dGMP deoxyguanylate
(31) Ki 45μM
(27) 4’
3
1
Pf TMK Hs TMK TMP dGMP Pf
TMK
2 7 Table 9.
Pf TMK (Figure 32.)
Figure 32. .
2
2-Aamino-6-chloropurine DMSO NaH
Pd[(C6H5)3P]4 2 3 triacetate (20)
-allylpalladium(0) 2 4 (32)
(Scheme 16.)
Scheme 16.
2-Amino-6-chloro (32) 0.2N NaOH 6
(33)
50 v/v% CF3CO2H (Scheme 17.)
Scheme 17.
50 v/v% CF3CO2H (33) 2 6
(33) 77%
3
2 6-chloropurine DMSO NaH
Pd[(C6H5)3P]4 Triacetate (20)
-allylpalladium(0) (34) 6-chloro (34)
50 v/v% CF3CO2H 2 6
(35) 78%
(Scheme 18.)
Scheme 18.
4 6-
-2-6-
52, 53)
4-amino-5-imidazolecarboxamide hydrochloride trifluoroacetamide 180
oC 5 ether
2-trifluoromethyl-6-hydroxypurine (36) 87% (36)
dry CH3CN N,N’-dimethylaniline POCl3
95 oC 5
15 hexane
2-trifluoromethyl-6-chloropurine (37) 89% (Scheme 19.)
Scheme 19.
2 2-trifluoromethyl-6-chloropurine (37)
DMSO NaH Pd[(C6H5)3P]4 triacetate (20)
-allylpalladium(0) (38) (Scheme
20.)
Scheme 20.
5
54, 55)
2,4-dihydro-3-nitropyridine POCl3 2
2,4-dichloro-3-nitropyridine (39) 77% (39) DMF
Et3N p-methoxybenzylamine (PMB-NH2) 4 PMB-NH
(40) (40)
Raney-Ni HCl
3-(41) 52% (Scheme 21.)
Scheme 21.
(41) HC(OEt)3 Ac2O deazapurine (42) 82%
trifluoroacetic acid (42) PMB
6-chloro-3-deazapurine (43) 60% (Scheme 22.)
Scheme 22.
2 6-chloro-3-deazapurine (43) DMSO
NaH Pd[(C6H5)3P]4 triacetate (20)
-allylpalladium(0) (44) 50 v/v%
CF3CO2H 2 6
(45) 66% (Scheme 23.)
Scheme 23.
6
Pf TMK 2
7
dGMP ATP
Figure 33A.
ATP
TMP dGMP (
Competitive inhibition) Figure 33B.
ATP (
Uncompetitive inhibition) Figure 33C.
ATP TMP dGMP
( Liner
mixed inhibition)
ATP TMP dGMP
(Non detectable inhibition)
Figure 33.
A
B
C
Table 10., Table 11.
Table 10. Pf TMK carbocyclic purine nucleoside analogues (1).
Substrate : TMP
I. (Liner mixed inhibition)
Cpd. 34
Ki (μM) 568
II. (Uncompetitive inhibition)
Cpd. 35 32 33
Ki (μM) 590 87 440
Cpd 44 45 38
Ki (μM) 550 412 635
TMP (Competitive inhibition)
(Figure 34.)
Pf TMK ATP TMP ( dGMP)
Figure 34.
TMP ATP (Uncompetitive inhibition)
(34) (Liner mixed inhibition) ATP dGMP
Table 11. Pf TMK carbocyclic purine nucleoside analogues (2).
Substrate : dGMP
I. (Competitive inhibition) II. (Liner mixed inhibition)
Cpd. 33 Cpd. 34
Ki (μM) 93 Ki (μM) 162
III. Uncompetitive inhibition
Cpd. 35 32 44
Ki (μM) 235 250 314
IV. Non detectable inhibition
Cpd 45 38
Ki (μM) N.A. N.A.
N.A. : No inhibitory activity was detectible at 10 μM concentration of the compound.
dGMP
(33) Ki 93 μM
(Figure 35.) TMP 5
TMP
dGMP
Figure 35.
