Recent Advances in the Chemical Synthesis and Evaluation of Anticancer Nucleoside Analogues

Abstract

Nucleoside analogues have proven to be highly successful chemotherapeutic agents in the treatment of a wide variety of cancers. Several such compounds, including gemcitabine and cytarabine, are the go-to option in first-line treatments. However, these materials do have limitations and the development of next generation compounds remains a topic of significant interest and necessity. Herein, we discuss recent advances in the chemical synthesis and biological evaluation of nucleoside analogues as potential anticancer agents. Focus is paid to 4'-heteroatom substitution of the furanose oxygen, 2'-, 3'-, 4'- and 5'-position ring modifications and the development of new prodrug strategies for these materials.

Keywords: anti-cancer; chemical synthesis; chemotherapeutic; heteroatom replacement; nucleoside analogue; prodrug.

Figure 1

Gemcitabine 1, clofarabine 2 and Ara-C 3. Modifications compared to native d-ribo-configured purine or pyrimidine nucleosides are shown in blue.

Figure 2

General scope for nucleoside analogues covered in this review. Base = purine or pyrimidine (i.e., C, U, T, A, G or close derivative thereof). X = heteroatom or carbon and Y and Z = ring functional group or modification of native d-ribo stereochemistry.

Figure 3

Structure of forodesine 4.

Scheme 1

Reagents and conditions: (i) NCS, pentane; (ii) LiTMP, −78 °C, 36% over two steps; (iii) ⁿBuLi, MeCN, THF, −78 °C then tetramethylpiperidine −78 °C, 100%; (iv) (Boc)₂O, CH₂Cl₂; (v) ^tBuOCH(NMe₂)₂, DMF, 70 °C; (vi) THF, AcOH, H₂O, 72% from 7; (vii) H₂NCH₂CO₂Et^·HCl, NaOAc, MeOH (viii) ClCO₂Bn, DBU, CH₂Cl₂, reflux, 67% from 10; (ix) H₂, Pd/C, EtOH; (x) H₂NCH=NH^·AcOH, EtOH, reflux, 91% from 12 and (xi) TFA, 81%.

Scheme 2

Reagents and conditions: (i) 6, ⁿBuLi, anisole, ether, −70 °C; (ii) (Boc)₂O, CH₂Cl₂, 85% over two steps; (iii) 1M HCl, MeOH, 30 °C, 96%; (iv) 1,3-Dichloro-1,1-3,3-tetraisopropyldisiloxane, pyridine, 81%; (v) O-Phenyl chlorothionoformate, MeCN, 90%; (vi) 1,1′-Azobis(cyclohexane-1-carbonitrile), toluene reflux, 91%; (vii) Pd(OH)₂, H₂, EtOH, conc. NH₄OH, 90% and (viii) conc. HCl, MeOH, reflux, 83%.

Scheme 3

Reagents and conditions: (i) BnBr, NaH, DMF, THF; (ii) 2M HCl, THF; (iii) NaIO₄, H₂O, MeOH; (iv) NaBH₄, MeOH, 84% from 20; (v) 5% HCl/MeOH, 91%; (vi) MsCl, pyridine; (vii) Na₂S, DMF, α-anomer 78% from 21, β-anomer 73% from 21; (viii) 4M HCl, THF; (ix) NaBH₄, MeOH, 90% from 2; (x) TBDPSCl, imidazole, DMF, 87%; (xi) Ac₂O, DMSO; (xii) Ph₃PCH₃Br, NaH, t-amyl alcohol, THF; (xiii) BCl₃, CH₂Cl₂, −78 °C then MeOH, pyridine, 92%; (xiv) m-CPBA, CH₂Cl₂, −78 °C, 74% from 23; (xv) 25, TMSOTf, ClCH₂CH₂Cl, 0 °C, 29%; (xvi) TBAF, THF and (xvii) aqueous NH₃, MeOH then HPLC separation.

