Abstract
Psorospermin is a natural product that has been shown to have activity against drug-resistant leukemia lines and AIDS-related lymphoma. It has also been shown to alkylate DNA through an epoxide-mediated electrophilic attack, and this alkylation is greatly enhanced at specific sites by topoisomerase II. In this article, we describe the synthesis of the two diastereomers of O5-methyl psorospermin and their in vitro activity against a range of solid and hematopoietic tumors. The diastereomeric pair (±)-(2′ R,3′ R) having the naturally occurring enantiomer (2′ R,3′ R) is the most active across all the cell lines and shows approximately equal activity in both drug-sensitive and drug-resistant cell lines. In subsequent studies using all four enantiomers of O5-methyl psorospermin, the order of biological potency is (2′ R,3′ R) > (2′ R,3′ S) = (2′ S,3′ R) > (2′ S,3′ S). This order of potency is also found in the topoisomerase II-induced alkylation of O5-methyl psorospermin and can be rationalized by molecular modeling of the psorospermin-duplex binding complex. Therefore, this study defines the optimum stereochemical requirements for both the topoisomerase II-induced alkylation of DNA and the biological activity by psorospermin and its O5-methyl derivatives. Finally, (2′ R,3′ R) psorospermin was found to be as effective as gemcitabine in slowing tumor growth in vivo in a MiaPaCa pancreatic cancer model. In addition, (2′ R,3′ R) psorospermin in combination with gemcitabine was found to show an at least additive effect in slowing tumor growth of MiaPaCa.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1729-1739 |
| Number of pages | 11 |
| Journal | Molecular Cancer Therapeutics |
| Volume | 4 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 2005 |
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ASJC Scopus subject areas
- Oncology
- Drug Discovery
- Pharmacology
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Determination of the importance of the stereochemistry of psorospermin in topoisomerase II-induced alkylation of DNA and in vitro and in vivo biological activity. / Fellows, Ingrid M.; Schwaebe, Michael; Dexheimer, Thomas S.; Vankayalapati, Hariprasad; Gleason-Guzman, Mary; Whitten, Jeffrey P.; Hurley, Laurence.
In: Molecular Cancer Therapeutics, Vol. 4, No. 11, 11.2005, p. 1729-1739.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Determination of the importance of the stereochemistry of psorospermin in topoisomerase II-induced alkylation of DNA and in vitro and in vivo biological activity
AU - Fellows, Ingrid M.
AU - Schwaebe, Michael
AU - Dexheimer, Thomas S.
AU - Vankayalapati, Hariprasad
AU - Gleason-Guzman, Mary
AU - Whitten, Jeffrey P.
AU - Hurley, Laurence
PY - 2005/11
Y1 - 2005/11
N2 - Psorospermin is a natural product that has been shown to have activity against drug-resistant leukemia lines and AIDS-related lymphoma. It has also been shown to alkylate DNA through an epoxide-mediated electrophilic attack, and this alkylation is greatly enhanced at specific sites by topoisomerase II. In this article, we describe the synthesis of the two diastereomers of O5-methyl psorospermin and their in vitro activity against a range of solid and hematopoietic tumors. The diastereomeric pair (±)-(2′ R,3′ R) having the naturally occurring enantiomer (2′ R,3′ R) is the most active across all the cell lines and shows approximately equal activity in both drug-sensitive and drug-resistant cell lines. In subsequent studies using all four enantiomers of O5-methyl psorospermin, the order of biological potency is (2′ R,3′ R) > (2′ R,3′ S) = (2′ S,3′ R) > (2′ S,3′ S). This order of potency is also found in the topoisomerase II-induced alkylation of O5-methyl psorospermin and can be rationalized by molecular modeling of the psorospermin-duplex binding complex. Therefore, this study defines the optimum stereochemical requirements for both the topoisomerase II-induced alkylation of DNA and the biological activity by psorospermin and its O5-methyl derivatives. Finally, (2′ R,3′ R) psorospermin was found to be as effective as gemcitabine in slowing tumor growth in vivo in a MiaPaCa pancreatic cancer model. In addition, (2′ R,3′ R) psorospermin in combination with gemcitabine was found to show an at least additive effect in slowing tumor growth of MiaPaCa.
AB - Psorospermin is a natural product that has been shown to have activity against drug-resistant leukemia lines and AIDS-related lymphoma. It has also been shown to alkylate DNA through an epoxide-mediated electrophilic attack, and this alkylation is greatly enhanced at specific sites by topoisomerase II. In this article, we describe the synthesis of the two diastereomers of O5-methyl psorospermin and their in vitro activity against a range of solid and hematopoietic tumors. The diastereomeric pair (±)-(2′ R,3′ R) having the naturally occurring enantiomer (2′ R,3′ R) is the most active across all the cell lines and shows approximately equal activity in both drug-sensitive and drug-resistant cell lines. In subsequent studies using all four enantiomers of O5-methyl psorospermin, the order of biological potency is (2′ R,3′ R) > (2′ R,3′ S) = (2′ S,3′ R) > (2′ S,3′ S). This order of potency is also found in the topoisomerase II-induced alkylation of O5-methyl psorospermin and can be rationalized by molecular modeling of the psorospermin-duplex binding complex. Therefore, this study defines the optimum stereochemical requirements for both the topoisomerase II-induced alkylation of DNA and the biological activity by psorospermin and its O5-methyl derivatives. Finally, (2′ R,3′ R) psorospermin was found to be as effective as gemcitabine in slowing tumor growth in vivo in a MiaPaCa pancreatic cancer model. In addition, (2′ R,3′ R) psorospermin in combination with gemcitabine was found to show an at least additive effect in slowing tumor growth of MiaPaCa.
UR - http://www.scopus.com/inward/record.url?scp=28044437963&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=28044437963&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-05-0183
DO - 10.1158/1535-7163.MCT-05-0183
M3 - Article
C2 - 16275994
AN - SCOPUS:28044437963
VL - 4
SP - 1729
EP - 1739
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 11
ER -