| Syntheses and Cellular Investigations of 17<sup>3</sup>-, 15<sup>2</sup>- and 13<sup>1</sup>-Amino Acid Derivatives of Chlorin e<sub>6</sub> | |
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MedLine Citation:
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PMID: 21936519 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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A series of amino acid conjugates of chlorin e6, containing either lysine or aspartic acid residues in positions 173, 152 or 131 of the chlorin macrocycle were synthesized and investigated as photosensitizers for the photodynamic therapy of tumors. All three regioisomers were synthesized in good yields and in 5 steps or less from pheophytin a (1), which is readily obtained by extraction from Spirulina pacifica alga. In vitro investigations using human carcinoma HEp2 cells show that the 152-lysyl regioisomers accumulate the most within cells, and that the most phototoxic are the 131 regioisomers. Our studies indicate that while the nature of amino acid and the presence of a centrally chelated Pd(II) ion affect cytotoxicity and cellular uptake, the main determinant of biological efficacy is the site of conjugation, probably because it determines molecule conformation. Molecular modeling investigations performed at the at the HF/6-31G level reveal that the 173-substituted chlorin e6 conjugates are L-shaped while the 152 and 131 regioisomers assume extended conformations, with the 131 derivatives being nearly linear. Such linear conformation may facilitate binding of the photosensitizer to multiple intracellular sites, as observed by fluorescence microscopy, causing efficient cell destruction upon light activation. It is hypothesized that the 131-aspartylchlorin e6 conjugate might be a more efficient photosensitizer for PDT than the currently used 152 derivative, known as NPe6, (talaporfin sodium), or most recently LS-11, (aptocine™). |
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Authors:
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Raja G Waruna Jinadasa; Xiaoke Hu; M Graca Henriques Vicente; Kevin Malcolm Smith |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-21 |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: - ISSN: 1520-4804 ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-9-22 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
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