Abstract
Apoptotic and antiproliferative activities of small heterodimer partner (SHP) nuclear receptor ligand (E)-4-[3′-(1-adamantyl)-4′- hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC), which was derived from 6-[3′-(1-adamantyl)-4′-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN), and several carboxyl isosteric or hydrogen bond-accepting analogues were examined. 3-Cl-AHPC continued to be the most effective apoptotic agent, whereas tetrazole, thiazolidine-2,4-dione, methyldinitrile, hydroxamic acid, boronic acid, 2-oxoaldehyde, and ethyl phosphonic acid hydrogen bond-acceptor analogues were inactive or less efficient inducers of KG-1 acute myeloid leukemia and MDA-MB-231 breast, H292 lung, and DU-145 prostate cancer cell apoptosis. Similarly, 3-Cl-AHPC was the most potent inhibitor of cell proliferation. 4-[3′-(1-Adamantyl)-4′-hydroxyphenyl]-3-chlorophenyltetrazole, (2E)-5-{2-[3′-(1-adamantyl)-2-chloro-4′-hydroxy-4-biphenyl]-ethenyl} -1H-tetrazole, 5-{4-[3′-(1-adamantyl)-4′-hydroxyphenyl]-3- chlorobenzylidene}diiazolidine-2,4-dione, and (3E)-4-[3′-(1-adamantyl)-2- chloro-4′-hydroxy-4-biphenyl]-2-oxobut-3-enal were very modest inhibitors of KG-1 proliferation. The other analogues were minimal inhibitors. Fragment-based QSAR analyses relating the polar termini with cancer cell growth inhibition revealed that length and van der Waals electrostatic surface potential were the most influential features on activity. 3-Cl-AHPC and the 3-chlorophenyltetrazole and 3-chlorobenzylidenethiazolidine-2,4-dione analogues were also able to inhibit SHP-2 protein-tyrosine phosphatase, which is elevated in some leukemias. 3-Cl-AHPC at 1.0 μM induced human microvascular endothelial cell apoptosis but did not inhibit cell migration or tube formation.
| Original language | English |
|---|---|
| Pages (from-to) | 2622-2639 |
| Number of pages | 18 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 50 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - May 31 2007 |
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All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Drug Discovery
Cite this
An adamantyl-substituted retinoid-derived molecule that inhibits cancer cell growth and angiogenesis by inducing apoptosis and binds to small heterodimer partner nuclear receptor : Effects of modifying its carboxylate group on apoptosis, proliferation, and protein-tyrosine phosphatase activity. / Dawson, Marcia I.; Xia, Zebin; Liu, Gang; Fontana, Joseph A.; Farhana, Lulu; Patel, Bhamik B.; Arumugarajah, Sankari; Bhuiyan, Mohammad; Zhang, Xiao Kun; Han, Young Hoon; Stallcup, William B.; Fukushi, Jun Ichi; Mustelin, Tomas; Tautz, Lutz; Su, Ying; Harris, Danni L.; Waleh, Nahid; Hobbs, Peter D.; Jong, Ling; Chao, Wan Ru; Schiff, Leonard J.; Sani, Brahma P.
In: Journal of Medicinal Chemistry, Vol. 50, No. 11, 31.05.2007, p. 2622-2639.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - An adamantyl-substituted retinoid-derived molecule that inhibits cancer cell growth and angiogenesis by inducing apoptosis and binds to small heterodimer partner nuclear receptor
T2 - Effects of modifying its carboxylate group on apoptosis, proliferation, and protein-tyrosine phosphatase activity
AU - Dawson, Marcia I.
AU - Xia, Zebin
AU - Liu, Gang
AU - Fontana, Joseph A.
AU - Farhana, Lulu
AU - Patel, Bhamik B.
AU - Arumugarajah, Sankari
AU - Bhuiyan, Mohammad
AU - Zhang, Xiao Kun
AU - Han, Young Hoon
AU - Stallcup, William B.
AU - Fukushi, Jun Ichi
AU - Mustelin, Tomas
AU - Tautz, Lutz
AU - Su, Ying
AU - Harris, Danni L.
AU - Waleh, Nahid
AU - Hobbs, Peter D.
AU - Jong, Ling
AU - Chao, Wan Ru
AU - Schiff, Leonard J.
AU - Sani, Brahma P.
