Synthesis, DNA binding and antitumor evaluation of styelsamine and cystodytin analogues.
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 (K(app) 5.33 × 10(6) and 3.64 × 10(6) 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 GI(50) 0.4 μM and 0.32 μM, respectively) with clogP ~4.0-4.5.
School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand. hfon009@aucklanduni.ac.nz
Hugo K H
HK
Fong
Brent R
BR
Copp
D000166:Acridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D014561:Urochordata / Q000737:chemistry
D000166:Acridines; D000970:Antineoplastic Agents; C583475:cystodytin; C583474:styelsamine; D004247:DNA