Adenosine: Synthetic Methods of Its Derivatives and Antitumor Activity

Abstract

Since 1929, several researchers have conducted studies in relation to the nucleoside of adenosine (1) mainly distribution identifying, characterizing their biological importance and synthetic chemistry to which this type of molecule has been subjected to obtain multiple of its derivatives. The receptors that interact with adenosine and its derivatives, called purinergic receptors, are classified as A1, A2A, A2B and A3. In the presence of agonists and antagonists, these receptors are involved in various physiological processes and diseases. This review describes and compares some of the synthetic methods that have been developed over the last 30 years for obtaining some adenosine derivatives, classified according to substitution processes, complexation, mating and conjugation. Finally, we mention that although the concentrations of these nucleosides are low in normal tissues, they can increase rapidly in pathophysiological conditions such as hypoxia, ischemia, inflammation, trauma and cancer. In particular, the evaluation of adenosine derivatives as adjunctive therapy promises to have a significant impact on the treatment of certain cancers, although the transfer of these results to clinical practice requires a deeper understanding of how adenosine regulates the process of tumorigenesis.

Keywords: Adenosine; adenosine derivatives; adenosine receptors; complexing; conjugation; glioblastoma; substitution..

Fig. (1)

Structure of adenosine [31].

Fig. (2)

Figure Schematic representation of metabolic routes adenosine levels (Source: Parkinson et al. [33]).

Fig. (3)

General synthesis of 2-substitution of N⁶-benzyladenosine- 5’-uronamides (5). Reagents and conditions: (i) TBDPSiCl, DMAP, DMF, r.t.; (ii) Bz₂O, Py; n-Bu₄NF, THF; (iv) RuO₂, NaIO₄, CHCl₃:CH₃CN:H₂O (2:2:3); (v) EDAC, DMAP, MeOH; (vi) MeNH₂, THF, 75ºC; (vii) BzCl, Py–CH₂Cl₂; (viii) Ac₂O, H₂SO₄, AcOH; (ix) TMSOTf, (1,2)-dichloroethane; reflux.9-silylated adenine derivative; (x) NH₃/MeOH, nucleophile. (Source: Modified from Kim et al., [46]).

Fig. (4)

General synthesis of N⁶-alkyl-2-alkynyl adenosine derivatives (22). Reagents and conditions: (i) amine, (ii) R-C≡CH, CuI, [(C₆H₅)₃P]₂PdCl₂, Et₃N (Source: Modified from Volpini et al., [3]).

Fig. (5)

Synthesis of 4-substituted-2-(1,2,3)-triazole-1-yl-N⁶-methyl adenosine analogues (26). Reagents and conditions: (i) CH₃NH₃⁺Cl^–, Et₃N, EtOH; (ii) NH₃ (7N) /MeOH; (iii) CuI, (Ph₃P)₂PdCl₂, alkyne, Et₃N, DMF; (iv) CuSO₄⋅5H₂O, sodium ascorbate, L-proline, Na₂CO₃, H₂O/t-BuOH (1:1), 60 ºC; (v) CuSO₄⋅5H₂O, sodium ascorbate, alkyne, H₂O/t-BuOH (3:1), r.t. (Source: Modified from Cosyn et al., [49]).

Fig. (6)

General synthesis of N⁶-alkyladenosine derivatives (27) (Source: Modified from Ottria et al., [52]).

Fig. (7)

Chemical structure of AdoR probe (Source: Obtained from Mahajan et al., [57]).

Fig. (8)

General synthesis of N⁶-(4-nitrobenzyl) adenosine (33) (Source: Modified from Rayala et al., [60]).

Fig. (9)

Chemical structure of adenosine derivative of tetraacetatodiruthenium (II, III) chloride (Source: Gangopadhyay et al. [61]).

Fig. (10)

Structural formula of the prepared platinum (II) oxalato complexes [Pt(ox)(nL)₂].1,5H₂O (Source: Modified from Štarha et al. [62, 63]).

Fig. (12)

Synthesis of 5’–aminoacyl–5’–deoxy-nucleosidesulfonamide (47-52).Reagents and conditions: (i) DMK, PTSA, DMP, r.t., 24 h; (ii) thioaceticacid, PPh₃, DEAD, THF, 0ºC, 1.5 h; (iii)NH₃/MeOH, 0ºC to r.t., overnight; (iv) CH₃CN/AcOH/H₂O (40:1.5:1 v/v) DCDMH, 1h; (v) NH₃, 0ºC to r.t., 1h; (vi) Boc/Cbz-aa-(tBu/Bn)-OSu, DBU, DMF; 6-8 h; (vii) TFA/H₂O (5:2 v/v), r.t. 2.5 h;(viii) Pd/C, methanol,HOAc, H₂, r.t. overnight. (Source: Modified of Gadakh et al., [67]).

Fig. (11)

General synthesis of N⁶-alkylated adenosine derivatives (43). Reagents and conditions: (i) acylating agent-benzoyl chloride; (ii) 1,4-dioxane, LiAlH₄; (iii) 80% HOAc, 75ºC. (Source: Modified from Lescrinier et al. [64]).

Fig. (13)

General methods of two steps for the preparation of 5’-adenosine linker conjugate (55). Reagents and conditions: (i) methylimidazole, EDC, diamine, r.t., pH: 6.2-6.8; (ii) folic acid, NHS, EDC, r.t., pH=7.5 (Source: Modified of Laing et al., [68]).

Fig. (14)

General synthetic routes of pGlu-SA (64) (Source: Modified of Kaybullin et al., [70]).

Fig. (15)

Structures of 7-deaza-cyclic adenosine-5′-diphosphate-carbocyclicribose and its 7-bromo derivative (Source: Takano et al., [74]).

Fig. (16)

Chemical structures of two N-methanocarba 5’-ester adenosine derivatives (Source: Tosh et al., [79]).