Kinase-mediated trapping of bi-functional conjugates of paclitaxel or vinblastine with thymidine in cancer cells.
In the present work, we explore the possibility of introducing selectivity to existing chemotherapeutics via the design of non-pro-drug, bi-functional molecules comprising a microtubule-binding agent and a substrate for a disease-associated kinase. The design, synthesis, and in vitro biological evaluation of paclitaxel-thymidine and vinblastine-thymidine bi-functional conjugates are reported here. This work provides the first account of 'kinase-mediated trapping' of cancer therapeutics.
Aspland
Simon E
SE
Acidophil LLC, 2330 W. Joppa Road, Suite 330, Lutherville, MD 21093, USA. saspland@acidophil.com
Ballatore
Carlo
C
Castillo
Rosario
R
Desharnais
Joel
J
Eustaquio
Trisha
T
Goelet
Philip
P
Guo
Zijian
Z
Li
Qing
Q
Nelson
David
D
Sun
Chengzao
C
Castellino
Angelo J
AJ
Newman
Michael J
MJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D017239:Paclitaxel / Q000008:administration & dosage*; D011494:Protein Kinases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013936:Thymidine / Q000008:administration & dosage*; D014747:Vinblastine / Q000008:administration & dosage*
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D014747:Vinblastine; D011494:Protein Kinases; D017239:Paclitaxel; D013936:Thymidine