Bioorganic Chemistry 91 (2019) 103152 Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg cAMPS derivatives. A minireview over synthetic medicinal chemistry T Kjell Undheim Department of Chemistry, University of Oslo, N-0315 Oslo, Norway ARTICLE INFO ABSTRACT Keywords: Cyclic nucleosides belonging to the cAMPS system can exert antagonistic or agonistic effects on the cAMP/PKA (Rp)-cAMP-phosphorothioates type 1 inhibitory pathway affecting T-lymphocyte replications. The stereochemistry at the phosphorus atom in cAMPS antagonists the phosphate group is important for the expressed selectivity. The two stereoisomers at the phosphorus atom in cAMPS agonists the phosphate arise by selective replacements of one of the oxygens pendant from the phosphorus atom by a Stereoselective phosphorus-thiation sulfur atom. Methods for the preparation of cAMPS derivatives as stereochemical mixtures at the phosphorus Pd-effected trans-coupling atom and separation of stereoisomers have been developed into highly stereoselective syntheses. Methods for Arylation Hetarylation halogenation in the purine 8-position afford corresponding halides. Heteronucleophilic substitution of the ha- lides afford corresponding amines, ethers or sulfides. Transition metal catalysis for carbylation of the8-halides affords simple and efficient routes for the preparation of 8-aryl, 8-hetaryl or 8-alkyl cAMPS derivatives. Preparations of prodrugs for improved cell membrane penetration are described. The prodrugs are S-alkylated derivatives which are constructed for selective cleavage of the SeP bond by an esterase to regenerate the bioactive cAMPS species at the site of the desired action. 1. Introduction 2. Synthesis The purine framework is widely incorporated in essential biological Two main procedures are available for the preparation of the target molecular systems. Purine chemistry and construction of purine derived cAMPS derivatives. In the first approach, appropriately substituted structures constitute an important part of medicinal chemistry. Hence adenosines are prepared as intermediates for cyclothiophosphorylation the purine ring system has been an object for intense chemical studies. (Scheme 1). In the second approach, cyclic phosphoramidates are pre- This report describes a summary of synthetic chemical work on purines pared in a stereoselective manner and subsequently thiated with steric for the construction of thiated adenosine derived analogues. The basis retention (Schemes 7 and 8). for this review is cyclic adenosine monophosphate (cAMP) which is an important second messenger that regulates a broad range of cellular 2.1. Adenosine substrates functions in response to various hormones [1–4]. One of the oxygen atoms pendant from the phosphorus atom in cAMP has been replaced The cAMPS parent compound was first synthesized in 1974 [7].A by a sulfur atom in attempts to modify the biological responses of subsequent stereoselective synthesis and configurational assignment cAMP. By this change a new stereogenic center is created at the phos- have been worked out. The configuration at the phosphorus atom can phorus atom. The resultant adenosine-3,5-cyclic monophosphorothioic be correlated with 31P NMR shifts [8,9]. acid (cAMPS) is stereochemically stable for isolation of the (Rp)- and In the first synthetic approach, cAMPS and derivatives are prepared (Sp)-diastereomers [5,6]. The pharmacological effect of the (Rp)- and in a one-pot procedure from unprotected nucleosides by thiopho- the (Sp)-isomers may differ at the protein kinase A effector insucha sphorylation with thiophosphoryl chloride followed by cyclization in way that (Rp)-cAMPS acts as a competitive antagonist and (Sp)-cAMPS the presence of sodium hydroxide in aqueous acetonitrile (Scheme 1). acts as an agonist [5,6]. The products are diastereomeric cAMPS mixtures that afford the pure General structures of target molecules (Rp)-cAMPS and (Sp)-cAMPS stereoisomers after chromatographic separations [10]. Scheme 1 shows are shown in Fig. 1. The target molecules differ in the configuration at that adenosine reacts with thiophosphoryl chloride in a triethyl phos- the phosphorus atom and may differ in the nature of the 8-R sub- phate solution followed by alkali promoted cyclization to afford a stituent. diastereomeric mixture of cAMPS (4). The 8-(2-furyl) substrate 5 in dry pyridine reacts in the same manner via a thiophosphoryl intermediate E-mail address: [email protected]. https://doi.org/10.1016/j.bioorg.2019.103152 Received 27 November 2018; Received in revised form 27 May 2019; Accepted 24 July 2019 Available online 26 July 2019 0045-2068/ © 2019 The Author. