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

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 a...

Full description

Saved in:
Bibliographic Details
Published in:European journal of medicinal chemistry 2015-12, Vol.106, p.85-94
Main Authors: Januchta, Wioleta, Serocki, Marcin, Dzierzbicka, Krystyna, Cholewiński, Grzegorz, Skladanowski, Andrzej
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
BAT
Batracylin
Bioavailability
Cell Cycle - drug effects
Cell Line
Cell Proliferation - drug effects
Cell Survival - drug effects
Cytotoxic activity
DNA Damage
DNA Topoisomerases - metabolism
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HL-60 Cells
Humans
Mice
Molecular Structure
NIH 3T3 Cells
Quinazolines - chemistry
Quinazolines - pharmacology
Retro-tuftsin
Structure-Activity Relationship
Topoisomerase
Topoisomerase Inhibitors - chemical synthesis
Topoisomerase Inhibitors - chemistry
Topoisomerase Inhibitors - pharmacology
Tuftsin
Tuftsin - analogs & derivatives
Tuftsin - chemistry
Tuftsin - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. [Display omitted] •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.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2015.10.012