- Synthesis and biological evaluation of colchicine C-ring analogues tethered with aliphatic linkers suitable for prodrug derivatisation
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Colchicine was modified at the 10-OCH3 position of the C-ring by reaction with heterocyclic amines or commercially available amines to afford a library of target colchicinoids in high yields (62-99%). Molecular modeling revealed that the incorporation of the linker groups led to a reduction in entropy and therefore binding affinity when compared with colchicine. Some colchicinoids were shown to be equicytotoxic with colchicine when evaluated in the DLD-1 colon cancer cells and retained activity in resistant A2780AD or HeLa cells with mutant Class III β-tubulin. Importantly, unlike colchicine, the analogues in this study are amenable for prodrug derivatisation and with potential for tumor-selective delivery.
- Fournier-Dit-Chabert, Jérémie,Vinader, Victoria,Santos, Ana Rita,Redondo-Horcajo, Mariano,Dreneau, Aurore,Basak, Ramkrishna,Cosentino, Laura,Marston, Gemma,Abdel-Rahman, Hamdy,Loadman, Paul M.,Shnyder, Steven D.,Díaz, José Fernando,Barasoain, Isabel,Falconer, Robert A.,Pors, Klaus
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- Development of nonsymmetrical 1,4-disubstituted anthraquinones that are potently active against cisplatin-resistant ovarian cancer cells
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A novel series of 1,4-disubstituted aminoanthraquinones were prepared by ipso-displacement of 1,4-difluoro-5,8-dihydroxyanthraquinones by hydroxylated piperidinyl- or pyrrolidinylalkyl-amino side chains. One aminoanthraquinone (13) was further derivatized to a chloropropyl-amino analogue by treatment with triphenylphosphine-carbon tetrachloride. The compounds were evaluated in the A2780 ovarian cancer cell line and its cisplatin-resistant variants (A2780/cp70 and A2780/MCP1). The novel anthraquinones were shown to possess up to 5-fold increased potency against the cisplatin-resistant cells compared to the wild-type cells. Growth curve analysis of the hydroxyethylaminoanthraquinone 8 in the osteosarcoma cell line U-2 OS showed that the cell cycle is not frozen, rather there is a late cell cycle arrest consistent with the action of a DNA-damaging topoisomerase II inhibitor. Accumulative apoptotic events, using time lapse photography, indicate that 8 is capable of fully engaging cell cycle arrest pathways in G2 in the absence of early apoptotic commitment. 8 and its chloropropyl analogue 13 retained significant activity against human A2780/cp70 xenografted tumors in mice.
- Pors, Klaus,Plumb, Jane A.,Brown, Robert,Teesdale-Spittle, Paul,Searcey, Mark,Smith, Paul J.,Patterson, Laurence H.
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- Pyrrolidin-2-one derivatives having nootropic activity
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Pyrrolidin-2-one derivatives of formula I: STR1 wherein X=H, OH, C2 -C7 acyloxy, C1 -C6 alkoxy, cycloalkoxy or phenoxy, n=0 or 1 and m=2 or 3, have a marked nootropic activity.
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- Pyrrolidin-2-one derivatives having nootropic activity
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Pyrrolidin-2-one derivatives of formula I: wherein X = H, OH, C2-C7 acyloxy, C1-C6 alkoxy, cycloalko-xy, aralkoxy or phenoxy, n = 0 or 1 and m = 2 or 3, have a marked nootropic activity.
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