Synthesis and evaluation of the antiproliferative activities of derivatives of carboxyalkyl isoflavones linked to N-t-Boc-hexylenediamine.
The isoflavones biochanin A ( 1a), genistein ( 1b), and daidzein ( 4) at concentrations >20 microM inhibit cell growth of various cancer cell lines. To enhance the antiproliferative activities of these compounds, we synthesized three analogs, 2-[3-carboxy-(6-tert-butoxycarbonylamino)-hexylamino-propyl]-7,5-dihydroxy-4'-methoxyisoflavone ( 3a), 2-[3-[N-[6-(tert-butoxycarbonyl)-aminohexyl]]-caboxamidopropyl]-5,7,4'-trihydroxyisoflavone ( 3b), and 5-{2-[3-(4-hydroxy-phenyl)-4-oxo-4 H-chromen-7-yloxy]-acetylamino}-pentyl)-carbamic acid tert-butyl ester ( 6). When cancer cells expressing predominantly estrogen receptor mRNA of the beta- relative to alpha-subtype were treated with 3a, 3b, or 6, DNA synthesis was inhibited in a dose-dependent manner, ranging from 15 to 3000 nmol/L, with little inhibitory effect in normal vascular smooth muscle cells. Compound 6 was the most potent one, and its antiproliferative effect in cancer cells was modulated by estrogen and by the apoptosis inhibitor Z-VADFK. When tested in vivo, compound 6 decreased tumor volume of ovarian xenografts by 50%, with no apparent toxicity. Compound 6 may be a promising agent for therapy of cancer either alone or in combination with chemotherapeutic agents.
Kohen
Fortune
F
Department of Biological Regulation and Chemical Research Support Unit, Weizmann Institute of Science, Rehovot, Israel. fortune.kohen@weizmann.ac.il
Gayer
Batya
B
Kulik
Tikva
T
Frydman
Veronica
V
Nevo
Nava
N
Katzburg
Sara
S
Limor
Rona
R
Sharon
Orli
O
Stern
Naftali
N
Somjen
Dalia
D
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002219:Carbamates / Q000737:chemistry*; D045744:Cell Line, Tumor; D002867:Chromones / Q000737:chemistry*; D003110:Colonic Neoplasms; D004247:DNA / Q000096:biosynthesis; D004347:Drug Interactions; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics; D047629:Estrogen Receptor beta / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D006801:Humans; D007529:Isoflavones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms; D010053:Ovary / Q000166:cytology; D011467:Prostate / Q000166:cytology; D012333:RNA, Messenger / Q000096:biosynthesis; D014183:Transplantation, Heterologous
C527125:5-(2-(3-(4-hydroxyphenyl)-4-oxo-4H-chromen-7-yloxy)acetylamino)hexylcarbamic acid tert-butyl ester; D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D002219:Carbamates; D002867:Chromones; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D007529:Isoflavones; D012333:RNA, Messenger; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D004247:DNA