title: Synthesis, characterization, antitumor activity and safety testing of novel polyphosphoesters bearing anthracene-derived aminophosphonate units.
abstract: Novel polyphosphoesters containing anthracene-derived aminophosphonate units, poly(oxyethylene aminophosphonate)s (4 and 5) and poly[oxyethylene(aminophosphonate-co-H-phosphonate)]s (6 and 7), were synthesized via an addition of poly(oxyethylene H-phosphonate)s to 9-anthrylidene-p-toluidine. The IR, NMR ((1)H, (13)C and (31)P) and fluorescence emission spectral data of the polymers are presented. The copolymers 6 and 7 were tested for in vitro antitumor activity on a panel of seven human epithelial cancer cell lines. Safety testing was performed both in vitro (3T3 NRU test) and in vivo on ICR mice for genotoxicity and antiproliferative activity. The copolymer 7 showed excellent antiproliferative activity to HBL-100, MDA-MB-231, MCF-7 and HepG2 cell lines. However, the in vitro safety testing revealed significant toxicity to Balb/c 3T3 mouse embryo cells. In contrast, the copolymer 6 showed complete absence of cytotoxicity to Balb/c 3T3 cells, but inhibited the growth of breast cancer cells, cervical carcinoma cells (HeLa) and hepatocellular carcinoma cell cultures after prolonged (72h) exposure. The polymers (4-6) exhibited low (4 and 6) to moderate (5) clastogenicity in vivo and slightly inhibited bone marrow cell division, compared to Mitomycin C. The subcellular distribution of the copolymers 6 and 7 were studied in model cell culture systems. The tested polyphosphoesters are expected to act in vivo as prodrugs of aminophosphonates and could be valuable as a new class of biodegradable polymer drug carriers.
authors.affiliation: Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 103A, 1113 Sofia, Bulgaria. Electronic address: igkraicheva@gmail.com.
authors.forename: I
authors.initials: I
authors.lastname: Kraicheva
authors.affiliation: Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 103A, 1113 Sofia, Bulgaria. Electronic address: elitcapetrova@abv.bg.
authors.forename: E
authors.initials: E
authors.lastname: Vodenicharova
authors.affiliation: Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 103A, 1113 Sofia, Bulgaria. Electronic address: shenkov@polymer.bas.bg.
authors.forename: S
authors.initials: S
authors.lastname: Shenkov
authors.affiliation: Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 103A, 1113 Sofia, Bulgaria. Electronic address: tashev@polymer.bas.bg.
authors.forename: E
authors.initials: E
authors.lastname: Tashev
authors.affiliation: Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 103A, 1113 Sofia, Bulgaria. Electronic address: ttosheva@polymer.bas.bg.
authors.forename: T
authors.initials: T
authors.lastname: Tosheva
authors.affiliation: Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 103A, 1113 Sofia, Bulgaria. Electronic address: ivelina_772000@yahoo.com.
authors.forename: I
authors.initials: I
authors.lastname: Tsacheva
authors.affiliation: Institute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 25, 1113 Sofia, Bulgaria. Electronic address: antonkrill@yahoo.com.
authors.forename: A
authors.initials: A
authors.lastname: Kril
authors.affiliation: Institute of Biodiversity and Ecosystems Research, Bulgarian Academy of Sciences, 2 Gagarin Str., 1113 Sofia, Bulgaria. Electronic address: topashka.mn@lycos.com.
authors.forename: M
authors.initials: M
authors.lastname: Topashka-Ancheva
authors.affiliation: Institute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 25, 1113 Sofia, Bulgaria. Electronic address: any@abv.bg.
authors.forename: A
authors.initials: A
authors.lastname: Georgieva
authors.affiliation: Institute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 25, 1113 Sofia, Bulgaria. Electronic address: taparsky@abv.bg.
authors.forename: I
authors.initials: I
authors.lastname: Iliev
authors.affiliation: Institute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 25, 1113 Sofia, Bulgaria. Electronic address: iepparasit@yahoo.com.
authors.forename: I
authors.initials: I
authors.lastname: Vladov
authors.affiliation: Institute of Biodiversity and Ecosystems Research, Bulgarian Academy of Sciences, 2 Gagarin Str., 1113 Sofia, Bulgaria. Electronic address: cvetij@yahoo.com.
authors.forename: Ts
authors.initials: Ts
authors.lastname: Gerasimova
authors.affiliation: Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 103A, 1113 Sofia, Bulgaria. Electronic address: ktroev@polymer.bas.bg.
authors.forename: K
authors.initials: K
authors.lastname: Troev
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000737:chemistry*; D050256:Antimitotic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D041702:BALB 3T3 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008938:Mitosis / Q000187:drug effects; D015394:Molecular Structure; D063065:Organophosphonates / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000873:Anthracenes; D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D063065:Organophosphonates; C034020:anthracene
keywords: Aminophosphonic acids; Antitumor activity; Cytotoxicity; Genotoxicity; NMR; Polyphosphoesters