TY - JOUR
T1 - 3β-hydroxy-6-aza-cholestane and related analogues as phosphatidylinositol specific phospholipase C (PI-PLC) inhibitors with antitumor activity
AU - Xie, Wenge
AU - Peng, Hairuo
AU - Zalkow, Leon H.
AU - Li, Yu Hua
AU - Zhu, Cheng
AU - Powis, Garth
AU - Kunkel, Mark
N1 - Funding Information:
We gratefully acknowledge support of this research by the NCI/NIH (Grant 5U19 CA52995). We thank Dr. Rosanne Bonjouklian of Lilly Research Laboratories for supplying the original sample of compound 1 for screening and Dr. Beverly A. Teicher of Lilly Research laboratories for helpful discussions and animal tests, not included in this manuscript. We are grateful to Dr. Leslie T. Gelbaum for his assistance in obtaining high resolution NMR spectra, and Mr. David E. Bostwick and Ms. Sarah J. Shealy for their assistance in obtaining high resolution mass spectra.
PY - 2000/4
Y1 - 2000/4
N2 - 6-Aza steroid analogues were synthesized as PI-PLC inhibitors. The most active compound, 3β-hydroxy-6-aza-cholestane (1) showed potent PI-PLC inhibition (IC50=1.8 μM), similar to that of the commercially available steroid analogue U73122 (IC50=1-2.1 μM). Compound 1 exhibited significant growth inhibition effects (IC50=1.3 μM in each case) against MCF-7 and HT- 29 cancer cells in in vitro cell culture. Compound 1 also inhibited the in vitro adhesion and transmigration of HT-1080 fibrosarcoma cells at 2.5 and 5.0 μM, respectively. In vivo, compound 1, at 1 mg/kg/day, reduced the volume of MCF-7 tumors in xenograft models, without weight loss in mice. Structure-activity relationships of this series of compounds revealed that a hydrophobic cholesteryl side chain, 3β-hydroxy group and a C-6 nitrogen containing a hydrogen atom at position-6 are crucial for activity. N-Maleic amidoacid derivative 11 also exhibited weak inhibition (IC50=16.2 μM). (C) 2000 Elsevier Science Ltd.
AB - 6-Aza steroid analogues were synthesized as PI-PLC inhibitors. The most active compound, 3β-hydroxy-6-aza-cholestane (1) showed potent PI-PLC inhibition (IC50=1.8 μM), similar to that of the commercially available steroid analogue U73122 (IC50=1-2.1 μM). Compound 1 exhibited significant growth inhibition effects (IC50=1.3 μM in each case) against MCF-7 and HT- 29 cancer cells in in vitro cell culture. Compound 1 also inhibited the in vitro adhesion and transmigration of HT-1080 fibrosarcoma cells at 2.5 and 5.0 μM, respectively. In vivo, compound 1, at 1 mg/kg/day, reduced the volume of MCF-7 tumors in xenograft models, without weight loss in mice. Structure-activity relationships of this series of compounds revealed that a hydrophobic cholesteryl side chain, 3β-hydroxy group and a C-6 nitrogen containing a hydrogen atom at position-6 are crucial for activity. N-Maleic amidoacid derivative 11 also exhibited weak inhibition (IC50=16.2 μM). (C) 2000 Elsevier Science Ltd.
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U2 - 10.1016/S0968-0896(00)00014-6
DO - 10.1016/S0968-0896(00)00014-6
M3 - Article
C2 - 10819158
AN - SCOPUS:0033625178
SN - 0968-0896
VL - 8
SP - 699
EP - 706
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 4
ER -