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Unprecedented anticancer activities of organorhenium sulfonato and carboxylato complexes against hormone-dependent MCF-7 and hormone-independent triple-negative MDA-MB-231 breast cancer cells

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Abstract

Cisplatin and other metal-based drugs often display side effects and tumor resistance after prolonged use. Because rhenium-based anticancer complexes are often less toxic, a novel series of organorhenium complexes were synthesized of the types: XRe(CO)3Z (X = α-diimines and Z = p-toluenesulfonate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, picolinate, nicotinate, aspirinate, naproxenate, flufenamate, ibuprofenate, mefenamate, tolfenamate, N-acetyl-tryptophanate), and their biological properties were examined. Specifically, in hormone-dependent MCF-7 and hormone-independent triple-negative MDA-MB-231 breast cancer cells, the p-toluenesulfonato, 1-naphthalenesulfonato, 2-naphthalenesulfonato, picolinato, nicotinato, acetylsalicylato, flufenamato, ibuprofenato, mefenamato, and N-acetyl-tryptophanato complexes were found to be far more potent than conventional drug cisplatin. DNA-binding studies were performed in each case via UV–Vis titrations, cyclic voltammetry, gel electrophoresis, and viscosity, which suggest DNA partial intercalation interaction, and the structure–activity relationship studies suggest that the anticancer activities increase with the increasing lipophilicities of the compounds, roughly consistent with their DNA-binding activities.

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Acknowledgements

This research was partially supported by the NCI disability supplement, and the NIH Grant No. T34 GM100831 to HNB and the NIH Grant No. G11HD038439; and Nuclear Regulatory Commission Grant No. NRC-HQ-12-G-27-0086 to SKM. The work was also supported, in part, with funds from the Center for Biomolecular Therapeutics (CBT) at the University of Maryland, School of Medicine (from DJW).

Author contributions

The authors’ contributions are as follows: Conceptualization: SKM, SKP, and HNB; Synthesis: TO, SP, TVH, SA, MS, DG, PO, BVP, and AW; Characterizations: AW, TO, and ST; Cytotoxicity studies: PTW and DJW; X-ray structure determinations: CC, JAG, ALR, JAK, DMH and PYZ; Structure optimizations: RS; DNA-binding studies: TO, SP, TVH, SA, MS, DG, BVP, AB, YZ, SG, PM and JMW; Writing of the original manuscript: SKM, SKP, HNB, DJW and PTW; Reviewing–editing: DJW, PTW, SKP, AW, HNB, DMH, ALR, YZ, RS and JMW; Final document approval: DJW and SKM.

Author information

Author notes

  1. Paul T. Wilder, David J. Weber, Angela Winstead, Sabreea Parnell, Tiara V. Hinton, Monet Stevenson, Dipak Giri, Samira Azemati, Pola Olczak, Brent V. Powell, Tijesunimi Odebode, Solomon Tadesse, Yongchao Zhang, Saroj K. Pramanik, James M. Wachira, Sujan Ghimire, Pumtiwitt McCarthy, Alexis Barfield, Hirendra N. Banerjee, Chao Chen, James A. Golen, Arnold L. Rheingold, Jeanette A. Krause, Douglas M. Ho, Peter Y. Zavalij, Roosevelt Shaw, and Santosh K. Mandal have contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics & Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA

    Paul T. Wilder & David J. Weber

  2. Department of Chemistry, Morgan State University, Baltimore, MD, USA

    Angela Winstead, Sabreea Parnell, Tiara V. Hinton, Monet Stevenson, Dipak Giri, Samira Azemati, Pola Olczak, Brent V. Powell, Tijesunimi Odebode, Solomon Tadesse, Yongchao Zhang, Sujan Ghimire, Pumtiwitt McCarthy, Roosevelt Shaw & Santosh K. Mandal