PY - 2007/5/31
Y1 - 2007/5/31
N2 - Apoptotic and antiproliferative activities of small heterodimer partner (SHP) nuclear receptor ligand (E)-4-[3′-(1-adamantyl)-4′- hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC), which was derived from 6-[3′-(1-adamantyl)-4′-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN), and several carboxyl isosteric or hydrogen bond-accepting analogues were examined. 3-Cl-AHPC continued to be the most effective apoptotic agent, whereas tetrazole, thiazolidine-2,4-dione, methyldinitrile, hydroxamic acid, boronic acid, 2-oxoaldehyde, and ethyl phosphonic acid hydrogen bond-acceptor analogues were inactive or less efficient inducers of KG-1 acute myeloid leukemia and MDA-MB-231 breast, H292 lung, and DU-145 prostate cancer cell apoptosis. Similarly, 3-Cl-AHPC was the most potent inhibitor of cell proliferation. 4-[3′-(1-Adamantyl)-4′-hydroxyphenyl]-3-chlorophenyltetrazole, (2E)-5-{2-[3′-(1-adamantyl)-2-chloro-4′-hydroxy-4-biphenyl]-ethenyl} -1H-tetrazole, 5-{4-[3′-(1-adamantyl)-4′-hydroxyphenyl]-3- chlorobenzylidene}diiazolidine-2,4-dione, and (3E)-4-[3′-(1-adamantyl)-2- chloro-4′-hydroxy-4-biphenyl]-2-oxobut-3-enal were very modest inhibitors of KG-1 proliferation. The other analogues were minimal inhibitors. Fragment-based QSAR analyses relating the polar termini with cancer cell growth inhibition revealed that length and van der Waals electrostatic surface potential were the most influential features on activity. 3-Cl-AHPC and the 3-chlorophenyltetrazole and 3-chlorobenzylidenethiazolidine-2,4-dione analogues were also able to inhibit SHP-2 protein-tyrosine phosphatase, which is elevated in some leukemias. 3-Cl-AHPC at 1.0 μM induced human microvascular endothelial cell apoptosis but did not inhibit cell migration or tube formation.
AB - Apoptotic and antiproliferative activities of small heterodimer partner (SHP) nuclear receptor ligand (E)-4-[3′-(1-adamantyl)-4′- hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC), which was derived from 6-[3′-(1-adamantyl)-4′-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN), and several carboxyl isosteric or hydrogen bond-accepting analogues were examined. 3-Cl-AHPC continued to be the most effective apoptotic agent, whereas tetrazole, thiazolidine-2,4-dione, methyldinitrile, hydroxamic acid, boronic acid, 2-oxoaldehyde, and ethyl phosphonic acid hydrogen bond-acceptor analogues were inactive or less efficient inducers of KG-1 acute myeloid leukemia and MDA-MB-231 breast, H292 lung, and DU-145 prostate cancer cell apoptosis. Similarly, 3-Cl-AHPC was the most potent inhibitor of cell proliferation. 4-[3′-(1-Adamantyl)-4′-hydroxyphenyl]-3-chlorophenyltetrazole, (2E)-5-{2-[3′-(1-adamantyl)-2-chloro-4′-hydroxy-4-biphenyl]-ethenyl} -1H-tetrazole, 5-{4-[3′-(1-adamantyl)-4′-hydroxyphenyl]-3- chlorobenzylidene}diiazolidine-2,4-dione, and (3E)-4-[3′-(1-adamantyl)-2- chloro-4′-hydroxy-4-biphenyl]-2-oxobut-3-enal were very modest inhibitors of KG-1 proliferation. The other analogues were minimal inhibitors. Fragment-based QSAR analyses relating the polar termini with cancer cell growth inhibition revealed that length and van der Waals electrostatic surface potential were the most influential features on activity. 3-Cl-AHPC and the 3-chlorophenyltetrazole and 3-chlorobenzylidenethiazolidine-2,4-dione analogues were also able to inhibit SHP-2 protein-tyrosine phosphatase, which is elevated in some leukemias. 3-Cl-AHPC at 1.0 μM induced human microvascular endothelial cell apoptosis but did not inhibit cell migration or tube formation.
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UR - http://www.scopus.com/inward/citedby.url?scp=34250173035&partnerID=8YFLogxK
U2 - 10.1021/jm0613323
DO - 10.1021/jm0613323
M3 - Article
C2 - 17489579
AN - SCOPUS:34250173035
VL - 50
SP - 2622
EP - 2639
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 11
ER -