Conformational stereospecificity in electrophilic reactions with cyclic anions

Lyle, Robert; Saavedra, Jose E.; Lyle, Gloria G.; Fribush, Howard M.; Marshall, John L.; Lijinsky, William; Singer, George M.

doi:10.1016/0040-4039(76)80135-9

Cited by 11 publications

(3 citation statements)

References 8 publications

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“…The reasons for these differences, particularly the failure of 56v to induce liver tumors, is probably not due to death of the animals before liver tumors can develop, since several nitrosamines have induced tumors in the liver of rats within 20 weeks from the bcginning of treatment. The increased potency of the 3-methyl derivative of 56s might be a consequence of the greater rigidity of the chair conformation of this compound compared with nitrosopiperidone, in conformity with the earlier suggestion of Lyle et al [120]. It is likely that all of these oxygenated cyclic nitrosamines are acting independcntly, and there is no evidence that 56, for example, exerts its carcinogenic action through oxidation at the 3-or 4-positions to alcohols or ketones.…”

Section: Effects Of Substituenl~ In Cyclic Nitrosarninessupporting

confidence: 61%

“…The trans form is considcrably more potent than the cis form, leading to death of the animals from the tumors at about the same time, but after administration of trans at only one sixth of the dose of cis isomer administered [119]. Although it has been suggestcd that the rigid chair forms of cyclic nitrosamines predispose to increased potency in inducing esophageal tumors in rats [120], this apparently is not the case for the isomers of 56d, nor its analog, nitroso-2,6-dimethylmorpholine (60b). Alkyl substituents affect the carcinogenicity of 56 at positions other than those alpha to the N-nitroso function.…”

Section: Effects Of Substituenl~ In Cyclic Nitrosarninesmentioning

confidence: 99%

“…leads to a reduction in carcinogenic potency compared with 69a) and again the tumors induced are in the upper GI tract and nasal mucosa, but not in liver of rats [149]. The 2,5-dimethyl derivative is considerably more potent than 69 itself, and the lesser activity compared with 69a might be due to the competition between the effect of the substituents in making the molecule a more rigid chair [120] and the blocking of some of the available t2-carbons by the methyl groups. This competition does not arise with the isomer 2,6-dimethyldinitrosopiperazine (69b), a very potent carcinogen in rats as measured by time-to-death with tumors (none in the liver), and much the most potent of the dinitrosopiperazines in inducing tumors of the upper G1 tract and nasal mucosa [149].…”

Section: Derivatives Of Piperazinementioning

confidence: 99%

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Structure-activity relations in carcinogenesis by N-nitroso compounds

Lijinsky

1987

Cancer Metast Rev

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111

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For a large number of N-nitroso compounds a comparison of their carcinogenic effects in rats and Syrian golden hamsters has been made. Nitrosamines, which require metabolic activation, and nitrosoalkylamides, which do not, produce quite different tumor responses. There are also large differences in the types of tumor induced in rats and in hamsters. In all the studies doses of the various compounds, equimolar to the extent that was possible, are administered orally. Continuous doses (in drinking water or food) often produce a response different from that after administration of the same compound in pulsed doses (by gavage), even though the same total dose is delivered. Continuous doses of nitrosamines are usually more effective than pulsed doses, but with the nitrosoalkylureas, the reverse is more generally the case. Rat and hamster liver is a common target of many nitrosamines, but rarely of nitrosamides. The most common site of tumor induction in rats by N-nitroso compounds is the esophagus, but the hamster esophagus never responds. The pancreas duct of the hamster is a common target of nitrosamines containing a beta-oxygenated propyl group, but pancreas duct tumors are never seen in rats. Nitrosomethyl-n-alkylamines (with an even numbered carbon chain) induce bladder tumors in rats and hamsters. Many nitrosoalkylureas induce tumors of the nervous system in rats, as well as a great variety of other tumors. In hamsters, nitrosoalkylureas give rise only to tumors of the forestomach and spleen, but no tumors of the nervous system. The similar carcinogenic actions of certain groups of N-nitroso compounds can be related to their generation, directly or by metabolism, of similar simple moieties having certain organs as their target.

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Section: Effects Of Substituenl~ In Cyclic Nitrosarninessupporting

confidence: 61%

Section: Effects Of Substituenl~ In Cyclic Nitrosarninesmentioning

confidence: 99%

Section: Derivatives Of Piperazinementioning

confidence: 99%

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Structure-activity relations in carcinogenesis by N-nitroso compounds

Lijinsky

1987

Cancer Metast Rev

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111

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1, 4, 5, 6‐Tetrahydro‐ν‐tetrazin‐Derivate

Seebàch

Dach

Enders

et al. 1978

Helvetica Chimica Acta

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1, 4, 5, 6‐Tetrahydro‐ν‐tetrazin‐Derivate The title compounds 2 and 13 are readily available from α‐lithiated N‐alkyl‐nitrosoamines 1 (see Tables 1 and 2) which decompose at − 73° to yield the N‐oxides 2. The ESR. spectra of two derivatives 1 are recorded (Fig. 1), and tentative mechanisms are proposed for the head to head dimerizations (la‐ 3‐ 4‐ 5‐ 2a and Scheme 1). Coupling of lithionitrosoamines with iodine (‐6) and alternative decomposition routes of representatives of this class of organometallics with special substitution [equations (2)‐(5)] are reported. The structures of the tetrazines are established by spectroscopic data [ESCA] (Fig. 2), IR., UV., 1H‐ (cf. Fig. 9) and 13C‐NMR., PE. (Scheme 2), by an X‐ray analysis of 2a (Fig. 4‐8 and Table 3), and by the chemical reactions. The crystal structure of 2a is a twisted boat with non planar terminal nitrogen atoms which reflects the electron repulsion in the 4‐atom‐6‐electron NNNN‐system. Comparisons are made with 2‐tetrazenes, the open chain analogues of 13, wherever possible. Raney‐Ni reductions of 2 or 13 gives diamines 14 to which is assigned the d, l‐configuration through the 1H‐NMR. spectra of the aminals 7 and 15. Neither the oxides 2 nor the tetrazines 13 undergo cycloaddition reactions [equation (6) and Section 4]. Compound 2a is dimerized to the bis (nitrosoamino)‐2‐tetrazene 18 by treatment with acid, ZnII, CuI or iodomethane. 2a is oxidized at nitrogen to the ethylene diamine derivative 6a (through 20, with H2O2), or at the CH2‐groups of the ring to give oxo‐N‐oxide 21 (with MnO2 or the ring contracted oxo‐tetrazoline‐N‐oxide 22 (with KMnO4). Pyrolysis or photolysis of the dimethyl tetrahydrotetrazine 13a furnishes the trimer 26 of N‐methylimine, but no diazetidine 27. Silver and mercury complexes 29 are obtained from 13a, while Cr(CO)5. THF does not furnish a complex as with azocompounds, but rather replaces N2 in 13a by CO (→ 28). Oxidation with permanganate converts 13a into the oxalic acid derivative 30 with unchanged tetrazine structure.

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Structure-Activity Relations in Carcinogenesis by N-Nitroso Compounds

Lijinsky¹

1984

Genotoxicology of N-Nitroso Compounds

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Conformational stereospecificity in electrophilic reactions with cyclic anions

Cited by 11 publications

References 8 publications

Structure-activity relations in carcinogenesis by N-nitroso compounds

Structure-activity relations in carcinogenesis by N-nitroso compounds

1, 4, 5, 6‐Tetrahydro‐ν‐tetrazin‐Derivate

Structure-Activity Relations in Carcinogenesis by N-Nitroso Compounds

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