title: Novel multi-targeting anthra[2,3-b]thiophene-5,10-diones with guanidine-containing side chains: interaction with telomeric G-quadruplex, inhibition of telomerase and topoisomerase I and cytotoxic properties.
abstract: Novel generations of antitumor anthraquinones are expected to be advantageous over the conventional chemotherapeutic agents. Previous structure-activity relationship studies demonstrated an importance of the positively charged side chains conjugated to anthra[2,3-b]thiophene-5,10-dione scaffolds. Exploring a role of individual side chain moieties in binding to the duplex and G-quadruplex DNA, modulation of telomerase and topoisomerase I activities, intracellular accumulation and cytostatic potency, we herein analyzed a series of reported and newly synthesized guanidine-containing derivatives of anthra[2,3-b]thiophene-5,10-dione. We found that the number of cationic side chains (namely, two) is critical for a tight interaction with human telomeric G-quadruplex (TelQ). Along with a larger drug-TelQ association constant, the telomerase attenuation by anthrathiophenediones with two basic groups in the side chains was more pronounced than by the analogs bearing one basic group. For mono-guanidinated compounds the substituent with the amino group in the side chain provided better TelQ affinity than the methylamine residue. The intracellular uptake of the mono-guanidino derivative with two side chains was >2-fold higher than the respective value for the bis(guanidino) derivative. This difference can explain a lower antiproliferative potency of bis(guanidine) containing compounds. Thus, the modifications of side chains of anthra[2,3-b]thiophene-5,10-dione differently modulated drug-target interactions and cellular effects. Nevertheless, the selected compound 11-(3-aminopropylamino)-4-(2-guanidinoethylamino)anthra[2,3-b]thiophene-5,10-dione 13 demonstrated a high affinity to TelQ and the ability to stabilize the quadruplex structure. These properties were paralleled by reasonable potency of 13 as a telomerase/topoisomerase I inhibitor and an antiproliferative agent. These results indicate that the structural elements of anthra[2,3-b]thiophene-5,10-dione derivatives can be balanced to yield a candidate for further preclinical study.
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia; Department of Biological and Medical Physics, Moscow Institute of Physics and Technology, 9 Institutskiy Per., Dolgoprudny 141700, Russia. Electronic address: ilinsky_nick@mail.ru.
authors.forename: Nikolay S
authors.initials: NS
authors.lastname: Ilyinsky
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Shchyolkina
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia.
authors.forename: Olga F
authors.initials: OF
authors.lastname: Borisova
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia.
authors.forename: Olga K
authors.initials: OK
authors.lastname: Mamaeva
authors.affiliation: Department of Chemistry, Lomonosov Moscow State University, GSP-1, 1-3 Leninskie Gory, Moscow 119991, Russia.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Zvereva
authors.affiliation: Department of Chemistry, Lomonosov Moscow State University, GSP-1, 1-3 Leninskie Gory, Moscow 119991, Russia; Skolkovo Institute of Science and Technology, 100 Novaya Street, Skolkovo 143025, Russia.
authors.forename: Dulat M
authors.initials: DM
authors.lastname: Azhibek
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia; Department of Biological and Medical Physics, Moscow Institute of Physics and Technology, 9 Institutskiy Per., Dolgoprudny 141700, Russia.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Livshits
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia.
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Mitkevich
authors.affiliation: Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Mendeleyev University of Chemical Technology, 9 Miusskaya Square, Moscow 125190, Russia.
authors.forename: Yuri B
authors.initials: YB
authors.lastname: Sinkevich
authors.affiliation: Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
authors.forename: Yuri N
authors.initials: YN
authors.lastname: Luzikov
authors.affiliation: Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
authors.forename: Lybov G
authors.initials: LG
authors.lastname: Dezhenkova
authors.affiliation: Blokhin Cancer Center, 24 Kashirskoye Shosse, Moscow 115478, Russia; Moscow Engineering and Physics Institute, 31 Kashirskoye Shosse, Moscow 115409, Russia.
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Kolotova
authors.affiliation: Blokhin Cancer Center, 24 Kashirskoye Shosse, Moscow 115478, Russia; Moscow Engineering and Physics Institute, 31 Kashirskoye Shosse, Moscow 115409, Russia.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Shtil
authors.affiliation: Mendeleyev University of Chemical Technology, 9 Miusskaya Square, Moscow 125190, Russia; Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
authors.forename: Andrey E
authors.initials: AE
authors.lastname: Shchekotikhin
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia.
authors.forename: Dmitry N
authors.initials: DN
authors.lastname: Kaluzhny
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D054856:G-Quadruplexes; D019791:Guanidine / Q000737:chemistry*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D019098:Telomerase / Q000037:antagonists & inhibitors*; D013876:Thiophenes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D013876:Thiophenes; D059004:Topoisomerase I Inhibitors; D019098:Telomerase; D019791:Guanidine
keywords: Anthra[2,3-b]thiophene-5,10-dione; Cytotoxicity; Small molecular weight inhibitors; Telomerase; Telomeric DNA G-quadruplex; Topoisomerase I