Elsevier

Inorganica Chimica Acta

Volume 436, 1 September 2015, Pages 69-81
Inorganica Chimica Acta

Phosphorus–nitrogen compounds: Part 31. Syntheses, structural and stereogenic properties, in vitro cytotoxic and antimicrobial activities, and DNA interactions of bicyclotetraphosphazenes containing bulky side group

https://doi.org/10.1016/j.ica.2015.07.027Get rights and content

Highlights

  • The partly and fully substituted spiro-ansa-spiro-cyclotetraphosphazenes were obtained.

  • The compounds were tested against A549 lung cancer and L929 fibroblast cell lines.

  • All of the phosphazenes were screened G(+) and G(−) bacteria and yeast strains.

  • Interactions between the conjugates and pBR322 plasmid DNA were scrutinized.

  • The crystallographic, stereogenic and spectral data of the compounds were presented.

Abstract

Hexachlorocyclotriphosphazene, N3P3Cl6, and octachlorocyclotetraphosphazene, N4P4Cl8, were reacted with K2N2O2 salt of symmetric tetradentate ligand to obtain spiro-bino-spiro [(sbs) (2)] and 2,6-spiro-ansa-spiro [(2,6-sas) (3)] phosphazenes, respectively. The sbs was obtained in a very poor yield, whereas, 2,6-sas was obtained in a moderate yield. The derivatives of 2,6-sas with mono- and diamines were synthesized. When the reactions were carried out, one equimolar amount of 2,6-sas with an excess pyrrolidine, piperidine, morpholine, 1,4-dioxa-8-azaspiro[4,5]decane (DASD), N-methylethane-1,2-diamine, N-ethylethane-1,2-diamine and N-methylpropane-1,3-diamine, along with the fully substituted 2,6-sas-cyclotetraphosphazene derivatives (4a, 4b and 5a7a), were prepared. However, the excess morpholine and DASD with 2,6-sas yielded the geminal bis- (4c and 4e) and tris- (4d and 4f) cyclotetraphosphazenes, respectively. The Cl replacement reaction of 2,6-sas with one equimolar amount of 7 led to the formation of partly substituted 2,6-sas (7b). The structures of the compounds were verified by elemental analyses, MS, FTIR, 1H, 13C{1H}, 31P NMR, HSQC, HMBC and X-ray crystallography (for 3 and 4a) techniques. All the 2,6-sas cyclotetraphosphazenes (except 3, 4a and 4b) have stereogenic P-atoms. All the compounds were screened for antibacterial and antifungal activities against bacteria and yeast strains. The interactions of the compounds with supercoiled plasmid pBR322 DNA were investigated. The evaluations for cytotoxic activity, and apoptotic and necrotic effects against A549 lung cancer and L929 fibroblast cell lines were introduced.

Graphical abstract

N4P4Cl8 was reacted with aminopodand to obtain 2,6-sas-phosphazene. The mono- and diamino-2,6-sas phosphazenes were prepared, and their characterizations were made. The interactions between the phosphazenes and pBR322 plasmid DNA, the evaluations for cytotoxic activity, and apoptotic and necrotic effects against A549 lung cancer and L929 fibroblast cell lines were studied.

  1. Download : Download full-size image

Introduction

Phosphazene derivatives are hybrid molecules with an essentially linear and/or cyclic backbone of alternating phosphorous nitrogen atoms with the same and/or different organic side groups bonded to each phosphorous atom [1]. The chlorocyclophosphazenes, N3P3Cl6 and N4P4Cl8, are the best-known starting compounds and as such they have been extensively studied in the field of phosphazene chemistry [2], [3]. Although a large number of N4P4Cl8 derivatives have been synthesized with mono- and difunctional ligands [4], [5], [6], discussions of the substitution reaction patterns with polyfunctional ligands are very limited in the literature [7], [8], [9]. Hexachlorocyclotriphosphazene, N3P3Cl6, and octachlorocyclotetraphosphazene, N4P4Cl8, with bidentate and/or polydentate amines can produce spiro, ansa, dispiro (2,4- and 2,6-), trispiro, tetraspiro, spiro-ansa (2,4- and 2,6-), spiro-ansa-spiro (sas), bino, spiro-bino, and di(spiro-bino) products depending on the reaction conditions [10], [11], [12]. Up to now, two kinds of 2,6-bicyclo tetraphosphazene derivatives were obtained from the reactions of N4P4Cl8 with mono-functional amines (Fig. 1a) [13] and multi- functional reagents (Fig. 1b) [8].

