Synthesis of a novel C2/C2'-aryl-substituted pyrrolo[2,1-c][1,4]benzodiazepine dimer prodrug with improved water solubility and reduced DNA reaction rate.
A prodrug form (17) of a novel C2/C2'-aryl-substituted pyrrolobenzodiazepine (PBD) dimer (16) has been synthesized by introducing sodium bisulfite groups to the C11/C11'-positions of the parent bis-imine. The prodrug form is highly water soluble, stable in aqueous conditions, and the rate of DNA cross-link formation is much slower compared to the parent bis-imine.
Howard
Philip W
PW
Spirogen Ltd, The School of Pharmacy, 29-39 Brunswick Square, London WC1N1AX, UK. philip.howard@spirogen.com
Chen
Zhizhi
Z
Gregson
Stephen J
SJ
Masterson
Luke A
LA
Tiberghien
Arnaud C
AC
Cooper
Nectaroula
N
Fang
Min
M
Coffils
Marissa J
MJ
Klee
Sarah
S
Hartley
John A
JA
Thurston
David E
DE
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004852:Epoxy Compounds / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D011355:Prodrugs; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C423343:1,1'-((propane-1,3-diyl)dioxy)bis(7-methoxy-2-methylidene-1,2,3,10,11,11a-hexahydro-5H-pyrrolo(2,1-c)(1,4)benzodiazepin-5,11-dione); D001570:Benzodiazepinones; D004852:Epoxy Compounds; D011355:Prodrugs; D011758:Pyrroles; D001569:Benzodiazepines; D004247:DNA