title: Design, synthesis, and biological evaluation of hybrid molecules containing alpha-methylene-gamma-butyrolactones and polypyrrole minor groove binders.
abstract: We have synthesized and evaluated a series of hybrids of polypyrrole minor groove binders structurally related to the natural antitumor agent distamycin A, and alpha-methylene-gamma-butyrolactones with methyl, phenyl, and 4-substituted phenyl groups at the lactone C(gamma) position, denoted 5-17, for in vitro cytotoxic activity against a variety of cancer cell lines. The apoptotic and cytotoxic activities against several tumor cell lines are reported and discussed in terms of their structural differences in relation to both the number of N-methylpyrrole rings and the type of the alkylating unit tethered to the oligopeptidic frame. It may be noted that in general, and especially for 11, 12, and 17, the cytotoxicity of the hybrids was much greater than that of the alpha-methylene-gamma-butyrolactone units 24a-g alone. Using the human leukemia cell line HL-60, we have tested the effects of a selected series of compounds on programmed cell death (apoptosis). The results clearly indicate that 11, 12, and 17, but not 9, are able to induce apoptosis as demonstrated from (i) identification of nuclear changes associated with apoptosis using fluorescence microscopy and (ii) by DNA laddering on agarose gel electrophoresis. Compound 12 was the most potent, especially 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 critical role in chromatin architecture and DNA metabolism.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44100 Ferrara, Italy. pgb@ifeuniv.unife.it
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Maria
authors.initials: M
authors.lastname: Del Carmen Nunez
authors.forename: Mojgan Aghazadeh
authors.initials: MA
authors.lastname: Tabrizi
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Jaime
authors.initials: J
authors.lastname: Bermejo
authors.forename: Francisco
authors.initials: F
authors.lastname: Estévez
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D053938:DNA Fragmentation; D004354:Drug Screening Assays, Antitumor; D004587:Electrophoresis, Agar Gel; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D008856:Microscopy, Fluorescence; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C487371:3-(1-methyl-4-(1-methyl-4-(1-methyl-3-(2-phenyl-4-methylene-5-oxotetrahydrofuran-2-ylmethoxy)-1H-pyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamidine; D000970:Antineoplastic Agents; D011758:Pyrroles; D011065:Poly(ADP-ribose) Polymerases; D015107:4-Butyrolactone