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. 2008 Mar;71(3):205-15.
doi: 10.1111/j.1747-0285.2008.00628.x.

Antiviral and anticancer optimization studies of the DNA-binding marine natural product aaptamine

John J Bowling  1 , Hari K Pennaka, Kelly Ivey, Subagus Wahyuono, Michelle Kelly, Raymond F Schinazi, Frederick A Valeriote, David E Graves, Mark T Hamann
Affiliations

Antiviral and anticancer optimization studies of the DNA-binding marine natural product aaptamine

John J Bowling et al. Chem Biol Drug Des. 2008 Mar.

Abstract

Aaptamine has potent cytotoxicity that may be explained by its ability to intercalate DNA. Aaptamine was evaluated for its ability to bind to DNA to validate DNA binding as the primary mechanism of cytotoxicity. Based on UV-vis absorbance titration data, the K(obs) for aaptamine was 4.0 (+/-0.2) x 10(3) which was essentially equivalent to the known DNA intercalator N-[2-(diethylamino)ethyl]-9-aminoacridine-4-carboxamide. Semi-synthetic core modifications were performed to improve the general structural diversity of known aaptamine analogs and vary its absorption characteristics. Overall, 26 aaptamine derivatives were synthesized which consisted of a simple homologous range of mono and di-N-alkylations as well as some 9-O-sulfonylation and bis-O-isoaaptamine dimer products. Each product was evaluated for activity in a variety of whole cell and viral assays including a unique solid tumor disk diffusion assay. Details of aaptamine's DNA-binding activity and its derivatives' whole cell and viral assay results are discussed.

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Figures

Figure 1
Figure 1
Structures of major aaptamine related marine natural products.
Figure 2
Figure 2
Four groups of aaptamine derivatives produced through semi-synthesis along with their calculated Log D values at pH 7.4.
Figure 3
Figure 3
Aaptamine was evaluated for its ability to bind DNA by UV-vis spectrophotometry. The figure shows the shift in absorbance of a fixed concentration of aaptamine as the DNA concentration is increased. The inset shows the absorbance at 381 nm as a function of log [DNA].
Scheme 1
Scheme 1
Synthetic routes for aaptamine derivatives.a [a(i) RI, KH, DMF, 0 °C; (ii) HBr, 115 °C; (iii) RS(O)2Cl, Et3N, DCM, 0 °C; (iv) RI2, Cs2CO3, MeC(O), Reflux; (v) BBr3, DCM, 0 °C.]
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