4
100 100
(Pf TMK)
5 4’
Pf TMK
Pf TMK
I.
(2-acetoxycyclopent-3-en-1-yl)methyl acetate (13)
thymine (7d)
(23)
(S)-1-((1S,2R)-2-acetoxycyclopent-3-en-1-yl)ethane-1,2-diyl diacetate (20) N-benzoylthymine (24) N-benzoyluracil (28)
(25) (29) (26) (30)
(27) (31)
Pf TMK (27)
TMP Ki 14 μM dGMP Ki 20.4 μM
II.
(20) 2-amino-6-chloropurine
6-chloropurine 2-trifluoromethyl-6-chloropurine (37) 6-chloro-
3-deazapurine (43) (32) (34) (38) (44)
(33) (35) (45)
Pf TMK dGMP
(33) Ki 93 μM TMP (Competitive inhibition)
Pf TMK
Pf TMK Hs TMK dGMP
Pf TMK
X Pf TMK
Hs TMK Pf TMK
( )
Mahmoud Kandeel
PS SD
Pyridine CaH2 4 Å
DMF 4 Å
THF
1H, 13C NMR JEOL JNM ECS-400 spectrometer (400 MHz for 1H-NMR,
100 MHz for 13C-NMR) 1H (δ)
(TMS) 0.00 ppm CDCl3 7.26 ppm, DMSO-d6 2.49
ppm, CD3OD 3.31 ppm 13C
CDCl3 77.0 ppm, DMSO-d6 39.5 ppm, CD3OD 49.0 ppm JEOL The AccuTOF LC-plus JMS-T100LP
Yanaco MP-J3
60N ( )
HITACHI U-2001 spectrophotometer SHIMADZU RF-5300PC
2 2
1,3-Cyclopentadiene (8)
Dicyclopentadiene (197.2 g, 200 mL, 1.49 mol) 180-190 oC
5 1,3-cyclopentadiene (8) (149.5 g, 2.26 mol, 76 %)
2-Oxabicyclo[3,3,0]oct-7en-3-one (9)
1,3-Cyclopentadiene (8) (56.7 g, 0.86 mol) 50 % glyoxylic acid (61 mL, 1.12 mol )
4 TLC (hexane : EtOAc = 1 : 2 )
EtOAc Na2SO4
(hexane : EtOAc = 1 : 1 ) 2-oxabicyclo[3,3,0]oct-7en-3-one (9) (39.8 g, 0.28 mol, 33 %)
1-(2-Hydroxycyclopent-3-en-1-yl)ethane-1,2-diol (10)
2-Oxabicyclo[3,3,0]oct-7en-3-one (9) (2.67 g, 19.1 mmol) dry THF (37.5 mL) LiAlH4 (0.85 g, 22.4 mmol)
70°C 2 H2O (0.85 mL)
15% NaOH (0.85 mL) H2O (2.6 mL) 10
1-(2-hydroxycyclopent-3-en-1-yl)ethane-1,2-diol (10) (0.874 g, 6.07 mmol, 32%)
5-(Hydroxymethyl)cyclopent-2-enol (12)
1-(2-Hydroxycyclopent-3-en-1-yl)ethane-1,2-diol (10) (10.5 g, 72.8 mmol, 1.0 eq.) diethyl ether (400 mL) H2O (400 mL)
NaIO4 (19.6 g, 91.6 mmol, 1.25 eq.) 1 1
ethylene glycol (1.73 mL, 31.1 mmol, 0.43 eq.) 1 1
H2O EtOH (150 mL)
NaBH4 (3.47 g, 91.6 mmol, 1.25 eq.) 1
1 ethylene glycol
sat NaCl EtOAc
Na2SO4
(CHCl3 : MeOH = 9 : 1 → 1 : 1 ) 5-(hydroxymethyl)cyclopent-2-enol (12) (3.26 g, 28.6 mmol, 39%)
1H-NMR (CDCl3, 400 MHz) δ 6.02 (m, 1H, H-4 or H-5), 5.84 (m, 1H, H-4 or H-5), 4.93 (m, 1H, H-1), 3.81 (m, 2H, C2-CH2), 2.38‒2.73 (m, 3H, H-2 and H-3), 2.24 (m, 2H, OH)
2-Acetoxycyclopent-3-en-1-yl)methyl acetate (13)
5-(Hydroxymethyl)cyclopent-2-enol (12) (687 mg, 6.02 mmol, 1.0 eq.) CH2Cl2 (10 mL) Et3N (3.8 mL, 27.2 mmol, 4.5 eq.)
