Novel amino substituted tetracyclic imidazo[4,5-b]pyridine derivatives: Design, synthesis, antiproliferative activity and DNA/RNA binding study

Lončar, Borka; Perin, Nataša; Mioč, Marija; Boček, Ida; Grgić, Lea; Kralj, Marijeta; Tomić, Sanja; Radić Stojković, Marijana; Hranjec, Marijana (2021) Novel amino substituted tetracyclic imidazo[4,5-b]pyridine derivatives: Design, synthesis, antiproliferative activity and DNA/RNA binding study. European journal of medicinal chemistry, 217 . ISSN 0223-5234

Preview

PDF - Accepted Version - article Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (1MB) | Preview

Abstract

A novel series of tetracyclic imidazo[4, 5- b]pyridine derivatives was designed and synthesized as potential antiproliferative agents. Their antiproliferative activity against human cancer cells was influenced by the introduction of chosen amino side chains on the different positions on the tetracyclic skeleton and particularly, by the position of N atom in the pyridine nuclei. Thus, the majority of compounds showed improved activity in comparison to standard drug etoposide. Several compounds showed pronounced cytostatic effect in the submicromolar range, especially on HCT116 and MCF-7 cancer cells. The obtained results have confirmed the significant impact of the position of N nitrogen in the pyridine ring on the enhancement of antiproliferative activity, especially for derivatives bearing amino side chains on position 2. Thus, regioisomers 6, 7 and 9 showed noticeable enhancement of activity in comparison to their counterparts 10, 11 and 13 with IC50 values in a nanomolar range of concentration (0.3–0.9 μM). Interactions with DNA (including G-quadruplex structure) and RNA were influenced by the position of amino side chains on the tetracyclic core of imidazo[4, 5-b]pyridine derivatives and the ligand charge. Moderate to high binding affinities (logKs = 5–7) obtained for selected imidazo[4, 5-b]pyridine derivatives suggest that DNA/RNA are potential cell targets.

Item Type:	Article
Uncontrolled Keywords:	amines ; imidazo[4 ; 5-b]pyridines ; antiproliferative activity ; DNA/RNA binding
Subjects:	NATURAL SCIENCES > Chemistry NATURAL SCIENCES > Chemistry > Analytic Chemistry NATURAL SCIENCES > Chemistry > Organic Chemistry NATURAL SCIENCES > Biology
Divisions:	Division of Molecular Medicine Division of Organic Chemistry and Biochemistry
Projects:	Project title Project leader Project code Project type Istraživanje antioksidativnog djelovanja benzazolskog skeleta u dizajnu novih antitumorskih agensa Hranjec, Marijana IP-2018-01-4379 HRZZ Molekularno prepoznavanje DNA:RNA hibridnih i višelančanih struktura u bioanalitičkim i in vitro sustavima Radić Stojković, Marijana IP-2018-01-4694 HRZZ
Depositing User:	Marijana Radić Stojković
Date Deposited:	07 Dec 2022 14:51
URI:	http://fulir.irb.hr/id/eprint/7654
DOI:	10.1016/j.ejmech.2021.113342

Actions (login required)

View Item