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). K. Undheim Bioorganic Chemistry 91 (2019) 103152 atom. When the reaction is carried out using a stereoisomeric mixture as substrate, the diastereomers of the phosphorothioic acid 14 can be separated by chromatography [13]. 3′,5′-Cyclic phosphorothioate nucleotides are available by cy- clothiophosphorylation of unprotected nucleosides 15.(Scheme 4). Initial phosphorylation presumably takes place at the 5′-OH group in the sugar. The reaction between adenosine and thiophoshoryl chloride proceeds well in dry pyridine at low temperature for 10 min. The pro- duct is a 1:1-mixture of the (Rp)- and (Sp)-8-substituted adenosine-3′,5′- cyclic phosphorothioic acid (17). The isomers are separated by reverse- Fig. 1. Target molecules. phase chromatography on a C18 functionalized silica gel column. The method delivers almost exclusively the desired 3′,5′-cyclic phosphor- to afford a (Rp/Sp)-diastereomeric mixture of the stereoisomers 6 in the othioates 17, but as stereochemical mixtures [13]. ratio 2:3 in favour of the (Sp)-isomer (6b) [11]. A simple method for the preparation of 8-alkyl substrates for the Alternative thiophosphoryl chloride reagents include bis(p-ni- cyclothiophosphorylation reactions is shown in Scheme 5. Similar re- trophenyl)phosphorochlorothioate (8) which reacts with N-benzoyl- actions are possible for aryl and hetaryl derivatives (vide infra). 8- adenosine 7 in pyridine at room temperature without protection of the Bromo derivatives are used as substrates for the trans-coupling reaction hydroxyl groups to afford the adenosine 5-bis(p-nitrophenyl)phos- [13]. Pd-promoted catalytic reactions with tetraethyltin provides the phorothioate 9 (Scheme 2). Potassium tbutoxide as base is used for the ethyl substrate 19. Trimethylaluminum is used for the methyl analogue cyclization in dry DMF. The phenolic ester 10 is cleaved by aq. am- 21. The vinyl ether 22, a protected acyl derivative, is prepared similarly monia at 50 °C to afford the thiophosphoric acid isomers 11 which can by Pd-catalysis. The resultant products 23 are subsequently used as be separated by ionic chromatography [12]. substrates for cyclothiophosphorylation reactions [13]. Adenosine reacts with trivalent phosphorus reagents to afford cyclic phosphites as shown for adenosine-3′,5′-cyclic methyl phosphite 13 2.2. cAMP substrate for stereoselective amidation and thiation (Scheme 3). Both the cis- and trans-cyclophosphite esters 13 are formed. At elevated temperature, the trans-ester 13b is inverted to the cis-isomer A general method for introduction of carbon substituents into the 13. The isomerization is promoted by 1H-tetrazole. Each isomer, or the purine 8-position is available employing stereoselectively prepared product as a stereoisomeric mixture 13, is thiated by oxidative addition amidates (vide infra). 8-Bromo or 8-chloro derivatives are substrates for of sulfur at the site of the lone pairs of electrons on the phosphorus 8-carbylation reactions promoted by palladium or other transition atom with retention of the relative configuration at the phosphorus metals for catalysis [11,13]. This approach is especially useful for the Scheme 1. Reagents and reaction conditions. 2 K. Undheim Bioorganic Chemistry 91 (2019) 103152 Scheme 2. Reagents and reaction conditions. Scheme 3. Reagents and reaction conditions. Scheme 4. Reagents and reaction conditions. 3 K. Undheim Bioorganic Chemistry 91 (2019) 103152 Scheme 5. Reagents and reaction conditions. preparation of aryl and hetaryl targets but includes also alkyl deriva- facilitates isolation of the thioic acid by precipitation of the product tives. The intermediate substrates are available from adenosine or de- from the complex aqueous mixture (vide infra). The bromine in the rivatives via stereoselective amidation reactions. Scheme 6 shows the electrophilic 8-position may be displaced by another halide ion during reaction between N,N,O2-tribenzoyladenosine cyclic 3′5′-phosphate the coupling procedure. The exchange is reduced or avoided when the (24) and aniline in the presence of triphenylphosphine-carbon tetra- silylation is effected under relatively mild conditions. Alternatively, chloride which affords the cyclic 3′,5′-phosphoranilidate nucleosides tbutyldimethylsilyl triflate (TBDMS-OTf) can be used as a silylating 25. A subsequent separation affords the individual diastereomers 25a reagent instead of TBDMS-Cl. Oxalyl chloride in the presence of DMF in and 25b. A stereorententive mode for the PN → PS conversion [9,14] THF or dichloromethane at low temperature (−60 °C to −20 °C) can be converts the amidates isomers 25 into the corresponding thionucleo- used for the amidation step. The actual chlorinating agent of phos-