Scheme 4

Reagents and conditions: (i) DAST, CH₂Cl₂, −78 °C, 77%; (ii) m-CPBA, CH₂Cl₂, −78 °C; (iii) Ac₂O, 100 °C, 77% from 23; (iv) 25, SnCl₄, MeCN, 93%; (v) BBr₃, MeOH; (vi) NH₄F, MeOH, 60 °C and (vii) aqueous NH₃, MeOH then HPLC separation, 43% (β-anomer) and 17% (α-anomer) from 32.

Scheme 5

Reagents and conditions: (i) Ac₂O, DMSO; (ii) DAST, benzene, 0 °C-r.t., 48%; (iii) BCl₃, CH₂Cl₂, −78 °C, then MeOH, pyridine; (iv) Bz₂O, Et₃N, DMAP, MeCN, 79% from 34; (v) m-CPBA, CH₂Cl₂, −78 °C; (vi) 25, TMSOTf, ClCH₂CH₂Cl, 0 °C, 57% from 35; (vii) TBAF, THF and (viii) aqueous NH₃, MeOH, then HPLC separation, 36% (α-anomer) and 15% (β-anomer) from 36.

Figure 4

Structures of 2′-deoxy-4’-thiacytidine nucleosides 38–41.

Scheme 6

Reagents and conditions: (i) NIS, pivalic acid, MeCN/CH₂Cl₂, 93%; (ii) Uracil, N,O-bis(trimethylsilyl)acetamide (BSA), TMSOTf, MeCN/CH₂Cl₂, 87%; (iii) Bu₃SnH, Et₃B, toluene, O₂, −60 °C, 98%; (iv) TBAF, Ac₂O, THF, 100%; (v) NH₃/MeOH; (vi) I₂, PPh₃, pyridine, dioxane; (vii) Ac₂O, DMAP, DIPEA, CH₂Cl₂; (viii) BDN, MeCN, 65% over four steps; (ix) NH₃/MeOH; (x) TBDMSCl, imidazole, DMF, 61% over two steps; (xi) Pb(OBz)₄, toluene, 63%; (xii) TMSN₃, SnCl₄, CH₂Cl₂, 61%; (xiii) NaOMe, MeOH; (xiv) Ac₂O, DMAP, DIPEA, MeCN, 83% over two steps; (xv) TPSCl, K₂O₄, MeCN, 60 °C; (xvi) NH₄OH, THF; (xvii) TBAF, Ac₂O, THF and (xviii) NaOMe, MeOH, 66% over four steps.

Scheme 7

Key intermediates to access 2’-deoxy-4’-thiocytidine nucleosides 39–41.

Scheme 8

Reagents and conditions: (i) TBDPSCl, Et₃N, DMAP, CH₂Cl₂, 92%; (ii) NaBH₄, MeOH, 98%; (iii) MsCl, Et₃N, DMAP, CH₂Cl₂, 97%; (iv) Se, NaBH₄, EtOH, THF, 60 °C, 96%; (v) m-CPBA, CH₂Cl₂, –78 °C, 85%; (vi) Uracil, Et₃N, TMSOTf, toluene, CH₂Cl₂, 53%; (vii) 50% aq. TFA, 81%; (viii) N^3-benzoylcytosine, Et₃N, TMSOTf, toluene, CH₂Cl₂, 35%; (ix) 50% Aq. TFA and (x) NH₃, MeOH, 82% over two steps.

Figure 5

Structures of 2’-substituted 4’-selenoarabinofuranosyl pyrimidine analogues 65–68.

Scheme 9

Reagents and conditions: (i) DAST, CH₂Cl₂, −78 °C, 23%; (ii) TESCl, DMAP, CH₂Cl₂; (iii) BzCl, pyridine, DIPEA, 70 °C; (iv) TBAF, THF, 0 °C, 81% over three steps and (v) DAST, CH₂Cl₂, −78 °C, 45%.

Figure 6

2’-Substituted-4’selenoribofuranosyl nucleosides reported by Jeong.

Figure 7

Structures of aristeromycin, 74, and neplanocin A, 75.

Figure 8

Structures of fluorocyclopentenyl nucleoside analogues 76–79.

