A novel achiral seco-cyclopropylpyrido[e]indolone (CPyI) analog of CC-1065 and the duocarmycins: synthesis, DNA interactions, in vivo anticancer and anti-parasitic evaluation.
The synthesis of an achiral seco-hydroxy-aza-CBI-TMI analog (8) of the duocarmycins is reported. Its specificity for the DNA minor groove of AT-rich sequences and covalent bonding to adenine-N3 was ascertained by a thermal cleavage assay. Compound 8 was found to be cytotoxic in the nanomolar range against murine and human cancer cells. It was further demonstrated that compound 8 was active against murine melanoma (B16-F0) grown in C57BL/6 mice. Compound 8 was also shown to inhibit the growth of the protozoan parasites Leishmania donovani, Leishmania mexicana, Trypanosoma brucei, and Plasmodium falciparum in culture.
Chavda
Sameer
S
Division of Natural Sciences and Department of Chemistry, Hope College, 35 East 12th Street, Holland, MI 49423, USA.
Babu
Balaji
B
Yanow
Stephanie K
SK
Jardim
Armando
A
Spithill
Terry W
TW
Kiakos
Konstantinos
K
Kluza
Jerome
J
Hartley
John A
JA
Lee
Moses
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D000080890:Duocarmycins; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D021261:Parasitic Sensitivity Tests; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
D000903:Antibiotics, Antineoplastic; D000981:Antiprotozoal Agents; D000080890:Duocarmycins; D007211:Indoles; D011760:Pyrrolidinones; C018782:CC 1065; D004247:DNA; C058289:duocarmycin A