The cytotoxicity, mutagenicity, and DNA damaging potential of trans-cyclopropylbis (diketopiperazine) (3) and chelating agents related to ICRF 159 (1) were examined as a function of concentration and duration of exposure in the Chinese hamster cell line V79A. At a concentration of 10(-3) M, 1 and the trans-cyclopropanediamine tetraacid 8 and ester 7 proved to be cytotoxic and mutagenic. The trans-cyclopropyl analogue 3 of ICRF 159 and acyclic tetraacid 6 were less cytotoxic at all concentrations; analogue 3 exhibited no mutagenic activity at any of the concentrations tested. Compounds 1, 7, and 8, at lethal concentrations, exhibited significantly different mutation frequencies with 7 being sixfold more mutagenic than 8 at the same molar concentration. At 10(-3) M compounds 8 was several times more effective blocking DNA replication than other analogues but did not induce unscheduled DNA synthesis as did 1,3, and 6. With the exception of 8, there was an excellent correlation between mutagenesis and the induction of unscheduled DNA synthesis.
Abstract— The levels of DNA excision repair, as measured by unscheduled DNA synthesis (UDS) and the UV‐endonuclease sensitive site assay, were compared in cells derived from human fetal brain and dermal tissues. The level of UDS induced following ultraviolet (UV) irradiation was found to be lower (approx. 60%) in the fetal brain cells than in fetal dermal cells. It was determined, using the UV‐endonuclease sensitive site assay to confirm the UDS observation, that 50% of the dimers induced by UV in fetal dermal cells were repaired in 8h, while only 15% were removed in the fetal brain cells during the same period of time. Even after 24 h, only 44% of the dimers induced by UV in the fetal brain cells were repaired, while 65% were removed in the dermal cells. These data suggest that cultured human fetal brain cells exhibit lower levels of excision repair compared to cultured human fetal dermal cells.
For purposes of studying stereostructure-activity relationships at the molecular, cellular, and animal levels and probing the mechanism of 2-mercaptoethylamine (MEA) radioprotection we synthesized several conformationally constrained cyclobutyl analogs. The comparative radioprotective properties for MEA, cis- and trans-2-mercaptocyclobutylamine (2), cis- and trans-2-mercaptocyclobutylmethylamine (3), and trans-2-mercaptomethylcyclobutylamine (4) are discussed in terms of their ability to chemically reduce transient free radicals, the formation of single strand breaks in DNA, and protect Chinese hamster cells (in vitro) and mice against the lethal effects of ionizing radiation. The results are interpreted in light of current proposed mechanisms of action for MEA. No correlation exists between ability of these analogs to enhance mice survival times and their ability to protect against the induction of DNA single strand breaks and the inactivation of proliferative capacity of hamster cells growing in vitro. Analysis of two isomers (cis- and trans-3) on the repair of single strand breaks showed both isomers only marginally influenced the rate and did not influence of extent of single strand break rejoining. The results are consistent with a mode of action involving chemical repair of transient radicals and protection against DNA and critical enzymatic sites.
Aus Cyclopropan‐trans‐dicarbonsäure (Ia) wird über das Chlorid (Ib) und das Azid (Ic) das Isocyanat (II) hergestellt, das über das tert.‐Butylurethan (IIIa) zum Diamin (IIIb) führt.
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