Synthesis and Cytotoxicity of a Diazirine‐Based Photopsammaplin

Abstract

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 IC50 value of 1.4 μM 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 IC50 values ≤ 0.6 μM. 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 (IC50 35 nM) 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.

Marine-Derived Natural Lead Compound Disulfide-Linked Dimer Psammaplin A: Biological Activity and Structural Modification

“…Soon afterwards, Lindel and coworkers synthesized the first photoreactive psammaplin A derivative 111 by adding 1-azi-2,2,2-trifluoroethyl moieties to benzene rings (Scheme 7) [94]. Photopsammaplin 111 showed antiproliferative activity in vitro with an average IC 50 value of 1.4 µM against 42 human cancer cell lines, which was especially sensitive to lung cancer (LXFA 526), melanoma (MEXF 276), mammary cancer (MAXF 401 and MCF-7), and bladder cancer (T-24), with IC 50 values below 0.6 µM.…”

Current advances of carbene-mediated photoaffinity labeling in medicinal chemistry

“…Its very similar cytotoxicity profile to that of psammaplin A makes compound 111 a candidate for cmPAL, which may assist in the identification of new targets of psammaplin A and a better understanding of the mode of action with zinc-dependent HDACs. 198 For the single-step detection and proteomic profiling of HDACs, Xie et al developed a novel fluorescent probe (112, Fig. 17 ) by combining a Kac ( N -acetyllysine) recognition unit, an O-NBD (nitrobenzoxadiazole) fluorophore and a minimalist photocrosslinker.…”

Enantioselective Synthesis and Photoreactivity of a Diazirinyl-substituted (R)-β-Phenylalanine

“…Our route was to start from m-diazirinyl-substituted benzaldehyde 4 which has served as building block for the synthesis of the first photo derivative of the marine natural product psammaplin A [26]. For the assembly of the amino acid head, we adopted an auxiliarybased protocol developed for the synthesis of (R)-(+)β -phenylalanine by Davis et al [27,28], which has also been applied by Ghosh et al for the synthesis of jasplakinolide and derivatives [29,30].…”

“…Diazirinyl-substituted benzaldehyde 4 [26] and commercially available (S)-sulfinamide 5 afforded sulfinimine 6 (62 %) in a Ti(OEt) 4 -mediated condensation (Scheme 1). Beforehand, it was not clear whether the diazirinyl unit of 4 would survive treatment with Ti(OEt) 4 , since [TiCp 2 (CO) 2 ] had cleaved the N=N bond of dialkyldiazirines [31].…”