Street, 80-233 Gdansk, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Cholewiński
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, 11/12 G. Narutowicza Street, 80-233 Gdansk, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Skladanowski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D026942:DNA Topoisomerases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059003:Topoisomerase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014405:Tuftsin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D059003:Topoisomerase Inhibitors; C057924:batracylin; D026942:DNA Topoisomerases; D014405:Tuftsin
keywords: BAT; Batracylin; Bioavailability; Cytotoxic activity; Retro-tuftsin; Topoisomerase; Tuftsin