Potent DNA-directed alkylating agents: Synthesis and biological activity of phenyl N-mustard-quinoline conjugates having a urea or hydrazinecarboxamide linker Journal Article
| Authors: | Kakadiya, R.; Dong, H.; Kumar, A.; Narsinh, D.; Zhang, X.; Chou, T. C.; Lee, T. C.; Shah, A.; Su, T. L. |
| Article 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. © 2010 Elsevier Ltd. All rights reserved. |
| Keywords: | controlled study; unclassified drug; human cell; cisplatin; nonhuman; gemcitabine; paclitaxel; cell proliferation; mouse; animals; mice; animal experiment; animal model; cyclophosphamide; antineoplastic activity; cancer cell culture; tumor xenograft; drug screening assays, antitumor; tumor cells, cultured; drug synthesis; structure activity relation; structure-activity relationship; vinblastine; animalia; mus musculus; cancer inhibition; dna; nude mouse; mice, nude; breast carcinoma; rat; antineoplastic agents, alkylating; neoplasms, experimental; molecular structure; rats; rattus; drug blood level; neoplasm transplantation; drug half life; ic 50; reaction analysis; dna cross linking; dna-directed alkylating agents; phenyl nitrogen mustards; brassicaceae; stereoisomerism; hydrazines; anticancer agents; dna interstrand cross-linking agents; urea; quinolines; bo 1037; hydrazine derivative; n [4 [bis(2 chloroethyl)amino]phenyl] 2 (6 methyl[1,3]dioxolo[4,5 g]quinolin 8 yl)hydrazinecarboxamide; n [4 [bis(2 chloroethyl)amino]phenyl] 2 [6 (dimethylamino) 2 methyl 4 quinolinyl]hydrazinecarboxamide; n [4 [bis(2 chloroethyl)amino]phenyl] n' (2 methyl 4 quinolinyl)urea; n [4 [bis(2 chloroethyl)amino]phenyl] n' [6 methoxy 2 (3 methoxyphenyl) 4 quinolinyl]urea; phenyl n mustard quinoline conjugate; quinoline derivative; urea derivative |
| Journal Title: | Bioorganic & Medicinal Chemistry |
| Volume: | 18 |
| Issue: | 6 |
| ISSN: | 0968-0896 |
| Publisher: | Pergamon-Elsevier Science Ltd |
| Date Published: | 2010-03-15 |
| Start Page: | 2285 |
| End Page: | 2299 |
| Language: | English |
| DOI: | 10.1016/j.bmc.2010.01.061 |
| PUBMED: | 20181487 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 4" - "Export Date: 20 April 2011" - "CODEN: BMECE" - "Source: Scopus" |
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