Regioselective synthesis and photophysical and electrochemical studies of 20-substituted cyanine dye-purpurinimide conjugates: incorporation of Ni(II) into the conjugate enhances its tumor-uptake and fluorescence-imaging ability.

Abstract

We report herein a simple and efficient approach to the synthesis of a variety of meso-substituted purpurinimides. The reaction of meso-substituted purpurinimide with N-bromosuccinimide regioselectively introduced a bromo functionality at the 20-position, which on further reaction with a variety of boronic acids under Suzuki reaction conditions yielded the corresponding meso-substituted analogues. Interestingly, the free base and the metalated analogues showed remarkable differences in photosensitizing efficacy (PDT) and tumor-imaging ability. For example, the free-base conjugate showed significant in vitro PDT efficacy, but limited tumor avidity in mice bearing tumors, whereas the corresponding Ni(II) derivative did not produce any cell kill, but showed excellent tumor-imaging ability at a dose of 0.3 μmol kg(-1) at 24, 48, and 72 h post-injection. The limited PDT efficacy of the Ni(II) analogue could be due to its inability to produce singlet oxygen, a key cytotoxic agent required for cell kill in PDT. Based on electrochemical and spectroelectrochemical data in DMSO, the first one-electron oxidation (0.52 V vs. SCE) and the first one-electron reduction (-0.57-0.67 V vs. SCE) of both the free base and the corresponding Ni(II) conjugates are centered on the cyanine dye, whereas the second one-electron reduction (-0.81 V vs. SCE) of the two conjugates is assigned to the purpurinimide part of the molecule. Reduction of the cyanine dye unit is facile and occurs prior to reduction of the purpurinimide group, which suggests that the cyanine dye unit as an oxidant could be the driving force for quenching of the excited triplet state of the molecules. An interaction between the cyanine dye and the purpurinimide group is clearly observed in the free-base conjugate, which compares with a negligible interaction between the two functional groups in the Ni(II) conjugate. As a result, the larger HOMO-LUMO gap of the free-base conjugate and the corresponding smaller quenching constant is a reason to decrease the intramolecular quenching process and increase the production of singlet oxygen to some degree.

• Authors: Manivannan Ethirajan, Ping Chen, Tymish Y Ohulchanskyy, Lalit N Goswami, Anurag Gupta, Avinash Srivatsan, Mahabeer P Dobhal, Joseph R Missert, Paras N Prasad, Karl M Kadish, Ravindra K Pandey
• Journal: Chemistry (Weinheim an der Bergstrasse, Germany) (Chemistry) Vol. 19 Issue 21 Pg. 6670-84 (May 17 2013) ISSN: 1521-3765 [Electronic] Germany
• PMID: 23526622 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Carbocyanines
• Photosensitizing Agents
• Porphyrins
• Singlet Oxygen
• Nickel
• Bromosuccinimide

Topics

• Animals
• Bromosuccinimide (chemistry)
• Carbocyanines (chemical synthesis, chemistry)
• Fluorescence
• Mice
• Molecular Structure
• Neoplasms (drug therapy)
• Nickel (chemistry)
• Optical Imaging
• Oxidation-Reduction
• Photochemotherapy (methods)
• Photosensitizing Agents (chemical synthesis, chemistry)
• Porphyrins (chemical synthesis, chemistry)
• Singlet Oxygen (chemistry)
• Stereoisomerism
• Structure-Activity Relationship