Synthesis and Biological Effects of 5′-Deoxy-5′-(Cyclo-Propylmethylthio)Adenosine

Abstract

A novel synthesis of the nucleoside analog, 5′-deoxy-5′-(cyclopropylmethylthio)adenosine (CPMTA, 1) has been developed. CPMTA is a closely related structural analog of 5′-deoxy-5′-(isobutylthio)-adenosine (SIBA, 2), which has been widely studied and shown to exert a multitude of biological effects. The in vitro and in vivo antitumor (L1210 leukemia) activity of CPMTA has been found to be comparable to that of SIBA, whereas its in vitro antiviral (HSV and VSV) activity is diminished. These agents are being developed as inhibitors of methylation and/or polyamine synthesis.     

Improved Synthesis of Adenosine Cyclic 3′, 5′-Phosphoramidates via Anhydrides. Preparation of Adenosine Cylic 3′, 5′-(Rp) - and (p)-N-Methylphosphoramidate

Abstract

The two-step method for the preparation of adenosine cyclic 3′,5′-phosphoramidate diastereoisomers, which involves the activation of adenosine cyclic 3′,5′-monophosphate (1) with an acid chloride and in situ aminolysis of the anhydride intermediate (Bentrude, W.G.; Tomsaz, J. Synthesis 1984, 27; Bottka, S.; Tomasz, J. Tetrahedron Lett. 1985, 24, 2909), has been improved. The best yields were attained when 1 was reacted with 4.4 molar equivalents of phosphorus oxychloride in trimethyl phosphate at O°C for 3 h, and the solution of phosphorus oxychloride in trimethyl phosphate was pretreated with 0.5 molar equivalent of water at room temperature for 20 min. R _p and S _p diastereoisomers of adenosine cyclic 3′,5′-N-methyphosphoramidate and N,N-dimethylphosphoramidate have been synthesized under these experimental conditions.     

A Synthesis of the Potent A2 Selective Adenosine Agonist N6-[2-(3,5-Dimethoxyphenyl)-2-(2-Methylphenyl)Ethyl]Adenosine,and Its 5′-N-Ethyl Ribofuranuronamide Derivative

Abstract

A detailed experimental procedure for the synthesis and resolution of 2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylamine, and its conversion into the titled adenosine reference agonists is given.     

Synthesis and cytokinin activity of (R)-(+)- and (S)-(−)-dihydrozeatins and their ribosides

(R)-(+)- and (S)-(?)-dihydrozeatins [(R)-(+)- and (S)-(?)-6-(4-hydroxy-3-methylbutylamino)purines, 1a and 1b] and their ribosides {(?)-6-[(R)-4-hydroxy-3-methylbutylamino]- and (?)-6-[(S)-4-hydroxy-3-methyl-butylamino]-9-β-D-ribofuranosylpurines, 3a and 3b} were synthesized and tested for their cytokinin activity by four bioassay systems, the growth of tobacco callus, the seed germination of lettuce, the fr. wt increase of excised radish cotyledons and the retardation of chlorophyll degradation in radish cotyledons. In tobacco callus bioassay, 1a was more active than 1b. The ribosides 3a and 3b were not less active than their corresponding aglycones 1a and 1b. In other bioassays used the activity followed the order: 1a >3a >1b >3b. In tobacco callus bioassay and lettuce seed germination, trans-zeatin [6-(4-hydroxy-3-methylbut-trans-2-enylamino)purine] showed stronger cytokinin activity than 1a.     

Role of Calcium and Adenosine Cyclic 3′-5′ Phosphate in Action of Adrenocorticotropin

ALTHOUGH adenosine cyclic monophosphate (cyclic AMP) has been proposed as a mediator through which many hormones exert their physiological effects¹, it is also well established that calcium plays a crucial role in hormone release². Both calcium^3,4 and cyclic AMP^1,5 have been implicated in the action of adrenocorticotropin (ACTH) on the adrenal cortex and although various hypotheses have been advanced concerning their roles in steroid production and release, elucidation of their functions in the adrenal gland is hindered because most studies have been carried out on in vitro systems where the physiological release response cannot be studied. The isolated cat adrenal gland perfused in situ ⁶ approximates the situation in vivo, yet eliminates the influence of several factors, including the anterior pituitary. In the intact adrenal preparation one can also measure both steroid synthesis and release and can better evaluate the respective effects of cyclic AMP and calcium on these processes.     

18O-Labeled Adenosine and 9-(β-D-Arabinofuranosyl)Adenine (ARA-A): Synthesis,Mass Spectrometry,and Studies of 18O-Induced 13C NMR Chemical Shifts

Abstract

[2′-¹⁸O]- and [3′-¹⁸O]-Adenosine and [2′-¹⁸O]- and [3′-¹⁸O]-9-(β-D-arabinofuranosyl) adenine were synthesized from^?appropriate nucleoside precursors. The sites of ¹⁸O-incorporation were determined by mass spectrometry. ¹⁸O-Induced ¹³C NMR shifts were measured for 2′-and 3′-labeled adenosines as 1.2 and 1.6 Hz, respectively.     

