Design, synthesis, and biological evaluation of novel water-soluble N-mustards as potential anticancer agents Journal Article
| Authors: | Kapuriya, N.; Kakadiya, R.; Dong, H.; Kumar, A.; Lee, P. C.; Zhang, X.; Chou, T. C.; Lee, T. C.; Chen, C. H.; Lam, K.; Marvania, B.; Shah, A.; Su, T. L. |
| Article Title: | Design, synthesis, and biological evaluation of novel water-soluble N-mustards as potential anticancer agents |
| Abstract: | A series of novel water-soluble N-mustard-benzene conjugates bearing a urea linker were synthesized. The benzene moiety contains various hydrophilic side chains are linked to the meta- or para-position of the urea linker via a carboxamide or an ether linkage. The preliminary antitumor studies revealed that these agents exhibited potent cytotoxicity in vitro and therapeutic efficacy against human tumor xenografts in vivo. Remarkably, complete tumor remission in nude mice bearing human breast carcinoma MX-1 xenograft and significant suppression against prostate adenocarcinoma PC3 xenograft were achieved by treating with compound 9aa′ at the maximum tolerable dose with relatively low toxicity. We also demonstrate that the newly synthesized compounds are able to induce DNA cross-linking through alkaline agarose gel shift assay. A pharmacokinetic profile of the representative 9aa′ in rats was also investigated. The current studies suggest that this agent is a promising candidate for preclinical studies. © 2010 Elsevier Ltd. All rights reserved. |
| Keywords: | controlled study; unclassified drug; human cell; drug tolerability; area under the curve; drug efficacy; nonhuman; paclitaxel; topotecan; glioma; antineoplastic agent; mouse; cell cycle; unindexed drug; animal experiment; animal model; cyclophosphamide; in vivo study; antineoplastic activity; in vitro study; tumor regression; tumor xenograft; drug design; drug synthesis; structure activity relation; vinblastine; mus musculus; irinotecan; drug distribution; colon cancer; breast carcinoma; rat; cell cycle arrest; drug clearance; prostate adenocarcinoma; optimal drug dose; rattus; drug cytotoxicity; drug determination; drug conjugation; dna cross linking; brassicaceae; chlormethine derivative; benzene derivative; anticancer agents; dna interstrand cross-linking agents; water soluble nitrogen mustards; 1 [3 [(2 dimethylamino)ethyl]carbamoyl]phenyl] 3 [4 [bis(2 chloroethyl)amino]phenyl]urea hydrochloride; 1 [3 [(2 morpholinoethyl)carbamoyl]phenyl] 3 [4 [bis (2 chloroethyl)amino]phenyl]urea hydrochloride; 1 [3 [[2 (piperidin 1 yl)ethyl]carbamoyl]phenyl] 3 [4 [bis (2 chloroethyl)amino]phenyl]urea hydrochloride; 1 [3 [[2 (pyrrolidin 1 yl)ethyl]carbamoyl]phenyl] 3 [4 [bis (2 chloroethyl)amino]phenyl]urea hydrochloride; 1 [3 [[3 (dimethylamino)propyl]carbamoyl]phenyl] 3 [4 [bis (2 chloroethyl)amino]phenyl]urea; 1 [4 [[2 (dimethylamino)ethyl]carbamoyl]phenyl] 3 [4 [bis (2 chloroethyl)amino]phenyl]urea hydrochloride; 1 [4 [[2 (piperidin 1 yl)ethyl]carbamoyl]phenyl] 3 [4 [bis (2 chloroethyl)amino]phenyl]urea hydrochloride; 1 [4 [[2 (pyrrolidin 1 yl)ethyl]carbamoyl]phenyl] 3 [4 [bis (2 chloroethyl)amino]phenyl]urea hydrochloride; 1 [4 [[2 morpholinoethyl)carbamoyl]phenyl] 3 [5 [bis (2 chloroethyl)amino]phenyl] urea hydrochloride; 1 [4 [[3 (dimethylamino)propyl]carbamoyl]phenyl] 3 [4 [bis (2 chloroethyl)amino]phenyl]urea; 1 [4 [bis (2 chloroethyl)amino]phenyl] 3 [3 (2 morpholinoethoxy)phenyl]urea; 1 [4 [bis (2 chloroethyl)amino]phenyl] 3 [3 [2 (dimethylamino)ethoxy]phenyl]urea; 1 [4 [bis (2 chloroethyl)amino]phenyl] 3 [3 [2 (piperidin 1 yl)ethoxy]phenyl]urea; 1 [4 [bis (2 chloroethyl)amino]phenyl] 3 [3 [2 (pyrrolidin 1 yl)ethoxy]phenyl]urea; 1 [4 [bis (2 chloroethyl)amino]phenyl] 3 [3 [3 (dimethylamino)propoxy]phenyl]urea; 1 [4 [bis (2 chloroethyl)amino]phenyl] 3 [3 [4 (piperidin 1 yl)piperidine 1 carbonyl]phenyl]urea hydrochloride; 1 [4 [bis (2 chloroethyl)amino]phenyl] 3 [4 [4 (piperidin 1 yl)piperidine 1 carbonyl]phenyl]urea hydrochloride; 1 [4 [bis (2 chloroethyl)amino]phenyl] 4 [3 [2 (dimethylamino)phenyl]urea hydrochloride; 1 [4 [bis (2 chloroethyl)amino]phenyl] 4 [3 [2 (piperidin 1 yl)ethoxy]phenyl]urea; 1 [4 [bis (2 chloroethyl)amino]phenyl] 4 [3 [2 (pyrrolidin 1 yl)ethoxy]phenyl]urea; 1 [4 [bis (2 chloroethyl)amino]phenyl] 4 [3 [3 (dimethylamino)propoxy]phenyl]urea hydrochloride; agar gel electrophoresis; drug dna binding; drug solubility; hydrophilicity |
| Journal Title: | Bioorganic & Medicinal Chemistry |
| Volume: | 19 |
| Issue: | 1 |
| ISSN: | 0968-0896 |
| Publisher: | Pergamon-Elsevier Science Ltd |
| Date Published: | 2011-01-01 |
| Start Page: | 471 |
| End Page: | 485 |
| Language: | English |
| DOI: | 10.1016/j.bmc.2010.11.005 |
| PROVIDER: | scopus |
| PUBMED: | 21106377 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 March 2011" - "CODEN: BMECE" - "Source: Scopus" |
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