Abstract
Rhabdoid tumors (RTs) are aggressive pediatric malignancies with poor prognosis that arise due to loss of the hSNF5/INI1 tumor suppressor. Molecular studies indicate that cyclin D1, a downstream effector of INI1 is up regulated in RT, and is essential for this tumor formation. Previously we demonstrated that 4-HPR, a synthetic retinoid that targets Cyclin D1, is a potential chemotherapeutic agent for RT. To facilitate further chemical development of this retinoid, and to determine its active moiety, we synthesized small chemical libraries of 4-HPR and tested their cytotoxic effect on RT cells. We synthesized 4-HPR (1) and the derivatives (5a-5n) starting from retinoic acid. First, retinoic acid was converted to acid chloride derivatives, then in the presence of DMF, base, and aniline derivatives, we synthesized the corresponding 4-hydroxy phenyl amine derivatives (5a-5n). This procedure gave 70-90% yield. Then, the 4-HPR derivatives were tested for their ability to inhibit RT cells using an in vitro cell survival assay. We found that the 4-hydroxy group at para-position is essential for cytotoxic activity against RT cells. Furthermore, we identified a few derivatives of 4-HPR with higher cytotoxic potencies than 4-HPR. In addition, we demonstrate that either chloro, fluoro or iodo derivatives at meta-position of phenyl ring retain the cytotoxic activity. Interestingly, substitution of iodo-moiety at meta-position (5j) substantially increased the efficacy (IC50 ∼ 3 μM, Fig. 1D). These results indicate that chemical modification of 4-HPR may result in derivatives with increased therapeutic potential for RTs and that halogen substituted 4-HPR that retain the activity can be synthesized for further therapeutic and diagnostic use.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3805-3808 |
| Number of pages | 4 |
| Journal | Bioorganic and Medicinal Chemistry Letters |
| Volume | 18 |
| Issue number | 13 |
| DOIs | |
| State | Published - Jul 1 2008 |
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Keywords
- 4-HPR
- Cyclin D1
- Rhabdoid tumor
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Organic Chemistry
- Drug Discovery
- Pharmaceutical Science
Cite this
Design and synthesis of 4-HPR derivatives for rhabdoid tumors. / Das, Bhaskar C.; Smith, Melissa E.; Kalpana, Ganjam V.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 18, No. 13, 01.07.2008, p. 3805-3808.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Design and synthesis of 4-HPR derivatives for rhabdoid tumors
AU - Das, Bhaskar C.
AU - Smith, Melissa E.
AU - Kalpana, Ganjam V.
PY - 2008/7/1
Y1 - 2008/7/1
N2 - Rhabdoid tumors (RTs) are aggressive pediatric malignancies with poor prognosis that arise due to loss of the hSNF5/INI1 tumor suppressor. Molecular studies indicate that cyclin D1, a downstream effector of INI1 is up regulated in RT, and is essential for this tumor formation. Previously we demonstrated that 4-HPR, a synthetic retinoid that targets Cyclin D1, is a potential chemotherapeutic agent for RT. To facilitate further chemical development of this retinoid, and to determine its active moiety, we synthesized small chemical libraries of 4-HPR and tested their cytotoxic effect on RT cells. We synthesized 4-HPR (1) and the derivatives (5a-5n) starting from retinoic acid. First, retinoic acid was converted to acid chloride derivatives, then in the presence of DMF, base, and aniline derivatives, we synthesized the corresponding 4-hydroxy phenyl amine derivatives (5a-5n). This procedure gave 70-90% yield. Then, the 4-HPR derivatives were tested for their ability to inhibit RT cells using an in vitro cell survival assay. We found that the 4-hydroxy group at para-position is essential for cytotoxic activity against RT cells. Furthermore, we identified a few derivatives of 4-HPR with higher cytotoxic potencies than 4-HPR. In addition, we demonstrate that either chloro, fluoro or iodo derivatives at meta-position of phenyl ring retain the cytotoxic activity. Interestingly, substitution of iodo-moiety at meta-position (5j) substantially increased the efficacy (IC50 ∼ 3 μM, Fig. 1D). These results indicate that chemical modification of 4-HPR may result in derivatives with increased therapeutic potential for RTs and that halogen substituted 4-HPR that retain the activity can be synthesized for further therapeutic and diagnostic use.
AB - Rhabdoid tumors (RTs) are aggressive pediatric malignancies with poor prognosis that arise due to loss of the hSNF5/INI1 tumor suppressor. Molecular studies indicate that cyclin D1, a downstream effector of INI1 is up regulated in RT, and is essential for this tumor formation. Previously we demonstrated that 4-HPR, a synthetic retinoid that targets Cyclin D1, is a potential chemotherapeutic agent for RT. To facilitate further chemical development of this retinoid, and to determine its active moiety, we synthesized small chemical libraries of 4-HPR and tested their cytotoxic effect on RT cells. We synthesized 4-HPR (1) and the derivatives (5a-5n) starting from retinoic acid. First, retinoic acid was converted to acid chloride derivatives, then in the presence of DMF, base, and aniline derivatives, we synthesized the corresponding 4-hydroxy phenyl amine derivatives (5a-5n). This procedure gave 70-90% yield. Then, the 4-HPR derivatives were tested for their ability to inhibit RT cells using an in vitro cell survival assay. We found that the 4-hydroxy group at para-position is essential for cytotoxic activity against RT cells. Furthermore, we identified a few derivatives of 4-HPR with higher cytotoxic potencies than 4-HPR. In addition, we demonstrate that either chloro, fluoro or iodo derivatives at meta-position of phenyl ring retain the cytotoxic activity. Interestingly, substitution of iodo-moiety at meta-position (5j) substantially increased the efficacy (IC50 ∼ 3 μM, Fig. 1D). These results indicate that chemical modification of 4-HPR may result in derivatives with increased therapeutic potential for RTs and that halogen substituted 4-HPR that retain the activity can be synthesized for further therapeutic and diagnostic use.
KW - 4-HPR
KW - Cyclin D1
KW - Rhabdoid tumor
UR - http://www.scopus.com/inward/record.url?scp=44849137194&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=44849137194&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2008.05.021
DO - 10.1016/j.bmcl.2008.05.021
M3 - Article
C2 - 18515102
AN - SCOPUS:44849137194
VL - 18
SP - 3805
EP - 3808
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 13
ER -