Synthesis, cytotoxicity, and antiviral activity of certain 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine nucleosides related to toyocamycin and sangivamycin

Abstract

A number of 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine derivatives related to the nucleoside antibiotics toyocamycin and sangivamycin were prepared and tested for their biological activity. Treatment of the sodium salt of 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidine (1) with (2-acetoxyethoxy)methyl bromide (2) afforded a mixture of 4-amino-6-bromo-5-cyano-7-[(2-acetoxyethoxy)methyl]pyrrolo[2,3-d] pyrimidine (3) and the corresponding N1 isomer. Debromination of this mixture gave the corresponding 4-amino-5-cyano-7-[(2-acetoxyethoxy)-methyl]pyrrolo[2,3-d]pyrimidi ne (4) and 4-amino-5-cyano-1-[(2-acetoxyethoxy)methyl]pyrrolo[2,3-d]pyrimidin e (5). Deacetylation of 4 and 5 furnished 4-amino-5-cyano-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine (6) and the corresponding N1 isomer (7), respectively. The sites of attachment for the acyclic moiety for 6 and 7 were assigned on the basis of UV spectral studies as well as 13C NMR spectroscopy. Conventional functional group transformation of 6 provided a number of novel 5-substituted derivatives (8-10), including the sangivamycin derivative 8. The methyl formimidate derivative 10 was converted to the thioamide derivative 11 and the carbohydrazide derivative 12. Compounds 6 and 8-12 were tested for cytotoxicity to L1210 murine leukemic cells in vitro. None of these compounds caused significant inhibition of cell growth. Evaluation of compounds 4 and 6-12 for activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) revealed that only the thioamide (11) was active. It inhibited HCMV but not HSV-1 at concentrations producing only slight cytotoxicity in human foreskin fibroblasts (HFF cells) and KB cells.

BF3·OEt2‐Mediated 1,3‐Hydride Shift Followed by 6π Electrocyclization: An Efficient Route for the Synthesis of Pyridopyrimidine, Pyranoquinoline, and Phenanthroline Derivatives

“…[31] A mixture of substrate 1 and 2a was heated in refluxing toluene in the presence of BF 3 ·OEt 2 for 12 h. Two products were obtained, that is, 6-(4-chlorophenyl)-1,3,7-trimethylpyrido[3,2-d]pyrimidine-2,4-(1H,3H)-dione (3a, 86 %) along with a small amount of 1,3,6-trimethylpyrrolo[3,2-d]pyrimidine-2,4-(1H,3H)-dione derivative 4 as a side product, which is also potentially bioactive [32,33] (Scheme 1). Compound 4 can also be obtained as a side product during the formation of the starting material from 5-(allylamino)-1,3-dimethylpyrimidine-2,4-(1H,3H)-dione by aza-Claisen rearrangement using BF 3 ·OEt 2 as a catalyst.…”

Antiviral Properties of Deazaadenine Nucleoside Derivatives

“…Derivatives closely related to tubercidin, toyocamycin, and sangivamycin were prepared and tested on the same antiviral assays [77][78][79]. Parent compounds 77, 78, and 79 were very active in inhibiting replication of Human CytoMegalo Virus (HCMV), but were also very cytotoxic [77] (Table 9).…”

“…Seco-ribose (95)(96)(97) and (dihydroxypropoxy)methyl derivatives (98-102) were inactive, except for compound 102, which was as active as ganciclovir and showed no appreciable cytotoxicity [77]. Also, 7[(2-hydroxyethoxy)methyl] derivatives (103-109) showed no antiviral efficacy, except for compound 108, which possessed some activity along with no cytotoxicity [79] (Table 9).…”

“…Previously, De Clerq and coworkers had tested tubercidin (77), toyocamycin (78), sangivamycin (79) and some sugarmodified analogues (80, 82, 85, 110-116) on a wide panel of replicating viruses [80,81] (Table 10). Overall, sugar modified derivatives were much less toxic on cells used for virus replication, although they were also less effective as antiviral drugs.…”

One-pot, three-component, catalyst-free synthesis of novel derivatives of pyrido-[2,3-d]pyrimidines under ultrasonic irradiations

“…ring is a common motif in several natural porducts and biologically active compounds and provide privileged scaffold for the generation of target compound in drug discovery [2][3][4][5]. Pyrido [2,3-d]pyrimidines exhibit diverse biological and pharmacological activities such as antitumor, antipyretic, analgesic, antiallergic, anti-hypertension, bronchitis dilator, strengthen the heart, blood vessel dilator, antimalarial, anti-fungal, adenosine kinase inhibitor, diuretic, tyrosine kinas inhibitors and antibacterial activity [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”