Naphthalene diimide-polyamine hybrids as antiproliferative agents: Focus on the architecture of the polyamine chains.
Naphthalene diimides (NDIs) have been widely used as scaffold to design DNA-directed agents able to target peculiar DNA secondary arrangements endowed with relevant biochemical roles. Recently, we have reported disubstituted linear- and macrocyclic-NDIs that bind telomeric and non-telomeric G-quadruplex with high degree of affinity and selectivity. Herein, the synthesis, biological evaluation and molecular modelling studies of a series of asymmetrically substituted NDIs are reported. Among these, compound 9 emerges as the most interesting of the series being able to bind telomeric G-quadruplex (ΔTm = 29 °C at 2.5 μM), to inhibit the activity of DNA processing enzymes, such as topoisomerase II and TAQ-polymerase, and to exert antiproliferative effects in the NCI panel of cancer cell lines with GI50values in the micro-to nanomolar concentration range (i.e. SR cell line, GI50= 76 nM). Molecular mechanisms of cell death have been investigated and molecular modelling studies have been performed in order to shed light on the antiproliferative and DNA-recognition processes.
Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy. Electronic address: andrea.milelli3@unibo.it.
Andrea
A
Milelli
Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy.
Chiara
C
Marchetti
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy.
Maria Laura
ML
Greco
Dipartimento di Scienze della Salute, Università 'Magna Græcia' di Catanzaro, 88100 Catanzaro, Italy.
Federica
F
Moraca
Dipartimento di Scienze della Salute, Università 'Magna Græcia' di Catanzaro, 88100 Catanzaro, Italy.
Giosuè
G
Costa
Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy.
Eleonora
E
Turrini
Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy.
Elena
E
Catanzaro
Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy.
Nibal
N
Betari
Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy.
Cinzia
C
Calcabrini
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy.
Claudia
C
Sissi
Dipartimento di Scienze della Salute, Università 'Magna Græcia' di Catanzaro, 88100 Catanzaro, Italy.
Stefano
S
Alcaro
Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy.
Carmela
C
Fimognari
Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, 47921 Rimini, Italy.
Vincenzo
V
Tumiatti
Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy.
Anna
A
Minarini
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D004247:DNA / Q000737:chemistry; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D054856:G-Quadruplexes; D006801:Humans; D007094:Imides / Q000737:chemistry*; D019169:Jurkat Cells; D008958:Models, Molecular; D009281:Naphthalenes / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010618:Phenanthrolines / Q000494:pharmacology*; D011073:Polyamines / Q000737:chemistry*; D019914:Taq Polymerase / Q000037:antagonists & inhibitors
C000616873:2-(3-((4-aminobutyl )amino)propyl )-7-(3-((2-methoxybenzyl)amino)propyl)benzo(lmn)(3,8)phenanthroline-1,3,6,8(2H,7H)-tetraone; D000970:Antineoplastic Agents; D007094:Imides; D009281:Naphthalenes; D010618:Phenanthrolines; D011073:Polyamines; C542131:naphthalenediimide; D004247:DNA; D019914:Taq Polymerase; D004250:DNA Topoisomerases, Type II
Antiproliferative; DNA; Drug design; G-quadruplex; Naphthalene diimides; Telomeric DNA; Topoisomerase