Ac2O (2.5 mL, 27.1 mmol, 4.5 eq.) 3 TLC
(hexane : EtOAc = 1 : 2 ) 24
24 5% HClaq. 2,3 CHCl3
sat.NaHCO3aq., sat.NaClaq. Na2SO4
(hexane EtOAc
= 5 : 1 → 1 : 1 ) 2-acetoxycyclopent-3-en-1-yl)methyl acetate (13) (930 mg, 4.69 mmol, 78%)
1H-NMR (CDCl3, 400 MHz) δ 6.10 (m, 1H, H-4 or H-5), 5.79 (m, 2H, H-4 or H-5 and H-1), 4.18 (m, 2H, C2-CH2), 2.70 - 2.49 (m, 2H, H-3), 2.25 (m, 1H, H-2), 2.07 (6H, dd, CH3).
2 3
endo-2-Oxabicyclo[3,3,0]oct-7en-3-one (9A)
1,3-Cyclopentadiene (8) (60 g, 0.91 mol) 50 % glyoxylic acid (95 mL, 2.95 mol )
40 oC 8
hexane (50mL × 4) 1,3-cyclopentadiene
NaCl EtOAc (50 mL × 10) EtOAc
CO2 sat.NaHCO3 aq. Na2SO4
NaHCO3 NaCl EtOAc Na2SO4
EtOAc Ether
Ether-hexane (9:1) Ether endo-2-oxabicyclo[3,3,0]oct- 7en-3-one (9A) (14.7 g, 0.10 mol, 11.5%)
endo-4-Butyryloxy-2-oxabicyclo[3,3,0]oct-7-en-3-one (17A)
endo-2-Oxabicyclo[3,3,0]oct-7en-3-one (9A) (8.363 g, 59.7 mmol) dry CH2Cl2 (60 mL) dry pyridine (7.08 g [7.2 mL], 89.6 mmol, 1.5 equiv.)
0 oC butyryl chloride (6.99 g, 89.6 mmol) dry CH2Cl2
(6mL) 1 3
sat.NaCl aq.
1 sat.NaCl aq. 10%HCl (5mL) 2 1
sat.NaHCO3 aq. 2 Na2SO4
(CHCl3 → CHCl3 : acetone
= 100 : 1 ) endo-4-butyryloxy-2-oxabicyclo-[3,3,0]oct-7-en-3- one (17Aa) (12.5 g)
(1R,4S,5R)-4-Hydroxy-2-oxabicyclo[3,3,0]oct-7-en-3-one (9Aa)
endo-4-Butyryloxy-2-oxabicyclo[3,3,0]oct-7-en-3-one (17A) (3.0 g, 14.3 mmol) lipase PS Amano SD (70 mg) phosphate buffer (0.1M KH2PO4 pH 7.0, 29 mL)
35 oC 30 pH pH 6.5-7.0
7 pH overnight brine
AcOEt Na2SO4
CHCl3 : acetone = 100 : 1 ester (17Ab) CHCl3 : acetone = 10 : 1
(1R,4S,5R)-4-hydroxy-2-oxabicyclo[3,3,0]oct-7-en-3-one (9Aa) (552 mg, 28%, 95%ee) (18Aa)
(3S,3aS,6aR)-2-Oxo-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-3-yl 4-methyl- benzoate (18Aa)
(1R,4S,5R)-4-Hydroxy-2-oxabicyclo[3,3,0]oct-7-en-3-one (9Aa) (70 mg, 0.5 mmol) dry pyridine (61 μL, 0.75 mmol) dichloromethane (0.5 mL) 0 oC
p-toluoyl chloride (93 mg, 0.6 mmol)
sat.NaCl aq. dichloromethane sat.NaHCO3 aq. Na2SO4
hexane AcOEt-hexane (3S,3aS,6aR)-2-oxo-
3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-3-yl 4-methyl-benzoate (18Aa) (93 mg, 72%, 95%ee)
Colorless prisms, mp 142 oC. Anal. Calcd for C15H14O4 : C, 69.76; H, 5.46 Fonud: C, 69.48;
H, 5.36.
