Synthesis of nitrogen-15-labeled 2-amino(glycofurano)oxazolines via glycosylamine intermediates (original) (raw)
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Synthesis of "9-deazaguanosine" and other new pyrrolo[3,2-d]pyrimidine C-nucleosides
The Journal of Organic Chemistry, 1983
The syntheses of several new pyrrolo[3,2-dlpyrimidine (9-deazapurine) C-nucleosides (3-5) and an improved synthesis of 9-deazainosine (1) are described. 9-Deazaguanosine 5 was obtained from the blocked 4-ribosylated 3-amino-2-carbethoxypyrrole key intermediate loa by its initial conversion to thiourea derivative 23 followed by S-methylation, ring closure with ammonia, and deprotection in acid. 9-Deazainosine 1 was also obtained from intermediate 10s by pyrimidine ring closure with formamidine acetate and final deprotection in acid. The 4-thiono and methylthio derivatives 3 and 4 were prepared via the corresponding 3-amino-2-cyanopyrrole 5 by its Conversion to thioamide 16 and cyclization with triethyl orthoformate. (1) This investigation was supported by funds from the National Cancer Institute DHHS (Grants CA-08748, 18856 and 24634). (2) (a)
Tetrahedron, 2008
A one-pot procedure for preparing chiral 1,3-oxazolidines derived from N-methyl-D-glucamine and aryl aldehydes is described. It has been carried out by using readily available reagents and operationally simple conditions allowing the preparation of the acyclic C-nucleoside analogs in high yields. The structure of these derivatives has been fully characterized by NMR correlations and single-crystal X-ray diffraction. Some reactions also provide access to the corresponding tetrahydro-1,3-oxazines by an alternative ring closure. Mechanistic considerations account for the observed steric course.
Journal of Enzyme Inhibition and Medicinal Chemistry, 2013
9-Substituted (pyrazol-5-yl)methyl-or (2-pyrazolin-5-yl)methyl-9H-purines were synthesized from 9-allyl-6-chloro-9H-purine through the 1,3-dipolar cycloaddition reaction with nitrile imines, prepared in situ from the corresponding hydrazone and NBS/Et 3 N under MW or from hydrazinoylchloride and Et 3 N under reflux. The coupling of new 6-chloropurines with amines in H 2 O under microwaves resulted quantitatively to modified pyrazol-5-yl-or 2-pyrazolin-5-yl adenine homo-N-nucleosides. The new compounds were tested in vitro for their ability to: (i) interact with 1,1-diphenyl-2-picryl-hydrazyl (DPPH), (ii) inhibit lipid peroxidation, (iii) inhibit the activity of soybean lipoxygenase, (iv) inhibit in vitro thrombin and for (v) their antiproliferative and cytotoxic activity. Pyrazolines were found to be more potent in vitro. Compound 7a exhibited satisfactory combined antioxidant and anti-lipid peroxidation activity, inhibition of lipoxygenase (89%) and thrombin inhibitory ability, whereas compound 7b exhibited high lipoxygenase inhibitory activity in combination to significant anti-thrombin activity. No compound exhibited a significant cytotoxic activity, while all showed moderate antiproliferative activity.
New acyclovir analogues were obtained by reaction of 1,2,4-triazolo[1,5-a]pyrimidin-7-ones 4aei with (2-acetoxyethoxy)methyl acetate 5 in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) as catalyst (Vorbr€ uggen procedure). Coupling between compounds 4aef and 5 led to a mixture of N3and N4-isomers 6 and 7, respectively. On the contrary, the reaction of compounds 4gei with 5 proceeded selectively with formation of N3-isomers only. It was found that the ratio of 6aef and 7aef depends on the presence or the absence of N,O-bis(trimethylsilyl)acetamide (BSA). Glycosylated products 6aef and 7aef underwent reversible isomerization under TMSOTf treatment. The ratio of glycosylated products of the coupling reaction between 4 and 5 was thermodynamically controlled. A similar reaction occurred if ZnCl 2 was chosen as a catalyst, although lower yields of the acyclic analogues of nucleosides were observed. The glycosylation of other purines (adenine and guanine) can be achieved via the non-BSA modification of the Vorbr€ uggen procedure.