Inhibitors of Adenosine Deaminase: Synthesis of Coformycin and 3′-Deoxycoformycin

Abstract

Glycosylation of the heterocycle, 6,7-dihydro-imidazo [4,5-d] [1,3] diazepin-8(3H)-one, with suitably protected sugars under the influence of Lewis acid catalysts gave the β-D-ribo- and 3′-deoxy-β-D-erythropento-furanosyl nucleosides. Deprotection and reduction of the keto nucleosides with sodium borohydride gave the (8R)- and (8S)-3-β-D-glycofuranosyl-3,6,7,8-tetrahydroimidazo [4,5-d]-[1,3] diazepin-8-ols, the (8R)-isomers of which are potent inhibitors of adenosine deaminase.     

The Inhibition of Adenosine Kinase by α,ω-Di (Adenosin - N 6- YL) Alkanes1

Abstract

Members of a series of α,ω-di(adenosin- N ⁶-yl)alkanes, comprising two adenosine residues linked with alkyl bridges from 1 to 14 methylene units in length, were found to be inhibitors of rat liver and BHK cell adenosine kinase. The inhibition was competitive with respect to adenosine and non-competitive with respect to ATP. The corresponding α,ω-di(cytidin-N ⁴-yl) alkanes were not inhibitors and N ⁶-alkyladenosines inhibited only weakly.     

2′- and 3′- Cholesterol-Conjugated Adenosine and Cytosine Nucleoside Building Blocks: Synthesis of Lipidic Nucleic Acids

Abstract

Recently our laboratory introduced¹ chemistries to synthesize 2′- and 3′- cholesteroluridine conjugates which were incorporated into several antisense oligonucleotides. We have now extended this chemistry to other nucleosides (adenosine and cytosine) and synthesized antisense oligonucleotide conjugates for several disease targets. Synthesis of these cholesterol nucleosides was carried out hy condensing choleskrol chloroformate with 2′-O-alkylamine or 3′-O-alkylamine of the appropriate nucleoside. The 2′-O-alkylamines were deiived from direct alkylation procedure.     

Synthesis of (±)-7,3′- and 7,4′-di-O-methyleriodictyol and of velutin and pilloin

Synthetic 2′-hydroxy-3,4′,6′-trimethoxy-4-benzyloxychalcone (I) affords (±)-7,3′-di-O-methyleriodictyol (II) and 7,3′-di-O-methylluteolin (or velutin, VII) identical with natural samples. Similarly synthetic 2′-hydroxy-4,4′,6′-trimethoxy-3-benzyloxychalcone (X) gives natural (±)-7,4′-di-O-methyleriodictyol (XI) and 7,4′-di-O-methylluteolin (or pilloin, IX). However, attempts to partially etherify II with one mole of prenyl bromide to obtain the natural prenyl ether failed; only the corresponding diprenyloxychalcone (IV) was obtained.     

Individual and combined effect of (±)-α-hydrastine and (±)-β-hydrastine on spore germination of some fungi

(+/-)-alpha-Hydrastine and (+/-)-beta-hydrastine were isolated from Corydalis longipes; both exhibited considerable efficacy against spore germination of some saprophytic and phytopathogenic fungi. While (+/-)-alpha-hydrastine was effective against most of the fungi, Helminthosporium echinoclova was least affected even at the highest dose (150 ppm). (+/-)-beta-Hydrastine was equally effective against several fungi. Mixture of both compounds was more effective than each one individually. Helminthosporium species were again the most resistant toward the mixture. The effect of both alkaloids independently on germination and development of E. pisi conidia on excised pea leaves was also shown. After pre-inoculation with (+/-)-alpha-hydrastine, the effect was more pronounced than the addition post-inoculation; maximum inhibition occurred at 200 ppm. (+/-)-beta-Hydrastine also reduced germination of conidia but was less effective than (+/-)-alpha-hydrastine. The number of primary and secondary branches of conidia and number of appressoria were not affected significantly by either compound.     

Photobromination of 1,5-Anhydro-2,3-O-isopropylidene-β-d-ribofuranose and Synthesis of (5R) and (5S)-(5-2H1)-d-Riboses

The photobromination of 1,5-anhydro-2,3-O-isopropylidene-β-d-ribofuranose gave the corresponding (5S)-5-bromo compound. The reduction of the bromide with triphenyltindeuteride gave (5S)-(5-²H₁)-1,5-anhydro-2,3-O-isopropylidene-β-d-ribofuranose, with a chiral purity of 76% at C-5, which was converted to (5R)- and (5S)-(5-²H₁)-d-riboses and other ribofuranose derivatives.     

