Synthesis, Cytostatic, Antimicrobial, and Anti-HCV Activity of 6-Substituted 7-(Het)aryl-7-deazapurine Ribonucleosides

Abstract

A series of 80 7-(het)aryl- and 7-ethynyl-7-deazapurine ribonucleosides bearing a methoxy, methylsulfanyl, methylamino, dimethylamino, methyl, or oxo group at position 6, or 2,6-disubstituted derivatives bearing a methyl or amino group at position 2, were prepared, and the biological activity of the compounds was studied and compared with that of the parent 7-(het)aryl-7-deazaadenosine series. Several of the compounds, in particular 6-substituted 7-deazapurine derivatives bearing a furyl or ethynyl group at position 7, were significantly cytotoxic at low nanomolar concentrations whereas most were much less potent or inactive. Promising activity was observed with some compounds against Mycobacterium bovis and also against hepatitis C virus in a replicon assay.

7-(2-Thienyl)-7-Deazaadenosine (AB61), a New Potent Nucleoside Cytostatic with a Complex Mode of Action

“…Structure-activity relationship studies revealed that modifications in the 2 0 position of the ribose moiety lead to a decrease of cytotoxicity in 7-hetaryl-7-deazapurine ribonucleosides 2 (12,13) and completely inactive compounds in 6-hetaryl-7-deazapurine ribonucleosides 1 (14,15). In contrast, base-modified 7-hetaryl derivatives bearing modifications in positions 2 and 6 of 7-deazapurine showed submicromolar cytotoxic activities (16). The most promising derivative among the 7-hetaryl-7-adenosines is a 2-thienyl derivative AB61 (Fig.…”

Concise synthesis of pyrrolo[2,3-d]pyrimidine derivatives via the Cu-catalyzed coupling reaction

“…The tube was evacuated and refilled with argon three times before the solution of 3,3-diethoxyprop-1-yne (2.1 g, 16 mmol) in DMSO (16 mL) was added. The reaction mixture was stirred at 115°C for 24 h. After the reaction mixture was cooled to room temperature, saturated NH 4 Cl solution (100 mL) was added. The mixture was extracted with EtOAc (3 × 70 mL) and the organic layer was washed with water, brine and dried over Na 2 SO 4 .…”

“…Pyrrolo [2,3-d]pyrimidine compounds, regarded as an important class of N-heterocycles, have played a significant role in medicinal chemistry (1)(2)(3)(4)(5)(6)(7) and material chemistry (8)(9)(10). Pyrrolo [2,3-d]pyrimidine skeleton is present in diverse naturally occurring products and synthesized bioactive compounds, most of which exhibit valuable bioactivities and fluorescence, as shown in Figure 1.…”

Synthesis of Purine and 7‐Deazapurine Nucleoside Analogues of 6‐N‐(4‐Nitrobenzyl)adenosine; Inhibition of Nucleoside Transport and Proliferation of Cancer Cells

“…[1] A sizeable number of active nucleoside compounds with such a pyrrolo[2,3- d ]pyrimidine base has been prepared by chemical modifications of the parent antibiotics as well as by coupling base derivatives with protected sugars. [2] Noteworthy examples of such molecules include: (a) 5-iodotubercidin, [3] an up-field activator of the p53 pathway; (b) sangivamycin analogues such as 6-hydrazinosangivamycin [4] and xylocidine, [5] in vitro down-field inhibitors of PKC and CDK in cancer cell lines; (c) a methyl-substituted tubercidin, [6] which acts against the replication of polio and dengue viruses; (d) the anti-HSV agent xylotubercidin; [7] (e) substituted toyocamycin analogues [8] and 2′-β- C -methyl derivative of toyocamycin, [9] sangivamycin, [9] and tubercidin [10] that have activity against HCV; (f) 2′-deoxy-2′-fluoroarabinotubercidin [11] and 2-amino-2′-deoxy-2′-fluoroarabinotubercidin, [12] which exhibit antiviral activity; (g) 4 N ,5-diaryltubercidin derivatives, which act as adenosine kinase inhibitors; [2 l , 13] and (h) tubercidin derivatives such as 4-(het)aryl, [14] 5-(het)aryl [15] and some 4-substituted-5-(het)aryl [16] compounds with nanomolar cytostatic activity against several cancer cell lines.…”

“…Treatment of tubercidin with methyl iodide followed by sodium hydroxide produced 4- N -methyltubercidin [2b] (6- N -methyl-7-deazaadenosine) via Dimroth rearrangement. Several other 4- N -substituted tubercidin derivatives have been prepared by S N Ar displacement of chloride from the 4-chloro analogue [2b, 16] of tubercidin or by displacement of 1,2,4-triazole from 4- N -(1,2,4-triazol-4-yl) intermediates. [17] Such 4- N -substituted toyocamycin derivatives also were prepared from the corresponding 4-chloro compounds.…”