Bioorganic & Medicinal Chemistry Letters 24 (2014) 4496–4500

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Asymmetric ZnPc–rhodamine B conjugates for mitochondrial targeted photodynamic therapy Dominic K. Muli a, Pallavi Rajaputra b, Youngjae You b,⇑, Dominic V. McGrath a,⇑ a b

Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, United States College of Pharmacy, University of Oklahoma Health Science Center, Oklahoma City, OK 73117, United States

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Article history: Received 3 June 2014 Revised 28 July 2014 Accepted 30 July 2014 Available online 7 August 2014 Keywords: Asymmetric zinc phthalocyanine Mitochondria targeting conjugates Photodynamic therapy Anticancer therapy Near IR absorption

a b s t r a c t Design, synthesis, characterization, and photodynamic activity of mitochondria specific asymmetric ZnPc–Rh B conjugates are described. Conjugation of asymmetric ZnPc–OH chromophores 3a and 3b with rhodamine B via the corresponding DIC-activated ester gave the desired near IR-absorbing asymmetric ZnPc–Rh B conjugates 1a and 1b. Conjugates 1a and 1b were shown to produce singlet oxygen upon illumination in DMSO, MeOH and THF. Fluorescence aggregation studies of the dyes 1a, 1b, 3a and 3b in DMSO and phosphate buffered saline (PBS) solution showed that conjugates 1a and 1b were less aggregated compared to the corresponding non-conjugates 3a and 3b suggesting that incorporation of Rh B lowered aggregation of the conjugates in the PBS solution. The four dyes studied have log D7.4 values between 2.31 and 2.48, with the sulfur-containing conjugate 1b being the most hydrophobic. All the dyes showed negligible dark toxicity when colon 26 cells were treated with 5 lM of the dyes while 10–15% cell death was observed for dye concentrations of 15 lM. Illumination (700 ± 40 nm, 45 J/cm2, 15 min) of the cells ([dye] = 15 lM) gave 70% cell death for ZnPc–Rh B conjugates 1a and 1b while no killing for non-conjugates 3a and 3b suggesting that the incorporation of the Rh B in the photosensitizer lowered the aggregation and subsequently improved cellular uptake and phototoxicity. Ó 2014 Elsevier Ltd. All rights reserved.

Photodynamic therapy (PDT) employs the synergy between a photosensitizer, molecular oxygen, and light to kill cancer cells. The photosensitizer transfers energy to molecular triplet oxygen and transforms it to singlet oxygen which is cytotoxic. PDT has become an attractive modality as a minimally invasive cancer therapy.1 The only known major side effect of PDT is skin photosensitivity2–4 that imposes limits on a patient’s exposure to light after treatment. Porphyrin derived photosensitizers have been used commercially as first generation therapeutics. These include PhotofrinÒ which was FDA approved to treat esophageal cancers in 1995.2 However, these photosensitizers have shown significant limitations. For instance, they have their strongest absorption at 400 nm and only weak absorption at 630 nm which is used in PDT. Weaker absorption (smaller molar absorptivity) requires larger doses of photosensitizer which is undesired because of skin photosensitivity. A good photosensitizer should have strong light absorption in the ‘therapeutic window’ of 600–800 nm where body tissue is transparent.1,3 Pcs have strong light absorption in the 600– 700 nm region which renders them superior to porphyrins in this ⇑ Corresponding authors. Tel.: +1 520 626 4690; fax: +1 5206218407. E-mail address: [email protected] (D.V. McGrath). http://dx.doi.org/10.1016/j.bmcl.2014.07.082 0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

regard. The last two decades have seen increased attention and research into closed shell metallated phthalocyanines (MPcs) as second and third generation photosensitizers with the main focus being more selective and less aggregated photosensitizers.5,6 ZnPcs have been most exploited7 due to their high singlet oxygen quantum yield (0.67),8 availability and biocompatibility.9 Additionally, a good photosensitizer should be monomeric in the cytoplasm since aggregation quenches the excited states of the photosensitizer that is required to interact with molecular oxygen.10 Selectivity of the photosensitizer is crucial because singlet oxygen has both a short lifetime (

Asymmetric ZnPc-rhodamine B conjugates for mitochondrial targeted photodynamic therapy.

Design, synthesis, characterization, and photodynamic activity of mitochondria specific asymmetric ZnPc-Rh B conjugates are described. Conjugation of ...
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