Design, synthesis, and evaluation of mixed imine-amine pyrrolobenzodiazepine dimers with efficient DNA binding affinity and potent cytotoxicity.
Synthesis of mixed imine-amine pyrrolobenzodiazepine (PBD) dimers that are comprised of DC-81 and secondary amine (N10) of DC-81 subunits tethered to their C8 positions through alkanedioxy linkers (comprised of three and five carbons) is described. These noncross-linking unsymmetrical molecules exhibit significant DNA minor groove binding ability and one of them 5b linked through the pentanedioxy chain exhibits efficient DNA binding ability (DeltaTm=11.0 degrees C) when compared to naturally occurring DC-81, 1 (DeltaTm=0.7 degrees C). The imine-amine PBD dimers exhibit promising in vitro antitumor activity in a number of human cancer cell lines.
Kamal
Ahmed
A
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India. ahmedkamal@iict.res.in
Ramesh
G
G
Srinivas
O
O
Ramulu
P
P
Laxman
N
N
Rehana
Tasneem
T
Deepak
M
M
Achary
M S
MS
Nagarajaram
H A
HA
D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity*; D001483:Base Sequence; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D015195:Drug Design; D006801:Humans; D007097:Imines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011758:Pyrroles / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity*
D000588:Amines; D000970:Antineoplastic Agents; D007097:Imines; D007364:Intercalating Agents; D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines; D004247:DNA