Synthesis and biological evaluation of certain C-4 substituted pyrazolo[3,4-b]pyridine nucleosides
Journal of Medicinal Chemistry, 1989
The key intermediate 9-(2,3,5,-tri-O-acetyl-beta-D-arabinofuranosyl)purine-6-carbonitrile (7) was synthesized in four steps from 9-beta-D-arabinofuranosylpurine-6-thione (3) via 6-(methylsulfonyl)-9-(2,3,5-tri-O-acetyl-beta-D-arabinofuranosyl)purine (6). Reaction of compound 7 with methanolic ammonia provided the rearranged compound 4-amino-8-(beta-D-arabinofuranosylamino)pyrimido[5,4-d]pyrimidine (8). Treatment of 7 with ammonium hydroxide and hydrogen peroxide provided 9-beta-D-arabinofuranosylpurine-6-carboxamide (9). Compound 7 was also treated with sodium hydrosulfide to yield 9-beta-D-arabinofuranosylpurine-6-thiocarboxamide (10). Similarly, 9-(2-deoxy-3,5-di-O-acetyl-beta-D-erythro-pentofuranosyl)purine 6-carbonitrile (17) was prepared from 6-chloro-9-(2-deoxy-beta-D-erythro-pentofluranosyl)purine (11) via 9-(2-deoxy-beta-D-erythro-pentofuranosyl)purine-6-thione. Compound 17 was converted into 4-amino-8-[(2-deoxy-beta-D-erythro-pentofuranosyl)amino]pyrimido[5,4-d]pyrimidi ne (18) and 9-(2-deoxy-beta-D-erythro-pentofuranosyl)purine-6-carboxamide (20), respectively. Compound 2 showed immunosuppressive activity and also inhibited the growth of L-1210 leukemia in mice. Arabinonucleoside analogues 8-10 were inactive when tested against RNA and DNA viruses in cell culture.
9-Substituted (pyrazol-5-yl)methyl- or (2-pyrazolin-5-yl)methyl-9H-purines were synthesized from 9-allyl-6-chloro-9H-purine through the 1,3-dipolar cycloaddition reaction with nitrile imines, prepared in situ from the corresponding hydrazone and NBS/Et3N under MW or from hydrazinoylchloride and Et3N under reflux. The coupling of new 6-chloropurines with amines in H2O under microwaves resulted quantitatively to modified pyrazol-5-yl- or 2-pyrazolin-5-yl adenine homo-N-nucleosides. The new compounds were tested in vitro for their ability to: (i) interact with 1,1-diphenyl-2-picryl-hydrazyl (DPPH), (ii) inhibit lipid peroxidation, (iii) inhibit the activity of soybean lipoxygenase, (iv) inhibit in vitro thrombin and for (v) their antiproliferative and cytotoxic activity. Pyrazolines were found to be more potent in vitro. Compound 7a exhibited satisfactory combined antioxidant and anti-lipid peroxidation activity, inhibition of lipoxygenase (89%) and thrombin inhibitory ability, whereas compound 7b exhibited high lipoxygenase inhibitory activity in combination to significant anti-thrombin activity. No compound exhibited a significant cytotoxic activity, while all showed moderate antiproliferative activity.
International Journal of Molecular Sciences
Cancer is a large group of diseases in which the rapid proliferation of abnormal cells generally leads to metastasis to surrounding tissues or more distant ones through the lymphatic and blood vessels, making it the second leading cause of death worldwide. The main challenge in designing a modern anticancer therapy is to develop selective compounds that exploit specific molecular targets. In this work, novel oxazolo[5,4-d]pyrimidine derivatives were designed, synthesized, and evaluated in vitro for their cytotoxic activity against a panel of four human cancer cell lines (lung carcinoma: A549, breast adenocarcinoma: MCF7, metastatic colon adenocarcinoma: LoVo, primary colon adenocarcinoma: HT29), along with their P-glycoprotein-inhibitory ability and pro-apoptotic activity. These oxazolo[5,4-d]pyrimidine derivatives, which are structurally similar to nucleic purine bases in general, are characterized by the presence of a pharmacologically favorable isoxazole substituent at position 2...