Potent inhibition of ornithine decarboxylase by β, γ unsaturated substrate analogs

Relyea, Noël M.; Rando, Robert R.

doi:10.1016/0006-291x(75)90328-9

Cited by 52 publications

(13 citation statements)

References 11 publications

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“…The administration of MGBG to cells in culture or to whole animals led to a decrease in spermidine levels and an increase in putrescine levels (Holtta et al, 1973;Heby and Russell, 1974;Heby et al, 1975), presumably because putrescine was not being converted to spermidine. In addition, ODC activity was stimulated (McCann et al, 1977;Relyea and Rando, 1975;Holtta et al, 1973); this also contributed to putrescine accumulation. The intracellular level of SAMDC was also increased by exposure to MGBG (Pegg et al, 1973;Holtta et al, 1973); thus increasing amounts of MGBG are required to maintain a depressed rate of spermidine synthesis.…”

Section: Dataare Means Of Triplicate Cultures; Standard Errors L D T mentioning

confidence: 99%

Effects of inhibitors of ornithine and S‐adenosylmethionine decarboxylases on L6 myoblast proliferation

Stoscheck¹,

Erwin²,

Richman³

et al. 1982

Journal Cellular Physiology

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The role of polyamines in myoblast proliferation was studied by treating cells of Yaffe's L6 line of rat myoblasts with inhibitors of polyamine synthesis. Both an irreversible inhibitor of ornithine decarboxylase--difluoromethyl-ornithine (DFMO)--and a competitive inhibitor of S-adenosyl-methionine decarboxylase--methylglyoxal-bis(guanylhydrazone) (MGBG)--depressed spermidine levels and inhibited myoblast proliferation. Spermine levels were not significantly depressed by either inhibitor and putrescine levels were decreased only by DFMO. Putrescine and spermidine, but not magnesium, prevented inhibition of myoblast proliferation by DFMO and MGBG; determination of 14C-DFMO uptake in the presence and absence of these compounds demonstrated that they did not reduce the rate or extent of inhibitor uptake and thus prevent its inhibition of ornithine decarboxylase. Thus it seems likely that these inhibitors reduce cell proliferation by inhibiting polyamine formation. Addition of spermidine to the cells led to a substantial reduction in the activity of S-adenosyl-methionine-decarboxylase, suggesting that the enzyme is subject to negative regulation by the products of the polyamine biosynthetic pathway. Unexpectedly, addition of spermidine also increased intracellular putrescine levels; this apparently resulted from conversion of spermidine to putrescine. Addition of putrescine or spermidine in the absence of serum did not increase the rate of myoblast proliferation although it did elevate intracellular polyamine levels as expected. We conclude that some threshold level of one or more polyamines (probably spermidine) is necessary but not sufficient for initiation and maintenance of myoblast proliferation in culture.

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Section: Dataare Means Of Triplicate Cultures; Standard Errors L D T mentioning

confidence: 99%

Effects of inhibitors of ornithine and S‐adenosylmethionine decarboxylases on L6 myoblast proliferation

Stoscheck¹,

Erwin²,

Richman³

et al. 1982

Journal Cellular Physiology

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“…Compound (R)-12 is a key intermediate of peptide-type growth hormone secretagogue, which can be used to promote the growth of food animals and to treat some human diseases, such as congestive heart failure and short stature in growth hormone-deficient children (47)(48)(49)(50). Previous studies on the synthesis of compound 12 was focused on the bioresolution approach using D-aminoacylase as a resolution enzyme (47)(48)(49)(50) and chiral auxiliaries-induced stoichiometric asymmetric synthesis (32) (51,52), and, so far, several relatively long routes using chiral starting materials or auxiliaries have been developed for this aim (53)(54)(55)(56)(57). The present catalytic asymmetric alkynylation of ␣-imino ester 1, combined with semireduction, provides a catalytic introduction of the vinyl group to amino acid derivatives.…”

Section: Resultsmentioning

confidence: 99%

Catalytic asymmetric alkynylation of α-imino ester: A versatile approach to optically active unnatural α-amino acid derivatives

Chan

2005

Proc. Natl. Acad. Sci. U.S.A.

