Single-site chemical modification at C10 of the baccatin III core of paclitaxel and Taxol C reduces P-glycoprotein interactions in bovine brain microvessel endothelial cells.
A single-site modification of paclitaxel analogs at the C10 position on the baccatin III core that reduces interaction with P-glycoprotein in bovine brain microvessel endothelial cells is described. Modification and derivatization of the C10 position were carried out using a substrate controlled hydride addition to a key C9 and C10 diketone intermediate. The analogs were tested for tubulin assembly and cytotoxicity, and were shown to retain potency similar to paclitaxel. P-glycoprotein interaction was examined using a rhodamine assay and it was found that simple hydrolysis or epimerization of the C10 acetate of paclitaxel and Taxol C can reduce interaction with the P-glycoprotein transporter that may allow for increased permeation of taxanes into the brain.
Spletstoser
Jared T
JT
Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA.
Turunen
Brandon J
BJ
Desino
Kelly
K
Rice
Antonie
A
Datta
Apurba
A
Dutta
Dinah
D
Huff
Jacquelyn K
JK
Himes
Richard H
RH
Audus
Kenneth L
KL
Seelig
Anna
A
Georg
Gunda I
GI
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000166:cytology*; D002417:Cattle; D004347:Drug Interactions; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D008833:Microcirculation; D017239:Paclitaxel / Q000737:chemistry* / Q000494:pharmacology; D010539:Permeability; D012235:Rhodamines / Q000378:metabolism; D043823:Taxoids / Q000737:chemistry* / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids; D000970:Antineoplastic Agents; D012235:Rhodamines; D043823:Taxoids; C073950:baccatin III; D017239:Paclitaxel