Design, synthesis, and biological evaluation of callophycin A and analogues as potential chemopreventive and anticancer agents.

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Shen L, Park EJ, Kondratyuk TP, Guendisch D, Marler L, Pezzuto JM, Wright AD, Sun D

Design, synthesis, and biological evaluation of callophycin A and analogues as potential chemopreventive and anticancer agents.

Bioorg Med Chem. 2011 Nov 1;19(21):6182-95. doi: 10.1016/j.bmc.2011.09.020. Epub 2011 Sep 16.

PubMed ID

21978950 [ View in PubMed

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Abstract

Callophycin A was originally isolated from the red algae Callophycus oppositifolius and shown to mediate anticancer and cytotoxic effects. In our collaborative effort to identify potential chemopreventive and anticancer agents with enhanced potency and selectivity, we employed a tetrahydro-beta-carboline-based template inspired by callophycin A for production of a chemical library. Utilizing a parallel synthetic approach, 50 various functionalized tetrahydro-beta-carboline derivatives were prepared and assessed for activities related to cancer chemoprevention and cancer treatment: induction of quinone reductase 1 (QR1) and inhibition of aromatase, nitric oxide (NO) production, tumor necrosis factor (TNF)-alpha-induced NFkappaB activity, and MCF7 breast cancer cell proliferation. Biological results showed that the n-pentyl urea S-isomer 6a was the strongest inducer of QR1 with an induction ratio (IR) value of 4.9 at 50 muM [the concentration to double the activity (CD)=3.8 muM] and its corresponding R-isomer 6f had an IR value of 4.3 (CD=0.2 muM). The isobutyl carbamate derivative 3d with R stereochemistry demonstrated the most potent inhibitory activity of NFkappaB, with the half maximal inhibitory concentration (IC(50)) value of 4.8 muM, and also showed over 60% inhibition at 50 muM of NO production (IC(50)=2.8 muM). The R-isomer urea derivative 6j, having an appended adamantyl group, exhibited the most potent MCF7 cell proliferation inhibitory activity (IC(50)=14.7 muM). The S-isomer 12a of callophycin A showed the most potent activity in aromatase inhibition (IC(50)=10.5 muM).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Naringenin	Cytochrome P450 19A1	IC 50 (nM)	230	N/A	N/A	Details