104

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The catalytic asymmetric introduction of alkynyl functionality to ␣-amino acid derivatives was realized by the direct addition of terminal alkynes to ␣-imino ester in the presence of chiral Cu(I) complex under mild reaction conditions. Owing to the rich chemistry to which alkyne can be subjected, the present system provides a remarkably versatile tool for the construction of optically active ␣-amino acid derivatives. Good yields and enantiomeric excess values were achieved with an array of terminal alkynes and challenging, biologically active, unnatural ␣-amino acid derivatives could be conveniently obtained. asymmetric catalysis Optically active nonproteinogenic ␣-amino acids are of exceptional and rapidly increasing popularity as important tools in protein engineering and peptide-based drug discovery due mainly to their implementation into nonscissile peptide mimics and peptide isosteres (1-7). Hence, intense research has been focused on the preparation of enantiomerically enriched unnatural ␣-amino acids, and, so far, several approaches, such as bioresolution routes (8-10) and the rhodium-or rutheniumcatalyzed asymmetric hydrogenation of dehydroamino acids derivatives (11-13), have shown much promise. Nevertheless, there is still a great demand for more efficient and, especially, technically feasible methods for convenient construction of various types of rational designed unnatural amino acid derivatives. In this regard, enantioselective nucleophilic addition to ␣-imino esters represents one of the most direct strategies (14), because a new chiral center and a new COC bond can be built in a single operation and an appropriately designed side chain can be introduced in the meantime. Previous work in this field mainly focused on the catalytic asymmetric alkylation of ␣-imino esters, in which enol silane (15-18), allyl-metal compounds (19,20), trimethylsilyl nitronate (21), ketone (22), and nitroalkane (23) have been used as nucleophiles.Recently, we reported the successful alkynylation of ␣-imino ester by demonstrating the feasibility of direct addition of terminal alkynes to ␣-imino ester 1 in the presence of Ag(I) salts under mild reaction conditions (Scheme 1) (24). In this process, a new bond between an sp 3 carbon and an sp carbon is formed.Capitalizing on this method, we envisioned an attractive route to optically active ␣-amino acid derivatives via the direct asymmetric alkynylation of ␣-imino ester. The following considerations are particularly noteworthy:1. The HC'C moiety is an excellent two-carbon medium for the delivery of biologically interesting units into the ␥-position of ␣-amino acids, because it could be easily hydrogenated to saturated status after completing the nucleophile role. In contrast, owing to the rich chemistry to which alkyne can be subjected, the presence of a C'C bond in the desired targets offers a unique and highly valuable opportunity for further synthetic elaboration on the ␤,␥-positions of ␣-amino acids. For example, semireduction of the products could directly afford vinyl...

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“…Inonue et al (1975) reported that a-hydrazino-3-aminovaleric acid (5-amino-2-hydrazinopentanoic acid; a derivative of ornithine) inhibited ornithine decarboxylase activity, putrescine accumulation and DNA synthesis in mouse parotid gland. Unsaturated derivatives of ornithine and putrescine have also been used as inhibitors of polyamine synthesis in chick-embryo muscle cultures (Relyea & Rando, 1975). One of these, dehydro-ornithine, has been shown to inhibit cell division and differentation when added to muscle cell cultures (Relyea & Rando, 1975 (Kay & Pegg, 1973).…”

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confidence: 99%

“…Unsaturated derivatives of ornithine and putrescine have also been used as inhibitors of polyamine synthesis in chick-embryo muscle cultures (Relyea & Rando, 1975). One of these, dehydro-ornithine, has been shown to inhibit cell division and differentation when added to muscle cell cultures (Relyea & Rando, 1975 (Kay & Pegg, 1973).…”

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confidence: 99%

Inhibition of polyamine accumulation and deoxyribonucleic acid synthesis in regenerating rat liver

Pösö¹,

Jänne²

1976

Biochemical Journal

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Repeated injections of 1,3-diaminopropane into rats after partial hepatectomy caused a repression-type inhibition of liver ornithine decarboxylase (EC 4.1.1.17) and totally prevented the marked increases in liver putrescine and spermidine concentrations that normally occur in response to partial hepatectomy. The inhibition of polyamine synthesis by diaminopropane was accompanied by a profound decrease (about 80 %) in the synthesis of DNA in the regenerating rat liver without any changes in the synthesis of RNA and total liver protein.

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Potent inhibition of ornithine decarboxylase by β, γ unsaturated substrate analogs

Cited by 52 publications

References 11 publications

Effects of inhibitors of ornithine and S‐adenosylmethionine decarboxylases on L6 myoblast proliferation

Effects of inhibitors of ornithine and S‐adenosylmethionine decarboxylases on L6 myoblast proliferation

Catalytic asymmetric alkynylation of α-imino ester: A versatile approach to optically active unnatural α-amino acid derivatives

Inhibition of polyamine accumulation and deoxyribonucleic acid synthesis in regenerating rat liver

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