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Synthesis and Cytotoxicity of a Diazirine‐Based Photopsammaplin
Author(s) -
Hentschel Fabia,
Raimer Björn,
Kelter Gerhard,
Fiebig HeinzHerbert,
Sasse Florenz,
Lindel Thomas
Publication year - 2014
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201301717
Subject(s) - diazirine , chemistry , cytotoxicity , stereochemistry , singlet state , acetic acid , photochemistry , in vitro , organic chemistry , biochemistry , physics , nuclear physics , excited state
The first photoreactive derivative of the cytotoxic marine natural product psammaplin A ( 1 ) has been synthesized by appending 1‐azi‐2,2,2‐trifluoroethyl moieties at both benzene rings. Photopsammaplin 8 exhibited anticancer activity in vitro with a geomean IC 50 value of 1.4 μ M in a panel of 42 human cancer cell lines. Particularly sensitive cell lines were found among bladder, lung, mammary, and prostate cancer as well as melanoma (MEXF 276), with IC 50 values ≤ 0.6 μ M . In a COMPARE analysis, diazirine‐functionalized photopsammaplin exhibited a very similar cytotoxicity profile to that of the natural product 1 . Furthermore, photopsammaplin 8 was found to be a potent HDAC inhibitor (IC 50 35 n M ) and can be considered as a suitable candidate for photoaffinity labeling, which may assist in the identification of new targets of psammaplin A. Irradiation experiments with a model diazirine‐functionalized α‐hydroxy iminoester in dichloromethane in the presence or absence of acetic acid and methanol revealed the stability of the oxime unit and confirmed that reactions took place solely at the carbene center. The isolation of triplet and singlet photoproducts is consistent with DFT calculations [B3LYP 6‐311G (2d,2p)] showing that, in polar solvents, the triplet‐singlet gap is very small.