(18Aa) 1A CHCl3: hexane =
3 : 7 endo-2-oxabicyclo[3,3,0]oct-7en-3-one (9A) (18A)
(3S,3aS,6aR)-2-Oxo-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-3-yl acetate (19Aa) endo-2-Oxabicyclo[3,3,0]oct-7en-3-one (9A) (1.4 g, 1.0 mmol) vinyl acetate (50 mL)
triethylamine (1.0 mL) lipase PS Amano SD (1.0 g)
(CHCl3 : acetone = 10 : 1) (3S,3aS,6aR)-2-oxo-3,3a,4,6a-tetrahydro-2H- cyclopenta[b]furan-3-yl acetate (19Aa) (0.76 g, 42 %)
1H-NMR (CDCl3, 400 MHz) δ 6.24 - 6.18 (m, 1H), 5.98 - 5.92 (m, 1H), 5.62 (dd, 1H, J = 9.6 Hz, 3.6 Hz), 5.41 - 5.35 (m, 1H), 3.41 - 3.31 (m, 1H), 2.60 - 2.37 (m, 2H), 2.19 (d, 3.6 Hz).
(S)-1-((1S,2R)-2-Hydroxycyclopent-3-en-1-yl)ethane-1,2-diol (10Aa)
LiAlH4 (1.52 g, 40 mmol, 2 eq.) dry THF (30 mL)
(1R,4S,5R)-4-hydroxy-2-oxabicyclo[3,3,0]oct-7-en-3-one (9Aa) (2.80 g, 20 mmol) dry
THF (5mL) 10 2
(1.5 mL) 15% NaOHaq. (1.5 mL) (4.5mL)
30 EtOH
THF EtOH Na2SO4
toluene ((1S,2R)-2-hydroxycyclo
-pent-3-en-1-yl)ethane-1,2-diol (10Aa) (1.50 g, 52%)
LiAlH4 (866 mg, 23 mmol) dry THF (20 mL)
(3S,3aS,6aR)-2-oxo-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-3-yl acetate (19Aa) (2.60 g,
14 mmol) dry THF (30 mL) 10 2
16
(0.9 mL) 15% NaOHaq. (0.9 mL) (2.7mL) 30
MeOH THF MeOH
Na2SO4 toluene
(S)-1-((1S,2R)-2-hydroxycyclopent-3-en-1-yl) ethane-1,2-diol (10Aa) (1.40 g, 68%)
(1R,5S)-5-((S)-2-((tert-Butyldiphenylsilyl)oxy)-1-hydroxyethyl)cyclopent-2-enol (21)
((1S,2R)-2-Hydroxycyclopent-3-en-1-yl)ethane-1,2-diol (10Aa) (1.136 g, 7.9 mmol) imidazole (1.076 g, 15.8 mmol, 2 eq.) dry DMF (16 mL)
tert-butyl(chloro)diphenylsilane (TBDPSCl) (2.382 g, 8.7 mmol, 1.1 eq.) sat.NaCl aq.
ether
Ether Na2SO4
CHCl3 : hexane = 1 : 3 silane CHCl3 : acetone = 100 : 1
(1R,5S)-5-((S)-1-((tert-butyldiphenylsilyl)oxy)-2-hydroxyethyl)cyclopent-2-enol (21) (2.20 g, 73%)
((1S,2R)-2-Hydroxycyclopent-3-en-1-yl)ethane-1,2-diol (10Aa) (1.416 g, 9.8 mmol) dry pyridine (35 mL) tert-butyl(chloro)diphenylsilane (TBDPSCl) (2.97 g, 10.8 mmol, 1.1 eq.)
