62462-38-8

Purine and pyrimidine bases react with epoxy carbonyl compounds in aqueous solution to yield ring-extended adducts.These products include etheno-modified bases as well as adducts in which the modification involves the formation of an additional six-membered ring.The latter examples are among the first known cases of this type of modification of pyrimidine bases.Plausible mechanisms for the formation of these adducts are discussed.

A class of polycyclic compounds of general formula (I), wherein Base1, Base2, Y, Za, Xa, Xa1, Xb, Xb1, Xc, Xc1, Xd, Xd1, R1, R1a, R2, R2a, R3, R4, R4a, R5, R6, R6a, R7, R7a, R8, R8a, and R9 are defined herein, that may be useful as inductors of type I interferon production, specifically as STING active agents, are provided. Also provided are processes for the synthesis and use of compounds.

The present invention is directed to compounds of the formula (I), wherein all substituents are defined herein, as well as pharmaceutically acceptable compositions comprising compounds of the invention and methods of using said compositions in the treatment of various disorders.

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) is a potent direct-acting bacterial mutagen and a rodent carcinogen occurring in chlorine-disinfected drinking water. In this study, we have reacted MX with guanosine, cytidine, thymidine, and calf thymus DNA in aqueous solutions, HPLC analyses of the reaction mixture of MX with guanosine showed that one main product peak was formed. In the reactions of MX with cytidine or thymidine, no product peaks representing base-modified nucleosides could be observed. The product from the MX guanosine reaction mixture was isolated by preparative chromatography on reversed phase C18 columns, and its structure was determined by UV absorbance, 1H and 13C NMR spectroscopy, and mass spectrometry. The product was identified as 3-(β-D-ribofuranosyl)-7- formylimidazo[1,2-a]purin-9(4H)-one (εfGuo), and the yield for the reaction carried out at pH 7.4 and 37 °C was about 0.3 mol %. The adduct could not be observed at the detection limit of five adducts per 107 bases in the hydrolysate of the calf thymus DNA reacted with MX. However, this failure does not rule out the possibility that lower amounts of the adduct might be involved in the observed mispairing (adenine incorporated opposite an adducted guanine base) caused by MX in the Salmonella typhimurium strain TA100.

Convenient syntheses of rac-glycidaldehyde from rac-but-3-ene-1,2-diol and (R)-glycidaldehyde from D-mannitol are described. (R)-Glycidaldehyde (1) reacts with guanosine in water (pH 4-11, faster reaction at higher pH) to give initially 6(S)-hydroxy-7(S)-(hydroxymethyl)-3-(β-D-ribofuranosyl)-5,6,7- trihydroimidazo[1,2-a]purin-9(3H)-one (7a) and 6(S),7(R)-dihydroxy-3-(β-D-ribofuranosyl)-5,6,73-tetrahydropyrimido[1,2-a] purin-10(3H)-one (8a). The former decomposes to 7-(hydroxymethyl)-5,9-dihydro-9-oxo-3-(β-D-ribofuranosyl)imidazo[1,2-a] purine (3a), 5,9-dihydro-9-oxo-3-(β-D-ribofuranosyl)imidazo[1,2-a]purine (5a, 1,N2-ethenoguanosine), and formaldehyde, while the latter adduct is relatively stable. The position of the hydroxymethyl group on the imidazo ring of 7-(hydroxymethyl)-5,9-dihydro-9-oxo-3-(β-D-ribofuranosyl)imidazo-[1,2-a] purine was proved by 13C NMR analysis of adducts derived from [1-15N]guanosine and [amino-15N]guanosine. At longer reaction times, the adduct 7,7′-methylenebis[5,9-dihydro-9-oxo-3-(β-D-ribofuranosyl)imidazo[1,2- a]purine[ (4a) is formed from guanosine and glycidaldehyde. The structure analysis of this adduct was also aided by 13C NMR analysis of the 15N-labeled adduct derived from [1-15N]guanosine. Analogous adducts were obtained from the reaction between glycidaldehyde and deoxyguanosine. Mechanisms of formation of the adducts from glycidaldehyde and guanosine/deoxyguanosine are proposed and supported by model studies with simple amines. The formaldehyde produced in the reactions described reacts with guanosine to give the known adduct N2-(hydroxymethyl)guanosine (9).

Reaction of guanosine (1a) with racemic glycidaldehyde (2) in aqueous medium at pH 10 gives 5,9-dihydro-9-oxo-3-β-D-ribofuranosylimidazopurine (1,N2-ethenoguanosine) (3c), its 7-hydroxymethyl derivative (3a), and methylene-7,7'-bis-5,9-dihydro-9-oxo-3-β-D-ribofuranosylimidazopurine (5); the structures of adducts (3a) and (5) were deduced from 13C n.m.r. analysis of 15N labelled adducts derived from guanosine (1b) and guanosine (1c).