6 Some Pyrimidines of Biological and Medicinal Interest—Part II

Cheng, C. C.; Roth, Barbara

doi:10.1016/s0079-6468(08)70356-4

Cited by 17 publications

(5 citation statements)

References 434 publications

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“…Diastereomer 23: [<x]25d = -47.5°(c 0.16, MeOH); Rf 0.61 (CHClg-MeOH, 9:1, v/v); oil; yield (20 mg, 26%); NMR (CDClg) <5 1.98 (s, 3H, CHg), 2.30-2.54 (m, 2H, H-2'), 3.86-4.06 (m, 3H total, H-4', H-5'), 4.32-4.40 (m, 1H, H-3'), 5.74 (s, 1H, H-6), 6.04 (t, Jr 2-= 7.2 Hz, 1H, H-l'), 8.25 (+)-tmne-(5fi,6R)-5-Chloro-6-azido-5,6-dihydro-3'-azido-3'-deoxythymidine (24), (-)-#rons-(5S,6S)-5-Chloro-6azido-5,6-dihydro-3'-azido-3'-deoxythymidine (25), (+)• cis-(5S,6H)-5-Chloro-6-azido-5,6-dihydro-3'-azido-3'deoxythymidine (26), and (-)-cts-(5H,6S)-5-Bromo-6azido-5,6-dihydro-3'-azido-3'-deoxythymidine (27). AT-Chlorosuccinimide (0.125 g, 0.8 mmol) was added slowly to a precooled (-5 °C) suspension prepared by mixing a solution of AZT (0.1 g, 4 mmol) in 1,2-dimethoxyethane (10 mL) and a solution of sodium azide (0.1 g, 1.6 mmol) in water (0.25 mL).…”

Section: Methodsmentioning

confidence: 99%

“…25 Physiological dihydro nucleosides play an important role in nucleic acid metabolism and appear frequently in the sequence of t-RNA. 26 Previous studies have shown that 5,6- Scheme 1"…”

mentioning

confidence: 99%

“…IV-bromosuccinimide, NaNg, 1,2-dimethoxyethane, 0 °C (products 21-23); AT-chlorosuccinimide, NaNg, 1,2-dimethoxyethane, 25 °C (products [24][25][26][27].…”

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confidence: 99%

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Synthesis, in vitro Biological Stability, and Anti-HIV Activity of 5-Halo-6-alkoxy(or azido)-5,6-dihydro-3'-azido-3'-deoxythymidine Diastereomers as Potential Prodrugs to 3'-Azido-3'-deoxythymidine (AZT)

Kumar¹,

Wang²,

Wiebe³

et al. 1994

J. Med. Chem.

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A new class of 5-halo-6-alkoxy(or azido)-5,6-dihydro-3'-azido-3'-deoxythymidines was investigated as potential anti-AIDS drugs. These 5,6-dihydro derivatives, which are also potential prodrugs to 3'-azido-3'-deoxythymidine (AZT), were designed in an effort to enhance the duration of action, lipophilicity, and cephalic delivery to the central nervous system. The 5-halo-6-alkoxy(or azido)-5,6-dihydro-3'-azido-3'-deoxythymidines, which differ in configuration at the C-5 and C-6 positions, were synthesized by the regiospecific addition of XR (X = Br, Cl, I; R = alkoxy, azido) to the 5,6-olefinic bond of AZT. The 5-halo-6-methoxy-5,6-dihydro derivatives of AZT are more lipophilic (P = 3.3-18.8 range) than the parent compound AZT (P = 1.29). These 5-halo-6-methoxy-5,6-dihydro compounds, like AZT, did not undergo glycosidic bond cleavage upon incubation with Escherichia coli thymidine phosphorylase. Regeneration of the 5,6-olefinic bond to give AZT, upon incubation of the 5-halo-6-methoxy-5,6-dihydro compounds with glutathione, mouse blood, or mouse liver homogenate, was dependent upon the nature of the 5-halo substituent (I > Br). No 5,6-olefinic bond regeneration was observed for the 5-chloro analogs. The ability of these 5-halo-6-alkoxy (or azido)-5,6-dihydro-3'-azido-3'-deoxythymidines to protect CEM cells against HIV-induced cytopathogenicity was evaluated. Structure-activity studies showed that the C-5 substituent (I, Br, Cl) was a determinant of anti-HIV-1 activity where the potency order was I > or = Br > Cl. In the 5-bromo series of compounds, the C-6 substituent was also a determinant of activity where 6-OMe and 6-OEt substituents exhibited a greater potency than the corresponding 6-i-PrO, 6-(1-octyloxy), 6-(1-hexadecyloxy), and 6-azido analogs. All of the 5-chloro-6-substituted-5,6-dihydro compounds were inactive, except for the approximately equipotent 6-OMe and 6-azido diastereomeric mixtures which were 2-3 log units less active than the reference drug AZT. The configuration at the C-5 and C-6 positions also influenced potency where the activity of the 5R,6R-diastereomer was generally greater than that of the corresponding 5S,6S-diastereomer.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Methodsmentioning

confidence: 99%

“…25 Physiological dihydro nucleosides play an important role in nucleic acid metabolism and appear frequently in the sequence of t-RNA. 26 Previous studies have shown that 5,6- Scheme 1"…”

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confidence: 99%

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Synthesis, in vitro Biological Stability, and Anti-HIV Activity of 5-Halo-6-alkoxy(or azido)-5,6-dihydro-3'-azido-3'-deoxythymidine Diastereomers as Potential Prodrugs to 3'-Azido-3'-deoxythymidine (AZT)

