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Novel bifunctional alkylating agents, 5,10-dihydropyrrolo[1,2-b]isoquinoline derivatives, synthesis and biological activity |
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| Authors: | Chaniyara Ravi Kapuriya Naval Dong Huajin Lee Pei-Chih Suman Sharda Marvania Bhavin Chou Ting-Chao Lee Te-Chang Kakadiya Rajesh Shah Anamik Su Tsann-Long |
| Affiliation: | a Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan b Preclinical Pharmacology Core Laboratory, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA c Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan d Department of Chemistry, Saurashtra University, Rajkot, Gujarat, India |
| Abstract: | A series of linear pyrrolo[1,2-b]isoquinoline derivatives was synthesized for antitumor evaluation. The preliminary antitumor studies reveal that both bis(hydroxymethyl) and their bis(alkylcarbamate) derivatives show significant antitumor activity in inhibiting various human tumor cell growth in vitro. 1,2-Bis(hydroxymethyl)-3-methyl-5,10-dihydropyrrolo[1,2-b]isoquinoline (20a) was selected for antitumor studies in animal models. The results show that this agent can induce complete tumor remission or significant suppression in nude mice bearing human breast (MX-1) xenograft and ovarian (SK-OV-3) xenografts, respectively. Alkaline agarose gel shifting assay showed that 20a is able to cross-link with DNA. Studies on the cell cycle inhibition revealed that this agent induces cell arrest at G2/M phase. The results warrant further antitumor investigation against other human tumor growth in animal models. |
| Keywords: | Pyrrolo[1,2-b]isoquinoline Structure-activity relationships DNA interstrand cross-linking Cell cycle Antitumor agents |
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