CH2Cl2 5%
Na2SO4
CHCl3 : hexane = 1 : 3 silane CHCl3 : acetone
= 100 : 1 (1R,5S)-5-((S)-1-((tert-butyldiphenylsilyl)oxy)-2-hydroxyethyl) -cyclopent-2-enol (21) (2.95 g, 82%)
(1R,5R)-5-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-hydroxyethyl)cyclopent-2-en-1-yl acetate (22)
(1R,5S)-5-((S)-2-((tert-Butyldiphenylsilyl)oxy)-1-hydroxyethyl)cyclopent-2-enol (21) (2.14
g, 5.6 mmol) dry pyridine (12 mL) DMAP (DMAP 21
mg) acetic anhydride (2.86 g, 28.0 mmol, 5 eq.)
CH2Cl2 5%
Na2SO4 hexane
(1R,5R)-5-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-hydroxyethyl)cyclo -pent-2-en-1-yl acetate (22) (2.229 g, 85%)
(S)-1-((1S,2R)-2-Acetoxycyclopent-3-en-1-yl)ethane-1,2-diyl diacetate (20)
(S)-1-((1S,2R)-2-Hydroxycyclopent-3-en-1-yl)ethane-1,2-diol (10Aa) (688 mg, 4.86 mmol)
dry pyridine (10 mL) (10mL) 1
CH2Cl2 CH2Cl2
sat.NaCl aq., 5%HCl, sat.NaHCO3 aq. Na2SO4
hexane (S)-1-((1S,2R)-2-acetoxy-cyclo-pent-3-en-1 -yl)ethane-1,2-diyl diacetate (20) (841 mg, 65%)
(1R,5R)-5-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-hydroxyethyl)cyclopent-2-en-1-yl acetate (22) (1.62 g, 3.45 mmol) dry THF (2.5 mL) BuN4F-THF
1 THF CHCl3 sat.NaCl
aq., sat.NaHCO3 aq. Na2SO4
dry pyridine (8mL) DMAP (13mg) (1.76g, 17.2
mmol) 1
pyridine CHCl3 CHCl3 sat.NaCl
aq., 5%HCl, sat.NaHCO3 aq. Na2SO4
CHCl3 : acetone = 50 : 1
(S)-1-((1S,2R)-2-acetoxycyclopent-3-en-1-yl)ethane-1,2-diyl diacetate (20) (741 mg, 79%)
1H-NMR (CDCl3, 400 MHz) δ 6.15 - 6.11 (m, 1H), 5.92 - 5.88 (m, 1H ), 5.68 (ddd, J = 6.4 Hz, 1.6 Hz, 1.6 Hz, 1H), 5.31 - 5.23 (m, 1H), 4.44 (dd, J = 2.6 Hz, 1.1 Hz, 1H), 4.01 (dd,12.2 Hz, 5.4 Hz, 1H), 2.64 - 2.53 (m, 1H), 2.42 – 2.25 (m, 2H), 2.62 (s, 3H), 2.01 (s, 3H), 1.95 (s, 3H).