Kumar¹,

Wang²,

Wiebe³

et al. 1994

J. Med. Chem.

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“…The purported pharmacologic uses of orotic acid are numerous (30). Orotic acid has been claimed t o increase the rate of regeneration after myocardial infarction; t o counteract galactose-induced cataract and aid in the management of galactosemia; t o nullify the diabetogenic action of alloxan; and t o have an anti-inflammatory action in gouty arthritis similar t o colchicine.…”

Section: Mammary Glandmentioning

confidence: 99%

A Review: Biological and Clinical Aspects of Pyrimidine Metabolism

1974

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Interest in pyrimidine nucleotide biosynthesis has stemmed largely from the importance of these molecules as components of nucleic acids. Regulation of pyrimidine biosynthesis has been most extensively investigated in micro-organisms in which cell division is effectively controlled by regulation of the activity of the enzymes of the d e n o v o pathway (77, 11 0). The relation between pyrimidine biosynthesis and cellular proliferation in mammals has become clearer with the accumulation of a considerable body of evidence which indicates that there is a close correlation between the activity of enzymes involved in pyrimidine biosynthesis and the rate of cellular proliferation.The d e n o v o pyrimidine biosynthetic pathway and the urea cycle b o t h utilize carbamyl phosphate, and important nitrogen carrier. The biosynthesis of pyrimidine and purine nucleotides are connected by a common intermediate, phosphoribosyl pyrophosphate (PRPP). In addition, pyrimidine nucleotides act as sugar and phospholipid carriers and are important in lipopolysaccharide biosynthesis. The importance of these interrelations is most forcibly emphasized b y certain clinical phenomena which will be discussed later. This paper will attempt t o review the broad biologic aspects of pyrimidine nucleotide biosynthesis. A detailed consideration of d e n o v o pyrimidine biosynthesis in eucaryotic cells is available in the recent review by Jones (81). Pyrimidine biosynthesis in procaryotes has been reviewed in depth by O'Donovan and Neuhard (1 10). PATHWAYS O F PYRIMIDINE NUCLEOTIDE BIOSYNTHESISIn cells from multicellular organisms, pyrimidine nucleotide biosynthesis can proceed b y two mechanisms. D e n o v o biosynthesis of uridylic acid proceeds from simple components such as carbon dioxide, a source of nitrogen (either ammonia or the amide nitrogen of glutamine), ATP, aspartate. and ribose in the form of phosphoribosyl p y r~p h o s~h a t e . A reutilization ("salvage") mechanism is also available t o cells.-.whereby preformed pyrimidine bases o r nucleosides can be converted t o the nucleotide by the addition of ribose phosphate or phosphate. DE NOVO MECHANISMD e n o v o biosynthesis of uridylic acid required six enzymatic steps (Fig. 1). In procaryotes one enzyme supplies the carbamyl phosphate required for both pyrimidine nucleotide and arginine biosynthesis. Consequently, aspartate transcarbamylase is the first enzyme unique to the d e n o v o pyrimidine pathway and an important locus for control of the pathway (77).In contrast, in ureotelic vertebrates, there are t w o carbamyl phosphate synthetases. The first, carbamyl phosphate synthetase I, is located in the inner membrane of the mitochondrion of the liver and also appears t o be present in small quantities in kidney and small intestine (82). The second, carbamyl phosphate syntlietase 11, has a more ubiquitous distribution and was first demonstrated t o be present in Ehrlich ascites cells (58,59) and in hematopoietic mouse spleen (75,143). This enzyme was originally difficult t o dete...

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“…[36] Monoaddition (dihydropyridines) and double-addition products (tetrahydropyridine-fused lactones) are of interest because of their biological activities. [16,17,[39][40][41][42] Specifically, we are interested in the reactivity of the monoactivated trifluoromethyl sulfonyl derivatives and how the trifluoromethanesulfonic moiety can be removed to afford the aromatic pyridine. The goal of the present work is to find a good methodology to complete the sequence of activation, nucleophilic reaction, and deprotection that will allow having an activated substrate again to perform new substitutions and thus opening endless synthetic possibilities.…”

Section: Introductionmentioning

confidence: 99%

Rearomatization of trifluoromethyl sulfonyl dihydropyridines: Thermolysis vs photolysis

Firpo

Cooke

Peláez

et al. 2017

J of Physical Organic Chem

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In this article, we describe the static gas‐phase pyrolysis, microwave‐induced pyrolysis, and photolysis reactions of trifluoromethyl sulfonyl dihydropyridines. The goal of this work was to find a methodology that allows obtaining of substituted pyridines—which are known to be difficult to synthesize—to be reused in a new substitution reaction. We demonstrated that it is possible to achieve the rearomatization process by the elimination of the trifluoromethyl sulfonyl moiety through the 3 processes, with the static pyrolysis being the best method to obtain the substituted pyridines. In addition, we propose the 1,4‐elimination (CF3SO2 + H) as the first step, since it is the less energetic process, as has also been corroborated by calculations. A competitive reaction (CO2 extrusion) also occurs, yielding undesired products.

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6 Some Pyrimidines of Biological and Medicinal Interest—Part II

Cited by 17 publications

References 434 publications

Synthesis, in vitro Biological Stability, and Anti-HIV Activity of 5-Halo-6-alkoxy(or azido)-5,6-dihydro-3'-azido-3'-deoxythymidine Diastereomers as Potential Prodrugs to 3'-Azido-3'-deoxythymidine (AZT)

Synthesis, in vitro Biological Stability, and Anti-HIV Activity of 5-Halo-6-alkoxy(or azido)-5,6-dihydro-3'-azido-3'-deoxythymidine Diastereomers as Potential Prodrugs to 3'-Azido-3'-deoxythymidine (AZT)

A Review: Biological and Clinical Aspects of Pyrimidine Metabolism

Rearomatization of trifluoromethyl sulfonyl dihydropyridines: Thermolysis vs photolysis

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