Synthesis, crystallization, and biological evaluation of an orally active prodrug of gemcitabine.
The design, synthesis, and biological characterization of an orally active prodrug (3) of gemcitabine are described. Additionally, the identification of a novel co-crystal solid form of the compound is presented. Valproate amide 3 is orally bioavailable and releases gemcitabine into the systemic circulation after passing through the intestinal mucosa. The compound has entered clinical trials and is being evaluated as a potential new anticancer agent.
Bender
David M
DM
Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana 46285, USA. dbender@lilly.com
Bao
Jingqi
J
Dantzig
Anne H
AH
Diseroad
William D
WD
Law
Kevin L
KL
Magnus
Nicholas A
NA
Peterson
Jeffrey A
JA
Perkins
Everett J
EJ
Pu
Yangwei J
YJ
Reutzel-Edens
Susan M
SM
Remick
David M
DM
Starling
James J
JJ
Stephenson
Gregory A
GA
Vaid
Radhe K
RK
Zhang
Deyi
D
McCarthy
James R
JR
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000188:drug therapy; D003460:Crystallization; D018360:Crystallography, X-Ray; D003562:Cytidine / Q000737:chemistry; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012995:Solubility; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D011355:Prodrugs; D003841:Deoxycytidine; D003562:Cytidine; D000093542:Gemcitabine