Synthesis, characterization, antitumor activity and safety testing of novel polyphosphoesters bearing anthracene-derived aminophosphonate units

I Kraicheva; E Vodenicharova; S Shenkov; E Tashev; T Tosheva; I Tsacheva; A Kril; M Topashka-Ancheva; A Georgieva; I Iliev; I Vladov; Ts Gerasimova; K Troev

doi:10.1016/j.bmc.2013.12.001

Synthesis, characterization, antitumor activity and safety testing of novel polyphosphoesters bearing anthracene-derived aminophosphonate units

Bioorg Med Chem. 2014 Jan 15;22(2):874-82. doi: 10.1016/j.bmc.2013.12.001. Epub 2013 Dec 8.

Authors

I Kraicheva¹, E Vodenicharova², S Shenkov³, E Tashev⁴, T Tosheva⁵, I Tsacheva⁶, A Kril⁷, M Topashka-Ancheva⁸, A Georgieva⁹, I Iliev¹⁰, I Vladov¹¹, Ts Gerasimova¹², K Troev¹³

Affiliations

¹ Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 103A, 1113 Sofia, Bulgaria. Electronic address: igkraicheva@gmail.com.
² Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 103A, 1113 Sofia, Bulgaria. Electronic address: elitcapetrova@abv.bg.
³ Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 103A, 1113 Sofia, Bulgaria. Electronic address: shenkov@polymer.bas.bg.
⁴ Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 103A, 1113 Sofia, Bulgaria. Electronic address: tashev@polymer.bas.bg.
⁵ Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 103A, 1113 Sofia, Bulgaria. Electronic address: ttosheva@polymer.bas.bg.
⁶ Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 103A, 1113 Sofia, Bulgaria. Electronic address: ivelina_772000@yahoo.com.
⁷ 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.
⁸ Institute of Biodiversity and Ecosystems Research, Bulgarian Academy of Sciences, 2 Gagarin Str., 1113 Sofia, Bulgaria. Electronic address: topashka.mn@lycos.com.
⁹ 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.
¹⁰ 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.
¹¹ 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.
¹² Institute of Biodiversity and Ecosystems Research, Bulgarian Academy of Sciences, 2 Gagarin Str., 1113 Sofia, Bulgaria. Electronic address: cvetij@yahoo.com.
¹³ Institute of Polymers, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 103A, 1113 Sofia, Bulgaria. Electronic address: ktroev@polymer.bas.bg.

PMID: 24365391
DOI: 10.1016/j.bmc.2013.12.001

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.

Keywords: Aminophosphonic acids; Antitumor activity; Cytotoxicity; Genotoxicity; NMR; Polyphosphoesters.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anthracenes / chemistry*
Antimitotic Agents / administration & dosage
Antimitotic Agents / chemical synthesis
Antimitotic Agents / pharmacology*
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
BALB 3T3 Cells
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Female
Hep G2 Cells
Humans
MCF-7 Cells
Male
Mice
Mice, Inbred BALB C
Mice, Inbred ICR
Mitosis / drug effects
Molecular Structure
Organophosphonates / administration & dosage
Organophosphonates / chemical synthesis
Organophosphonates / pharmacology*
Structure-Activity Relationship

Substances

Anthracenes
Antimitotic Agents
Antineoplastic Agents
Organophosphonates
anthracene