Scheme 10

Reagents and conditions: (i) I₂, pyridine, THF, 55%; (ii) NaBH₄, CeCl₃, MeOH, 93%; (iii) TBDPSCl, imidazole, DMF, 97%; (iv) NFSI, ⁿBuLi, THF, −78 °C, 80%; (v) TBAF, THF, 80%; (vi) N³-benzoyluracil, DEAD, PPh₃, THF; (vii) NH₃/MeOH; (viii) BBr₃, DCM, −78 °C, 49% over three steps; (ix) Ac₂O, pyridine; (x) POCl₃, Et₃N, 1,2,3-triazole; (xi) NH₄OH, 1,4-dioxane and (xii) NH₃/MeOH, 40% over four steps.

Scheme 11

Reagents and conditions: (i) PDC, CH₂Cl₂, 82%; (ii) NaBH₄, MeOH, 88%; (iii) MsCl, pyridine, 99%; (iv) NaN₃, DMF, 115 °C, 92% and (v) LiAlH₄, THF, 59%.

Scheme 12

Reagents and conditions: (i) MsCl, pyridine, CH₂Cl₂, 98%; (ii) NaN₃, DMF, 110 °C, 91% and (iii) Pd(OH)₂/C, MeOH, 87%.

Scheme 13

Reagents and conditions: (i) TIPSCl, imidazole, DMF, 92%; (ii) NFSI, LiHMDS, THF, −78 °C, 72%; (iii) DIBAL-H, toluene, −78 °C, 91%; (iv) MsCl, Et₃N, CH₂Cl₂, quant.; (v) 2,6-dichloropurine, dichloroethane, reflux; (vi) NH₃/isopropanol, sealed tube, 105 °C, 66% over two steps and (vii) Me₄NF, AcOH, DMF, 90%.

Scheme 14

Reagents and conditions: (i) 2,6-diaminopurine, BSA, TMSOTf, MeCN, 100%; (ii) 2,6-dicholoro-9H-purine, BSA, TMSOTf, 64%; (iii) NaOH, THF, 94%; (iv) BzCl, pyridine, 52%; (v) HF, pyridine, 50%; (vi) Allyl(tri-n-butyl)tin, PdCl₂(PPh₃)₂, DMF then NaOH, THF, 42%, 2 steps and (vii) HF, pyridine, 87%.

Scheme 15

Reagents and conditions: (i) LiCHCl₂, THF then ZnCl₂; (ii) PhCH₂ONa, 97%; (iii) Pinanediol, Et₂O, H₂O, 96%; (iv) CH₂Br₂, LDA, THF then ZnCl₂, 83%; (v) CH₂CHCH₂MgBr, 86%; (vi) NaIO₄/K₂OsO₄, 2,6-lutidine, dioxane/H₂O, 63%; (vii) H₂ Pd/C, EtOAc, 81% and (viii) Ac₂O,DMAP, CH₂Cl₂, 98%. Cy = cyclohexyl, T = thymine, 5F-U = 5-fluorouracil, C = cytosine, 5I-U = 5-iodouracil.

Scheme 16

Reagents and conditions: (i) KMnO₄, KOH, H₂O, 79%; (ii) EDC, HOBt, cyclopropylamine, Et₃N, DMF, 70%; (iii) 50% Aq. HCO₂H, 73% and (iv) Pd(PPh₃)₂Cl₂, CuI, Et₃N, DMF, MeCN, R = 115 = 86%, R = 116 = 85%.

Figure 9

5’-β-Hydroxyphosphonate analogues developed by Peyrottes and active compound 117 from this series, Y = NH₂ or OH.

Figure 10

Ferronucleosides developed by Tucker.

Scheme 17

Reagents and conditions: (i) (Me)₃PO₄, POCl₃ and (ii) Amino acid ester salt, DIPEA. X and Y represent different functional groups for analogue classes e.g. X = Y = F, Base = C = gemcitabine phosphorodiamidate. See Reference [77] for full list of analogues synthesised and evaluated.

Figure 11

Structures of vitamin E-gemcitabine conjugates 121–124, highlighting changes to the tocopherol or tocotrienol component.