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1	Polar, Functionalized Guanine-O6 Derivatives Resistant to Repair by O6-Alkylguanine-DNA Alkyltransferase: Implications for the Design of DNA-modifying Drugs. Wheelhouse, Richard T., Bibby, Michael C., Nicolaou, Anna, Pletsas, Dimitrios 28 July 2009 (has links) No / The protein O6-alkylguanine-DNA alkyltransferase (Atase) is responsible for the repair of DNA lesions generated by several clinically important anti-cancer drugs; this is manifest as active resistance in those cancer cell lines proficient in Atase expression. Novel O6-substituted guanine analogues have been synthesized, bearing acidic, basic and hydrogen bonding functional groups. In contrast to existing O6-modified purine analogues, such as methyl or benzyl, the new compounds were found to resist repair by Atase even when tested at concentrations much higher than O6-benzylguanine, a well-established Atase substrate active both in vitro and in vivo. The inactivity of the new purines as covalent substrates for Atase indicates that agents to deliver these groups to DNA would represent a new class of DNA-modifying drug that circumvents Atase-mediated resistance. Structure activity relation Guanine derivatives Competitive inhibition Purine derivatives Enzyme inhibitor In vitro Chemical synthesis Enzyme Transferases DNA Repair
2	Synthesis and biological evaluation of novel chloroethylaminoanthraquinones with potent cytotoxic activity against cisplatin-resistant tumor cells Pors, Klaus, Paniwnyk, Z., Patterson, Laurence H., Ruparelia, K.C., Hartley, J.A., Kelland, L.R. January 2004 (has links) No / Novel 1- and 1,4-substituted chloroethylaminoanthraquinones with DNA binding and alkylating properties along with their respective hydroxyethylaminoanthraquinone intermediates were synthesized. Selected chloroethylaminoanthraquinones were shown to cross-link DNA and alkylate guanines (at low nM concentration) with a preference for reaction sites containing 5'-PyG. A compound (Alchemix) with the bis-chloroethyl functionality confined to one side chain alkylated but did not cross-link DNA. All the 1,4-disubstituted chloroethylaminoanthraquinones were potently cytotoxic (nM IC50s) against cisplatin-resistant ovarian cancer cell lines. Platinum II Complexes Alkylating agent Organic chlorine compounds Diamine Aromatic amine Quinone Anthraquinone derivatives Chemical synthesis Ovary Human Cell line In vitro Cisplatin Tumor cell Resistance Cytotoxicity Antineoplastic agent Structure activity relation
3	Development of nonsymmetrical 1,4-disubstituted anthraquinones that are potently active against cisplatin-resistant ovarian cancer cells Teesdale-Spittle, P.H., Pors, Klaus, Brown, R., Patterson, Laurence H., Plumb, J.A. January 2005 (has links) No / 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. Treatment resistance Transition metal Complexes Divalent metal Complexes Platinum II Complexes Malignant tumour Alkylating agent Vertebrata Mammalia Rodentia Cell line Chlorine Organic compounds Animal Ovary Tumour cell Human Alcohol Antineoplastic agent Mechanism of action Antimitotic Intraperitoneal administration Chemotherapy Cytotoxicity In vivo Pyrrolidine derivatives Piperidine derivatives Tricyclic compound Condensed benzenic compound Structure activity relation Diphenols Aromatic amine Ovarian cancer In vitro Chemical synthesis Cisplatin

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