A wide range of side groups (R1 and R2, Fig. 1a) may be bonded to this skeleton, leading to products with a similarly diverse range of physical and chemical properties [14]. Previously, to our knowledge there were only two papers about 2,4-sas and 2,6-sas bicyclophosphazenes in the literature [8], [9]. As part of our ongoing study of the reactions of N4P4Cl8 with multidendate ligands, we have concentrated primarily on the substituent exchange reactions of N4P4Cl8 with potassium {2,2′-[1,3-phenylenebis(methyleneiminomethylene)]diphenoxide, K2N2O2, (1a)} with the aim of obtaining bicyclotetraphosphazene derivatives and also exploring their biological activity. As known, mono- and polyamino substituted cyclotriphosphazene derivatives (e.g., aziridine, spermine and spermidine) have attracted a great deal of attention for their potential as anti-cancer agents [15], [16]. They exhibited cytotoxic activity against HT-29 (human colon adenocarcinoma), Hep2 (Human epidermoid carcinoma of the larynx), and Vero (African green monkey kidney) cells and stimulated apoptosis [17]. In addition, the antimicrobial activity of cyclotri- and tetraphosphazene derivatives was investigated against various bacteria and fungi [18], [9]. On the other hand, studies on the biological activity of cyclotetraphosphazene derivatives are very limited. It is known that octapyrrolidinocyclotetraphosphazene demonstrates significant anticancer activity [15]. The Cu(II) complex of a fully phenoxy-substituted star-branched cyclotetraphosphazene is active in the oxidative cleavage of DNA [19].

The present study focuses on the Cl replacement reactions of N4P4Cl8 with N2O2 tetradentate ligand (1) (Scheme 1) with the aim of obtaining the new 2,6-sas-bicyclotetraphosphazene derivatives, and to investigate the in vitro cytotoxic activity and apoptosis and necrosis effects against A549 lung cancer and L929 fibroblast cell lines. The evaluation of antimicrobial activity and DNA interactions of all the compounds were also presented.

Section snippets

Materials and method

All reactions were monitored using thin-layer chromatography (TLC) on Merck DC Alufolien Kiesegel 60 B254 sheets. Column chromatography was performed on Merck Kiesegel 60 (230–400 mesh ATSM) silica gel. The reactions were run out under argon atmosphere. Melting points were assessed with a Gallenkamp apparatus using a capillary tube. The Fourier transform infrared (FTIR) spectra were recorded on a Jasco FT/IR-430 spectrometer in KBr discs and reported in cm−1 units. One-dimensional (1D) 1H, 13C

Synthesis

The reaction of N3P3Cl6 with an equimolar amount of K2N2O2 (1a) in THF and toluene gave only sbs (2) product in a poor yield. When the reaction was carried out in acetonitrile, no product was isolated. However, the reaction of N4P4Cl8 with an equimolar amount of 1a in THF produces the partly (2,6-dispiro-bicyclo) substituted 2,6-sas compound (3) with 35% yield. The yield of 3 in acetonitrile was 3%, but the same compound was not obtained in toluene. The other expected products e.g., 2,4-sas, 2,4

Conclusions

The Cl replacement reactions of N4P4Cl8 with the dipotassium salt, K2N2O2 (1a) of ligand (1) gave 2,6-sas-cyclotetraphosphazene (3) in THF. When the reactions were made one equimolar amount of 3 with an excess mono- and diamines, along with the fully substituted 2,6-sas cyclotetraphosphazenes (4a, 4b and 5a7a) were prepared. Although the excess morpholine and DASD were used in the reactions, the geminal bis- (4c and 4e) and tris- (4d and 4f) cyclotetraphosphazenes occurred. In addition, the

Acknowledgements

The authors thank the “Scientific and Technical Research Council of Turkey” (Grant No. 211T019), and Z.K. thanks Turkish Academy of Sciences (TÜBA) for partial support.

References (41)

  • H. Ibişoğlu et al.

    Inorg. Chim. Acta

    (2014)
  • G.Y. Çiftçi et al.

    Polyhedron

    (2014)
  • M. Yıldız et al.

    J. Mol. Struct.

    (1999)
  • V. Chandrasekhar et al.

    Adv. Inorg. Chem.

    (2002)
  • M. Işıklan et al.

    J. Mol. Struct.

    (2003)
  • J.O. Bovin et al.

    J. Mol. Struct.

    (1978)
  • T. Yıldırım et al.

    Eur. J. Med. Chem.

    (2012)
  • X. Zhu et al.

    Phosphorus, Sulfur Silicon Relat. Elem.

    (2011)
  • S.J. Coles et al.

    J. Organomet. Chem.

    (2007)
  • Y. Tümer et al.

    J. Mol. Struct.

    (2013)
  • A.A. Legin et al.

    J. Inorg. Biochem.

    (2014)
  • A. Okumuş et al.

    Polyhedron

    (2011)
  • S. Beşli et al.

    Inorg. Chem.

    (2015)
  • M. Gleria et al.

    Phosphazenes a Worldwide Insight

    (2004)
  • C.W. Allen

    Chem. Rev.

    (1991)
  • A. Kılıç et al.

    Phosphorus, Sulfur Silicon

    (1991)
  • H. Ibişoğlu et al.

    J. Chem. Sci.

    (2009)
  • G. Elmas (nee Egemen) et al.

    Inorg. Chem.

    (2012)
  • S. Bilge et al.

    Inorg. Chem.

    (2006)
  • E.W. Ainscough et al.

    Inorg. Chem.

    (2007)
  • Cited by (0)

    View full text