title: Potent DNA-directed alkylating agents: Synthesis and biological activity of phenyl N-mustard-quinoline conjugates having a urea or hydrazinecarboxamide linker.
abstract: A series of N-mustard-quinoline conjugates bearing a urea or hydrazinecarboxamide linker was synthesized for antitumor evaluation. The in vitro cytotoxicity studies revealed that compounds with hydrazinecarboxamide linkers were generally more cytotoxic than the corresponding urea counterparts in inhibiting human lymphoblastic leukemia and various solid tumor cell growths in culture. The therapeutic efficacy against human tumor xenografts in animal model was studied. It was shown that complete tumor remission in nude mice bearing human breast carcinoma MX-1 xenograft by 17a, i and 18c, d was achieved. In the present study, it was revealed that both linkers are able to lower the chemically reactive N-mustard pharmacophore and thus the newly synthesized conjugates possess a long half-life in rat plasma. Moreover, the new N-mustard derivatives are able to induce DNA cross-linking either by modified comet assay or by alkaline agarose gel shift assay.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Department of Chemistry, Saurashtra University, Rajkot, Gujarat, India.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kakadiya
authors.affiliation: Preclinical Pharmacology Core Laboratory, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Huajin
authors.initials: H
authors.lastname: Dong
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Dodia
authors.initials: D
authors.lastname: Narsinh
authors.affiliation: Preclinical Pharmacology Core Laboratory, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Xiuguo
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Preclinical Pharmacology Core Laboratory, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Ting-Chao
authors.initials: TC
authors.lastname: Chou
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Te-Chang
authors.initials: TC
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Saurashtra University, Rajkot, Gujarat, India.
authors.forename: Anamik
authors.initials: A
authors.lastname: Shah
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
authors.forename: Tsann-Long
authors.initials: TL
authors.lastname: Su
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006834:Hydrazines / Q000737:chemistry*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014508:Urea / Q000737:chemistry*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D006834:Hydrazines; D011804:Quinolines; D014508:Urea; D004247:DNA; C037219:quinoline