Potent antitumor bifunctional DNA alkylating agents, synthesis and biological activities of 3a-aza-cyclopenta[a]indenes Journal Article
| Authors: | Kakadiya, R.; Dong, H.; Lee, P. C.; Kapuriya, N.; Zhang, X.; Chou, T. C.; Lee, T. C.; Kapuriya, K.; Shah, A.; Su, T. L. |
| Article Title: | Potent antitumor bifunctional DNA alkylating agents, synthesis and biological activities of 3a-aza-cyclopenta[a]indenes |
| Abstract: | A series of bifunctional DNA interstrand cross-linking agents, bis(hydroxymethyl)- and bis(carbamates)-8H-3a-azacyclopenta[a]indene-1-yl derivatives were synthesized for antitumor evaluation. The preliminary antitumor studies revealed that these agents exhibited potent cytotoxicity in vitro and antitumor therapeutic efficacy against human tumor xenografts in vivo. Furthermore, these derivatives have little or no cross-resistance to either Taxol or Vinblastine. Remarkably, complete tumor remission in nude mice bearing human breast carcinoma MX-1 xenograft by 13a,b and 14g,h and significant suppression against prostate adenocarcinoma PC3 xenograft by 13b were achieved at the maximum tolerable dose with relatively low toxicity. In addition, these agents induce DNA interstrand cross-linking and substantial G2/M phase arrest in human non-small lung carcinoma H1299 cells. The current studies suggested that these agents are promising candidates for preclinical studies. © 2009 Elsevier Ltd. All rights reserved. |
| Keywords: | controlled study; unclassified drug; human cell; nonhuman; paclitaxel; antineoplastic agent; mouse; cell cycle; lung non small cell cancer; animal experiment; animal model; alkylating agent; antineoplastic activity; cancer cell culture; tumor xenograft; drug synthesis; structure activity relation; vinblastine; mus musculus; cancer inhibition; nude mouse; breast carcinoma; cell cycle arrest; prostate adenocarcinoma; ic 50; reaction analysis; antitumor agents; cyclopenta[a]indene; interstrand cross-linking; structure-activity relationships; (3 ethyl 2 hydroxymethyl 8h 3a azacyclopenta[a]inden 1 yl)methanol; (3 methyl 2 hydroxymethyl 8h 3a azacyclopenta[a]inden 1 yl)methanol; bis(carbamate) 8h 3a azacyclopenta[a]inden 1 yl derivative; bis(hydroxymethyl) 8h 3a azacyclopenta[a]inden 1 yl derivative; indene derivative; methylcarbamic acid 3 (2 methoxyphenyl) 2 methylcarbamoyloxymethyl 8h 3a azacyclopenta[a]inden 1 ylmethyl ester; methylcarbamic acid 3 (4 methoxyphenyl) 2 methylcarbamoyloxymethyl 8h 3a azacyclopenta[a]inden 1 ylmethyl ester; dna cross linking |
| Journal Title: | Bioorganic & Medicinal Chemistry |
| Volume: | 17 |
| Issue: | 15 |
| ISSN: | 0968-0896 |
| Publisher: | Pergamon-Elsevier Science Ltd |
| Date Published: | 2009-08-01 |
| Start Page: | 5614 |
| End Page: | 5626 |
| Language: | English |
| DOI: | 10.1016/j.bmc.2009.06.018 |
| PROVIDER: | scopus |
| PUBMED: | 19576785 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 3" - "Export Date: 30 November 2010" - "CODEN: BMECE" - "Source: Scopus" |
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