Synthesis and biological properties of actinomycin D chromophoric analogues substituted at carbon 7 with aziridine and cyclopropyl functions.
The growing importance of functionalized tricyclic rings, e.g., cyclopropyl and aziridine, in numerous organic biomolecules led us to develop syntheses of novel actinomycin D (AMD) analogues substituted with aziridine and cyclopropyl functions. Reaction of 7-hydroxyactinomycin D with 1-aziridineethyl iodide and bromomethylcycloporopane afforded the desired 7-[2-(1-aziridinyl)ethoxy] and cyclopropylmethoxy analogues, respectively. Calf thymus DNA binding of these analogues was comparable to that of AMD as examined by UV-vis difference spectral measurements, CD techniques, and relaxation of supercoiled closed circular SV40 DNA, indicating an intercalative mode of binding to the DNA duplex. Thermal denaturation of DNA experiments employing higher temperatures than room temperature exhibit a thermal lability of the DNA analogue complexes, suggestive of a probable covalent bond formation with DNA bases. The analogues were found to be 1/4-1/40 as cytotoxic to human lymphoblastic CCRF-CEM leukemia and B16 melanoma cells in vitro as AMD, with ID50 values in the nanomolar concentration range.
Sehgal
R K
RK
Department of Obstetrics and Gynecology, Boston University School of Medicine, Massachusetts 02118.
Almassian
B
B
Rosenbaum
D P
DP
Zadrozny
R
R
Sengupta
S K
SK
D001388:Aziridines; D004247:DNA / Q000378:metabolism; D003609:Dactinomycin / Q000031:analogs & derivatives*; D006801:Humans; D007945:Leukemia, Lymphoid / Q000473:pathology; D008545:Melanoma / Q000473:pathology; D009691:Nucleic Acid Denaturation
D001388:Aziridines; D003609:Dactinomycin; D004247:DNA