Hybrids of polypyrrole minor groove binders structurally related to the natural antitumor agent distamycin A and -methylene--butyrolactones with Me, Ph, and 4-substituted Ph groups at the lactone C() position were prepd. and evaluated for in vitro cytotoxic activity against a variety of cancer cell lines. The apoptotic and cytotoxic activities against several tumor cell lines were reported and discussed in terms of their structural differences in relation to both the no. of N-methylpyrrole rings and the type of the alkylating unit tethered to the oligopeptidic frame. For polypyrroles I [R = C(:NH)NH2, n = 2, 3; R = NHC(:NH)NH2, n = 3] the cytotoxicity of the hybrids was much greater than that of the -methylene--butyrolactone units II (R1 = Me, Ph, 4-ClC6H4, 4-PhC6H4; m = 1, 3, 5, 7) alone. Using the human leukemia cell line HL-60, the effects of a selected series of compds. on programmed cell death (apoptosis) were detd. I [R = C(:NH)NH2, n = 2, 3; R = NHC(:NH)NH2, n = 3] induce apoptosis as demonstrated from identification of nuclear changes assocd. with apoptosis using fluorescence microscopy and by DNA laddering on agarose gel electrophoresis. I [R = C(:NH)NH2, n = 2] was the most potent, esp. after a short incubation period. It induced extensive hydrolysis of poly ADP-ribose polymerase (PARP), considered to be a hallmark of apoptosis, which plays a crit. role in chromatin architecture and DNA metab.
Design, synthesis, and biological evaluation of hybrid molecules containing alpha-methylene-gamma-butyrolactones and polypyrrole minor groove binders
BARALDI, Pier Giovanni;AGHAZADEH TABRIZI, Mojgan;ROMAGNOLI, Romeo
2004
Abstract
Hybrids of polypyrrole minor groove binders structurally related to the natural antitumor agent distamycin A and -methylene--butyrolactones with Me, Ph, and 4-substituted Ph groups at the lactone C() position were prepd. and evaluated for in vitro cytotoxic activity against a variety of cancer cell lines. The apoptotic and cytotoxic activities against several tumor cell lines were reported and discussed in terms of their structural differences in relation to both the no. of N-methylpyrrole rings and the type of the alkylating unit tethered to the oligopeptidic frame. For polypyrroles I [R = C(:NH)NH2, n = 2, 3; R = NHC(:NH)NH2, n = 3] the cytotoxicity of the hybrids was much greater than that of the -methylene--butyrolactone units II (R1 = Me, Ph, 4-ClC6H4, 4-PhC6H4; m = 1, 3, 5, 7) alone. Using the human leukemia cell line HL-60, the effects of a selected series of compds. on programmed cell death (apoptosis) were detd. I [R = C(:NH)NH2, n = 2, 3; R = NHC(:NH)NH2, n = 3] induce apoptosis as demonstrated from identification of nuclear changes assocd. with apoptosis using fluorescence microscopy and by DNA laddering on agarose gel electrophoresis. I [R = C(:NH)NH2, n = 2] was the most potent, esp. after a short incubation period. It induced extensive hydrolysis of poly ADP-ribose polymerase (PARP), considered to be a hallmark of apoptosis, which plays a crit. role in chromatin architecture and DNA metab.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.