2 4
4-(5-Methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)cyclopent-2-en-1-yl)methyl acetate (7c)
Thymine (636 mg, 5.04 mmol, 2.0 eq.) dry DMSO (20 mL) Ar NaH (60% in mineral oil) (151 mg, 3.78 mmol, 1.5 eq.) thymine Na
2 Ar 2-acetoxycyclopent-3-en-1-yl)methyl
acetate (13) (500 mg, 2.52 mmol, 1.0 eq.) Pd(PPh3)4 (291 mg, 0.252 mmol, 0.1 eq.), PPh3
(66 mg, 0.252 mmol, 0.1eq.) in dry THF (20 mL) π-60 oC 24
TLC (CHCl3 : MeOH = 10 : 1)
CHCl3
(CHCl3 : MeOH = 60 : 1 → 30 : 1) × 2
4-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)cyclopent-2-en-1-yl)methyl acetate (23) (0.491 g, 1.86 mmol, 74%)
1H-NMR (CDCl3, 400 MHz) δ 8.13 (s, 1H, NH-3), 7.05 (s, 1H, H-6), 6.10 (dt, 1H, H-2), 5.74 - 5.69 (m, 2H, H-1, H-3), 4.17, 4.08 (2dd, 2H, H-6α, 6β), 3.09 (m, 1H, H-4), 2.78 (dt, 1H, H-5α), 2.08 (s, 3H, CH3), 1.92 (s, 3H, CH3), 1.37 (dt, 1H, H-5β); 13C-NMR (CDCl3, 100 MHz) δ 170.89, 163.51, 150.82, 138.13, 136.38, 130.60, 111.05, 66.40, 60.88, 44.03, 33.97, 20.90, 12.63; DIFNOE: H-4 (H-1; 2.8 %, H-2; 6.1 %, H-5α; 10.1%, H-6α; and H-6β; 4.9% and 5.2% ), H-5β (H-1; 4.6%, H-4; 2.7%, H-5β; 18.5%); MS (DART) m/z 265 (M++H), HRMS (DART) Calcd for C13H16N2O4 (M++H): 265.1188 Fonud: 265.1224
1-(4-(Hydroxymethyl)cyclopent-2-en-1-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (7d)
4-(5-Methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)cyclopent-2-en-1-yl)methyl acetate
(23) (262 mg, 0.991 mmol) MeOH 28% CH3ONa pH 9 1
2 18 TLC (CHCl3 : MeOH = 10 : 1)
AcOH 1 2
(CHCl3 : MeOH = 10 : 1) 1-(4-(hydroxymethyl)cyclopent-2-en -1-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (7d) (212mg, 0.954 mmol, 96%)
1H-NMR (CDCl3, 400 MHz) δ 7.98 (s, 1H, NH-3), 6.12 (dt, 1H, H-2), 5.71 (m, 2H, H-1, H-3), 3.82, 3.67 (2dd, 2H, H-6α, 6β), 2.97 (br, 1H, H-4), 2.71 (dt, 1H, H-5α), 1.90 (s, 3H,
CH3), 1.24 (dt, 1H, H-5β); MS (DART) m/z 223 (M++H), HRMS (DART) Calcd for C13H14N2O3 (M++H): 223.1083 Fonud: 223.1105
1-(4-(Fluoromethyl)cyclopent-2-en-1-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (23) 1,4-(Hydroxymethyl)cyclopent-2-en-1-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (7d)(23.6
mg, 0.106 mmol) CH2Cl2 (4.6 mL) DAST (27.8
µL, 0.212 mmol, 2 eq.) TLC (CHCl3 : MeOH = 10 : 1)
2 sat.NaHCO3aq. CHCl3
Na2SO4
(CHCl3 : MeOH = 50 : 1)
1-(4-(fluoromethyl)cyclopent-2-en-1-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (23) (11.3 mg, 0.0504 mmol, 48%)
1H-NMR (CDCl3, 400 MHz) δ 8.46 (s, 1H, NH-3), 7.20 - 7.06 (m, 1H, H-Ar), 6.12 - 6.11 (m, 1H, H-2’), 5.74 - 5.66 (m, 2H, H-1 and H-3), 4.65 - 4.05 (m, 2H, H-6), 3.26 - 3.02 (m, 1H, H-4), 2.80 - 2.69 (m, 1H, H-5α), 1.96 - 1.90 (m, 3H, CH3), 1.55 - 1.43 (m, 1H, H-5β); MS (DART) m/z 225 (M++H)
2 5
3-Benzoylthymine (24)
Thymine (1.21 g, 9.59 mmol) MeCN (10 mL) pyridine (4 mL) benzoyl chloride (2.55
mL, 22.1 mmol, 2.2 eq.) Ar 20 TLC (CHCl3 : MeOH
= 15 : 1) CHCl3
0.5 M K2CO3 aq. (20 mL) 1,4-dioxane (20 mL) 1 pH 5
AcOH sat.NaHCO3aq. (50 mL)
1
acetone 13 (0.843g, 3.66 mmol, 52%)
1H-NMR (CDCl3, 400MHz) δ 9.94 (s, 1H, N-H), 7.95 - 7.01 (m, 6H, Ar-H), 1.91 (s, 3H, -CH3)
(S)-1-((1S,4R)-4-(3-Benzoyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)cyclope nt-2-en-1-yl)ethane-1,2-diyl diacetate (25)
3-Benzoylthymine (24) (0.230 g, 1.00 mmol, 2.0 eq.) dry DMSO (7 mL) Ar NaH (60% in mineral oil) (18.0 mg, 0.75 mmol, 1.5 eq.)