Microbial Resolution of (±)-1 and 2-Decalols

By microorganisms or esterase they produce, (±)-1 and 2-decalyl acetates were asymmetrically hydrolyzed to (?)-1-(R)-trans,cis-1-decalol (IIa), (+)-1-(S)-cis,cis-1-decalol (IIIb), (+)-1-(R)-cis,trans-1-decalol (IVa) and (+)-1-(S)-trans,trans-2-decalol (VIIb), (?)-cis,cis-2-decalol (IXb) with the acetates of their antipodes, whereas the axial acetates of (±)-decalols were scarecely hydrolyzed.     

Synthesis of D-ring-substituted (5'R)- and (5'S)-17β-pyrazolinylandrostene epimers and comparison of their potential anticancer activities

Various steroidal benzylidenes were synthetized from pregnenolone with benzaldehyde and p-substituted benzaldehydes. The resulting 17β-chalconyl derivatives of pregnenolone were reacted with hydrazine hydrate in acetic acid solution. Regardless of the starting material, the ring-closure reaction afforded (in contrast with the literature data) a mixture of two steroidal pyrazoline epimers. The epimers were critical isomer pairs, which could be separated only in their acetylated form; their structures were investigated by NMR techniques. The in vitro inhibition of rat testicular C(17,20)-lyase activity and the antiproliferative effects on four human cancer cell lines were measured, and the results obtained from the two epimer series were compared.     

Adenosine analogue–oligo-arginine conjugates (ARCs) serve as high-affinity inhibitors and fluorescence probes of type I cGMP-dependent protein kinase (PKGIα)

Introduction

Type I cGMP-dependent protein kinase (PKGIα) belongs to the family of cyclic nucleotide-dependent protein kinases and is one of the main effectors of cGMP. PKGIα is involved in regulation of cardiac contractility, vasorelaxation, and blood pressure; hence, the development of potent modulators of PKGIα would lead to advances in the treatment of a variety of cardiovascular diseases. Aim: Representatives of ARC-type compounds previously characterized as potent inhibitors and high-affinity fluorescent probes of PKA catalytic subunit (PKAc) were tested towards PKGIα to determine that ARCs could serve as activity regulators and sensors for the latter protein kinase both in vitro and in complex biological systems. Results: Structure–activity profiling of ARCs with PKGIα in vitro demonstrated both similarities as well as differences to corresponding profiling with PKAc, whereas ARC-903 and ARC-668 revealed low nanomolar displacement constants and inhibition IC₅₀ values with both cyclic nucleotide-dependent kinases. The ability of ARC-based fluorescent probes to penetrate cell plasma membrane was demonstrated in the smooth muscle tissue of rat cerebellum isolated arteries, and the compound with the highest affinity in vitro (ARC-903) showed also potential for in vivo applications, fully abolishing the PKG1α-induced vasodilation.     

Synthesis of 7-(tetrahydropyran-2-yl)- and 7-(4-acetoxytetrahydropyran-2-yl)-ε-rhodomycinone and 7-(tetrahydropyran-2-yl)-ε-pyrromycinone

The ¹³C.n.m.r spectra of water-soluble and -insoluble glucans synthesized by enzymes isolated from six strains of Streptococcus mutans are interpreted. The glucans are shown to be composed primarily of α(1→3)- and α-(1→6)-linked glucosyl residues, and the relative abundance of each linkage is estimated from peak areas. Treatment of water-insoluble glucans with dextranase is found to result in water-soluble and -insoluble products, the former enriched in α-(1→6)-linkages and the latter in α-(1→3)-linkages. The structural conclusions arrived at by ¹³C-n.m.r. spectroscopy are consistent with data from methylation analysis and ¹H-n.m.r. spectroscopy.     

Synthesis and gastrointestinal pharmacology of some 15- and 16- modified (±)-11-deoxyprostaglandins

The synthesis and gastrointestinal pharmacology of some 11-deoxyprostaglandin E₁ analogues are described with results analysed for selectivity from side effects. 11-Deoxygenation reduced potency relative to PGE₂ but, as has been reported for natural PGs, 15- or 16-methyl analogues were more potent than the unsubstituted parent compound in the order 16-methyl > 15-methyl > 16, 16-dimethyl. The results suggest that a complex interaction between C-15 and C-16 in methyl analogues affects their profile of activity, but that none of the modifications studied conferred a substantial potency or selectivity advantage over PGE₂.     

Microbiological synthesis of 5-ethyl- and (E)-5-(2-bromovinyl)-2′-deoxyuridine

Summary The title compounds were prepared by an enzymatic transdeoxyribosylation from 2 dGuo or 2 dThd to the respective heterocyclic bases, 5-ethyluracil and (E)-5-(2-bromovinyl)uracil, using the whole bacterial cells ofEscherichia coli as a biocatalyst.