2. Academic Validation
  3. Potent DNA-directed alkylating agents: Synthesis and biological activity of phenyl N-mustard-quinoline conjugates having a urea or hydrazinecarboxamide linker

Potent DNA-directed alkylating agents: Synthesis and biological activity of phenyl N-mustard-quinoline conjugates having a urea or hydrazinecarboxamide linker

  • Bioorg Med Chem. 2010 Mar 15;18(6):2285-2299. doi: 10.1016/j.bmc.2010.01.061.
Rajesh Kakadiya 1,  Huajin Dong 2,  Amit Kumar 3,  Dodia Narsinh 3,  Xiuguo Zhang 2,  Ting-Chao Chou 2,  Te-Chang Lee 3,  Anamik Shah 4,  Tsann-Long Su 5
Affiliations

Affiliations

  • 1 Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Department of Chemistry, Saurashtra University, Rajkot, Gujarat, India.
  • 2 Preclinical Pharmacology Core Laboratory, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
  • 3 Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
  • 4 Department of Chemistry, Saurashtra University, Rajkot, Gujarat, India.
  • 5 Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan.
PMID: 20181487 DOI: 10.1016/j.bmc.2010.01.061
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.

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