Design, synthesis, and biological evaluation of achiral analogs of duocarmycin SA.
The design, synthesis, as well as biochemical and biological evaluation of two novel achiral analogs of duocarmycin SA (DUMSA), 1 and 2, are described. Like CC-1065 and adozelesin, compounds 1 and 2 covalently reacted with adenine-N3 in AT-rich sequences and led to the formation of DNA strand breaks upon heating. The cytotoxicity of compounds 1 and 2 against human cancer cells (K562, LS174T) was determined using a MTT assay giving IC(50) values in the low nanomolar. Further cytotoxicity screening of compound 2 conducted by the NCI against a panel of 60 different human cancer cell lines indicated that it was particularly active against several solid tumor cells lines derived from the lung, colon, CNS, skin, and breast.
Daniell
Kristen
K
Department of Chemistry, Furman University, Greenville, SC 29613, USA.
Stewart
Michelle
M
Madsen
Erik
E
Le
Minh
M
Handl
Heather
H
Brooks
Natalie
N
Kiakos
Konstantinos
K
Hartley
John A
JA
Lee
Moses
M
D001483:Base Sequence; D045744:Cell Line, Tumor; D004249:DNA Damage; D017931:DNA Primers; D004353:Drug Evaluation, Preclinical; D000080890:Duocarmycins; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D017931:DNA Primers; D000080890:Duocarmycins; D007211:Indoles; D011758:Pyrroles; C066098:duocarmycin SA