Antitumor agents. 272. Structure-activity relationships and in vivo selective anti-breast cancer activity of novel neo-tanshinlactone analogues.
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 IC(50) values of 0.3, 0.2, 0.1, and 0.1 microg/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.
Dong
Yizhou
Y
Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina 27599, USA.
Shi
Qian
Q
Pai
Huei-Chen
HC
Peng
Chieh-Yu
CY
Pan
Shiow-Lin
SL
Teng
Che-Ming
CM
Nakagawa-Goto
Kyoko
K
Yu
Donglei
D
Liu
Yi-Nan
YN
Wu
Pei-Chi
PC
Bastow
Kenneth F
KF
Morris-Natschke
Susan L
SL
Brossi
Arnold
A
Lang
Jing-Yu
JY
Hsu
Jennifer L
JL
Hung
Mien-Chie
MC
Lee
Eva Y-H P
EY
Lee
Kuo-Hsiung
KH
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D016513:Mice, SCID; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D005663:Furans; D011753:Pyrones