3-Benzoylthymine Na 2 Ar
(S)-1-((1S,2R)-2-acetoxycyclopent-3-en-1-yl)ethane-1,2-diyl diacetate (20) (0.140 g, 0.52 mmol, 1.0 eq.), Pd(PPh3)4 (62 mg, 0.0535 mmol, 0.1 eq..), PPh3 (13.9 mg, 0.053 mmol, 0.1
eq.) in dry THF (5 mL) π- 60 oC
24 TLC (CH3Cl : MeOH = 20 : 1) THF
DMSO CHCl3
(CHCl3 )
(S)-1-((1S,4R)-4-(3-benzoyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H) -yl)cyclopent-2-en-1-yl)ethane-1,2-diyl diacetate (25) (108 mg, 0.246 mmol, 47%)
1-((1R,4S)-4-((S)-1,2-Dihydroxyethyl)cyclopent-2-en-1-yl)-5-methylpyrimidine-2,4(1H,3 H)-dione (26)
(S)-1-((1S,4R)-4-(3-Benzoyl-5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)cyclo -pent-2-en-1-yl)ethane-1,2-diyl diacetate (25) (98 mg, 0.223 mmol) NH3/MeOH (15 mL)
120 °C 14
TLC (CHCl3 : MeOH = 10 : 1)
1-((1R,4S)-4-((S)-1,2-dihydroxyethyl)cyclopent-2-en-1-yl)-5-methyl- pyrimidine-2,4(1H,3H)-dione (26) (54.1 mg, 0.388 mmol, 96 %.)
1H-NMR (CD3OD, 400MHz) δ 8.02 (s, 1H, NH-3), 7.47 (d, J =4.0 1H, H-Ar), 6.27 - 6.13 (m, 1H, H-2), 5.73 - 5.66 (m, 1H, H-1), 5.64 - 5.52(m, 1H, H-3), 3.63 - 3.46 (m, 3H, H-6 and H-7), 3.01 - 2.80 (m, 1H, H-4), 2.73 - 2.49 (m, 1H, H-5α), 1.87 - 1.76 (m, 3H, CH3), 1.54 - 1.36 (m, 1H, H-5β); MS (DRAT) m/z 253 [M+H]+, HRMS (DART) Calcd for C12H17N2O4
[M+H]+: 253.1188. Found: 253.1180.
1-((1R,4S)-4-((S)-2-Fluoro-1-hydroxyethyl)cyclopent-2-en-1-yl)-5-methylpyrimidine-2,4 (1H,3H)-dione (27)
1-((1R,4S)-4-((S)-1,2-Dihydroxyethyl)cyclopent-2-en-1-yl)-5-methylpyrimidine-2,4(1H,3H )-dione (26) (30.2 mg, 0.217 mmol) CH2Cl2 (5mL)
DAST (15.6μL) 30 TLC
sat.NaHCO3aq. CHCl3 TLC (CHCl3 : MeOH = 10 : 1)
1-((1R,4S)-4-((S)-2-fluoro-1-hydroxyethyl)cyclopent-2-en-1-yl) -5-methylpyrimidine-2,4(1H,3H)-dione (27) (11.3mg, 0.044mmol, 21 %.)
