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Synthesis, DNA Binding and Antitumor Evaluation of Styelsamine and Cystodytin Analogues
School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand
* Author to whom correspondence should be addressed.
Received: 4 December 2012; in revised form: 16 January 2013 / Accepted: 21 January 2013 / Published: 28 January 2013
Abstract: A series of N-14 sidechain substituted analogues of styelsamine (pyrido[4,3,2-mn]acridine) and cystodytin (pyrido[4,3,2-mn]acridin-4-one) alkaloids have been prepared and evaluated for their DNA binding affinity and antiproliferative activity towards a panel of human tumor cell lines. Overall it was found that styelsamine analogues were stronger DNA binders, with the natural products styelsamines B and D having particularly high affinity (Kapp 5.33 × 106 and 3.64 × 106 M−1, respectively). In comparison, the cystodytin iminoquinone alkaloids showed lower affinity for DNA, but were typically just as active as styelsamine analogues at inhibiting proliferation of tumor cells in vitro. Sub-panel selectivity towards non-small cell lung, melanoma and renal cancer cell lines were observed for a number of the analogues. Correlation was observed between whole cell activity and clogP, with the most potent antiproliferative activity being observed for 3-phenylpropanamide analogues 37 and 41 (NCI panel average GI50 0.4 μM and 0.32 μM, respectively) with clogP ~4.0–4.5.
Keywords: marine natural products; styelsamine; cystodytin; pyridoacridine; DNA binding
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Fong, H.K.H.; Copp, B.R. Synthesis, DNA Binding and Antitumor Evaluation of Styelsamine and Cystodytin Analogues. Mar. Drugs 2013, 11, 274-299.
Fong HKH, Copp BR. Synthesis, DNA Binding and Antitumor Evaluation of Styelsamine and Cystodytin Analogues. Marine Drugs. 2013; 11(2):274-299.
Fong, Hugo K.H.; Copp, Brent R. 2013. "Synthesis, DNA Binding and Antitumor Evaluation of Styelsamine and Cystodytin Analogues." Mar. Drugs 11, no. 2: 274-299.