  3. Department of Biology, Morgan State University, Baltimore, MD, USA

    Saroj K. Pramanik & James M. Wachira

  4. Department of Natural, Pharmacy and Health Sciences, Elizabeth City State University – University of North Carolina, Elizabeth City, NC, USA

    Alexis Barfield & Hirendra N. Banerjee

  5. Department of Chemistry, University of California, San Diego, CA, USA

    Chao Chen, James A. Golen & Arnold L. Rheingold

  6. Department of Chemistry, University of Cincinnati, Cincinnati, OH, USA

    Jeanette A. Krause

  7. Department of Chemistry, Princeton University, Princeton, NJ, USA

    Douglas M. Ho

  8. Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, USA

    Peter Y. Zavalij

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  1. Paul T. Wilder
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  2. David J. Weber
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  3. Angela Winstead
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  27. Santosh K. Mandal
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Corresponding author

Correspondence to Santosh K. Mandal.

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Electronic supplementary material

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Supplementary material 1 (DOCX 2869 kb)

S1 Table. Change in fluorescence intensity after 72-h treatment of MCF-7 and MDA-MB-231 breast cancer cells with various concentrations of the organorhenium sulfonato and carboxylate complexes

Supplementary material 2 (DOCX 24 kb)

S2 Table. The IC50 values (in µM) of all organorhenium complexes on MCF-7 breast cancer cells

Supplementary material 3 (DOCX 17 kb)

S3 Table. The IC50 values (in µM) of all organorhenium complexes on MDA-MB-231 breast cancer cells

Supplementary material 4 (DOCX 9894 kb)

S1 – S9 Figs. IR spectra of TOS7, TOS6, NIC7, 1NS7, 2NS6, PIC7, IB6, PIC6 and 1NS6, respectively, in CH 2 Cl 2 . Each spectrum is shown in the C ≡ O and C = O regions, 2200-1600 cm−1

S10 – S27 Figs. 1 H and 13 C NMR spectra of TOS7, TOS6, NIC7, 1NS7, 2NS6, PIC7, IB6, PIC6 and 1NS6, respectively. CD2Cl2 was used for NIC7, 1NS7, 2NS6, IB6, PIC6 and 1NS6 and CDCl3 was used for TOS7, TOS6 and PIC7

Supplementary material 5 (DOCX 198 kb)

S28 - S35 Figs. UV titration graphs. Electronic absorption spectra for the titration of 25 µM of TOS6, 1NS6, 2NS6, NIC7, PIC7, PIC6, and IB6 and 75 µM of 1NS7, respectively, in the absence and presence of varied amount of DNA. The concentration of the stock solution of DNA was 1693 µM. The corresponding Kb graphs are shown in the insets

Supplementary material 6 (DOCX 674 kb)

S36 – S43 Figs. Cyclic voltammograms. TOS7 (0.6 mM), TOS6 (0.7 mM), 1NS7 (0.6 mM), 2NS6 (0.7 mM), NIC7 (0.7 mM), PIC7 (0.9 mM), PIC6 (0.8 mM), IB6 (0.7 mM) in the absence and presence of 0.1 mM DNA. Scan rate 0.05 V/s

Supplementary material 7 (DOCX 273 kb)

S44 Fig. X-ray structures. (a) TOS2, (b) ASP2, and (c) NIC4 showing the planarity of the phenanthroline rings

Supplementary material 8 (DOCX 67 kb)

S45 Fig. Optimized structures. (a) NIC-7, (b) PIC-7, (c) PIC-6 and (d) TOS-6 obtained from DFT calculations showing the planarity of the phenanthroline rings

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Wilder, P.T., Weber, D.J., Winstead, A. et al. Unprecedented anticancer activities of organorhenium sulfonato and carboxylato complexes against hormone-dependent MCF-7 and hormone-independent triple-negative MDA-MB-231 breast cancer cells. Mol Cell Biochem 441, 151–163 (2018). https://doi.org/10.1007/s11010-017-3181-z

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