Antitumor agents. 272. Structure-activity relationships and in vivo selective anti-breast cancer activity of novel neo-tanshinlactone analogues
Journal
Journal of Medicinal Chemistry
Journal Volume
53
Journal Issue
5
Pages
2299-2308
Date Issued
2010
Author(s)
CHE-MING TENG
Abstract
Neo-tanshinlactone (1) and its previously reported analogues, such as 2, are potent and selective in vitro antibreast cancer agents. The synthetic pathway to 2 was optimized from seven to five steps, with a better overall yield. Structure-activity relationships studies on these compounds revealed some key molecular determinants for this family of antibreast agents. Several derivatives (19-21 and 24) exerted potent and selective antibreast cancer activity with IC50 values of 0.3,0.2,0.1, and 0.1 μg/mL, respectively, against the ZR-75-1 cell lines. Compound 24 was 2- to 3-fold more potent than 1 against SK-BR-3 and ZR-75-1. Importantly, 21 exhibited high selectivity; it was 23 times more active against ZR-75-1 than MCF-7. Compound 20 had an approximately 12-fold ratio of SK-BR-3/MCF-7 selectivity. In addition, analogue 2 showed potent activity against a ZR-75-1 xenograft model, but not PC-3 and MDA-MB-231 xenografts, as well as high selectivity against breast cancer cell line compared with normal breast tissue-derived cell lines. Further development of lead compounds 19-21 and 24 as clinical trial candidates is warranted. ? 2010 American Chemical Society.
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1 (4 methoxyphenyl) 11h benzo [h] furo [3,2 c] chromen 11 one; 1 ethyl 11h benzo [h] furo [3,2 c] chromen 11 one; 1 ethyl 6 methyl 11h benzo [h] furo [3,2 c] chromen 11 one; 1 methyl 11 oxo 11h benzo [h] furo [3,2 c] chromen 6 yl acetate; 1 methyl 11h benzo [h] furo [3,2 c] chromene 11 thione; 1 methyl 11h benzo [h] furo [3,2 c] thiochromen 11 one; 1 methyl 1h benzo [h] furo [3,2 c] chromen 11(2h) one; 1 methyl 6 propyl 11h benzo [h] furo [3,2 c] chromen 11 one; 1 methylbenzo [h] furo [3,2 c] quinolin 11 (10h) one; 1,2 dimethyl 11h benzo [h] furo [3,2 c] chromen 11 one; 1,6 diethyl 11h benzo [h] furo [3,2 c] chromen 11 one; 2 methyl 11h benzo [h] furo [3,2 c] chromen 11 one; 5 aza n methyl 1 methyl 4h benzo [h] furo [3,2,c] chromene 4,11 dione; 5 aza n propyl 1 methyl 4h benzo [h] furo [3,2,c] chromene 4,11 dione; 6 (1 bromoethyl) 1 methyl 11h benzo [h] furo [3,2 c] chromen 11 one; 6 [2 (dimethylamino) ethoxy] 1 methyl 11h benzo [h] furo [3,2 c] chromen 11 one; 6 ethoxy 1 methyl 11h benzo [h] furo [3,2 c] chromen 11 one; 6 ethyl 1 (4 methoxyphenyl) 11h benzo [h] furo [3,2 c] chromen 11 one; 6 ethyl 1 methyl 11h benzo [h] furo [3,2 c] chromen 11 one oxime; 6 ethyl 1 methyl 11h benzo [h] furo [3,2 c] chromene 11 thione; 6 ethyl 1 methyl 1h benzo [h] furo [3,2 c] chromen 11(2h) one; 6 ethyl 1,2 dimethyl 11h benzo [h] furo [3,2 c] chromen 11 one; 6 ethyl 2 methyl 11h benzo [h] furo [3,2 c] chromen 11 one; 6 fluoro 1 methyl 11h benzo [h] furo [3,2 c] chromen 11 one; 6 hydroxy 1 methyl 11h benzo [h] furo [3,2 c] chromen 11 one; 6 isopropyl 1 methyl 11h benzo [h] furo [3,2 c] chromen 11 one; 6 methoxy 1 methyl 11h benzo [h] furo [3,2 c] chromen 11 one; antineoplastic agent; neo tanshinlactone; unclassified drug; unindexed drug; animal experiment; animal model; antineoplastic activity; article; cancer cell; controlled study; cytotoxicity; drug selectivity; drug synthesis; female; human; human cell; human tissue; IC 50; male; mouse; nonhuman; structure activity relation; tumor xenograft; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Female; Furans; Humans; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Mice; Mice, SCID; Pyrones; Structure-Activity Relationship; Xenograft Model Antitumor Assays
Type
journal article