Potent antitumor 9-anilinoacridines bearing an alkylating N-mustard residue on the anilino ring: Synthesis and biological activity Journal Article
| Authors: | Bacherikov, V. A.; Chou, T. C.; Dong, H. J.; Zhang, X.; Chen, C. H.; Lin, Y. W.; Tsai, T. J.; Lee, R. Z.; Liu, L. F.; Su, T. L. |
| Article Title: | Potent antitumor 9-anilinoacridines bearing an alkylating N-mustard residue on the anilino ring: Synthesis and biological activity |
| Abstract: | A series of N-mustard derivatives of 9-anilinoacridine was synthesized for antitumor and structure-activity relationship studies. The alkylating N-mustard residue was linked to the C-3′ or C-4′ position of the anilino ring with an O-ethylene (O-C2), O-butylene (O-C4), and methylene (C1) spacer. All of the new N-mustard derivatives exhibited significant cytotoxicity in inhibiting human lymphoblastic leukemic cells (CCRF-CEM) in culture. Of these agents, (3-(acridin-9-ylamino)-5-{2-[bis (2-chloroethyl)amino]ethoxy}phenyl)methanol (10) was subjected to antitumor studies, resulting in an approximately 100-fold more potent effect than its parent analogue 3-(9-acridinylamino)-5-hydroxymethylaniline (AHMA) in inhibiting the growth of human lymphoblastic leukemic cells (CCRF-CEM) in vitro. This agent did not exhibit cross-resistance against vinblastine-resistant (CCRF-CEM/VBL) or Taxol-resistant (CCRF-CEM/Taxol) cells. Remarkably, the therapeutic effect of 10 at a dose as low as one tenth of the Taxol therapeutic dose [i.e., 1-2 mg/kg (Q3D × 7) or 3 mg/kg (Q4D × 5); intravenous injection] on nude mice bearing human breast carcinoma MX-1 xenografts resulted in complete tumor remission in two out of three mice. Furthermore, 10 yielded xenograft tumor suppression of 81-96% using human T-cell acute lymphoblastic leukemia CCRF-CEM, colon carcinoma HCT-116, and ovarian adenocarcinoma SK-OV-3 tumor models. © 2005 Elsevier Ltd. All rights reserved. |
| Keywords: | controlled study; unclassified drug; human cell; nonhuman; antineoplastic agents; paclitaxel; chemotherapy; topotecan; antineoplastic agent; neoplasms; mouse; animals; mice; cell growth; etoposide; animal experiment; animal model; antineoplastic activity; cytotoxicity; drug potency; in vitro study; tumor regression; dose-response relationship, drug; drug resistance, neoplasm; drug screening assays, antitumor; xenograft model antitumor assays; cell line, tumor; drug synthesis; structure activity relation; structure-activity relationship; breast neoplasms; vinblastine; mus musculus; cancer inhibition; human cell culture; xenograft; mice, nude; leukemia cell; breast carcinoma; ovary carcinoma; remission induction; 3 (9 acridinylamino) 5 hydroxymethylaniline; 9 anilinoacridine derivative; lymphatic leukemia; amsacrine; alkylating agents; colon carcinoma; synthesis; acridines; chlormethine derivative; cross resistance; growth inhibition; ethylene; carbene; alkene derivative; antitumour compounds; 2 [(2 hydroxyethyl) [4 (3 nitrophenoxy)butyl]amino]ethanol; [3 (acridin 9 ylamino) 5 [2 [bis(2 chloroethyl)amino]ethoxy]phenyl] methanol; acridin 9 yl [3 [2 [bis(2 chloroethyl)amino]ethoxy]phenyl]amine; bis(2 chloroethyl) [2 (3 nitrophenoxy)ethyl]amine; bis(2 chloroethyl) [4 (3 nitrophenoxy)butyl]amine |
| Journal Title: | Bioorganic & Medicinal Chemistry |
| Volume: | 13 |
| Issue: | 12 |
| ISSN: | 0968-0896 |
| Publisher: | Pergamon-Elsevier Science Ltd |
| Date Published: | 2005-06-02 |
| Start Page: | 3993 |
| End Page: | 4006 |
| Language: | English |
| DOI: | 10.1016/j.bmc.2005.03.057 |
| PUBMED: | 15911312 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 15" - "Export Date: 24 October 2012" - "CODEN: BMECE" - "Source: Scopus" |
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