1H-NMR (CDCl3, 400MHz) δ 7.06 (dd, J = 1.2 Hz, 20.8 Hz 1H, ), 6.30 - 6.10 (m, 1H, H-2), 5.89 - 5.64 (m, 2H, H-1, and H-3), 4.96 - 4.75 (m, 1H), 4.62 - 4.42 (m, 1H), 3.24 - 2.96 (m, 1H), 2.94 - 2.68 (m, 1H, H-5α), 1.98 - 1.86 (m, 3H, CH3), 1.60 - 1.38 (m, 1H,), 1.37 - 1.16 (m, 1H,); MS (DRAT) m/z 255 [M+H]+, HRMS (DART) Calcd for C12H16FN2O3 [M+H]+: 255.1145. Found: 255.1162.
2 6
3-Benzoyluracil (28)
Uracil (1.13 g, 10.0 mmol) MeCN (10 mL) pyridine (4 mL) benzoyl chloride (2.6 mL,
22.4 mmol, 2.2 eq.) Ar 68 TLC (CHCl3 : MeOH =
10 : 1) CHCl3
0.5 M K2CO3aq. (10 mL) 1,4-dioxane (20 mL) 1 pH 5
AcOH sat.NaHCO3aq. (50 mL)
1
acetone 3-benzoyluracil (18) (0.864 g, 4.00 mmol, 40%)
1H-NMR (DMSO-d6, 400 MHz) δ 11.5 (s, 1H, H-N), 7.95 - 7.57 (m, 7H, H-Ar)
(S)-1-((1S,4R)-4-(3-Benzoyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)cyclopent-2-en-1-yl)ethane-1,2-diyl diacetate (29)
3-Benzoyluracil (28) (0.303 g, 1.4 mmol, 2.0 eq.) dry DMSO (7 mL) Ar NaH (60% pure in mineral oil) (44 mg, 1.1mmol) 3-benzoyl uracil
Na 2 Ar (S)-1-((1S,2R)-2-acetoxy
-cyclopent-3-en-1-yl)ethane-1,2-diyl diacetate (20) (0.190 g, 0.71 mmol, 1.0 eq.), Pd(PPh3)4
(82 mg, 0.071 mmol, 0.1 eq.), PPh3 (18.6 mg, 0.071 mmol, 0.1 eq.) in dry THF (7 mL)
π- 60 oC 24 TLC
(CH3Cl : MeOH = 20 : 1) THF DMSO
CHCl3
(CHCl3 ) (124.6 mg,
0.29 mmol, 41%) (S)-1-((1S,4R)-4-(3-benzoyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H) -yl)cyclopent-2-en-1-yl)ethane-1,2-diyl diacetate (29)
1-((1R,4S)-4-((S)-1,2-Dihydroxyethyl)cyclopent-2-en-1-yl)pyrimidine-2,4(1H,3H)-dione (30)
(S)-1-((1S,4R)-4-(3-Benzoyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)cyclopent-2-en-1-yl )ethane-1,2-diyl diacetate (29) (116 mg, 0.272 mmol) NH3/MeOH (10 mL)
120°C 14
TLC (CHCl3 : MeOH = 10 : 1)
1-((1R,4S)-4-((S)-1,2-dihydroxyethyl)cyclopent-2-en-1-yl)pyrimidine-2,4(1H,3H)-dione (30) (57.7 mg, 0.242 mmol, 89 %.)
MS (DRAT) m/z 239 [M+H]+, HRMS (DART) Calcd for C11H15N2O4 [M+H]+: 239.1032.
Found: 239.1034.
1-((1R,4S)-4-((S)-2-Fluoro-1-hydroxyethyl)cyclopent-2-en-1-yl)pyrimidine-2,4(1H,3H)-dione (31)
1-((1R,4S)-4-((S)-1,2-Dihydroxyethyl)cyclopent-2-en-1-yl)pyrimidine-2,4(1H,3H)-dione (30) (37.6 mg, 0.158 mmol) CH2Cl2 (5mL)
DAST (11.4μL) 30 TLC
sat.NaHCO3aq. CHCl3 TLC (CHCl3 : MeOH = 10 : 1)
1-((1R,4S)-4-((S)-2-fluoro-1-hydroxyethyl)cyclopent-2-en-1-yl)- pyrimidine-2,4(1H,3H)-dione (31) (9.6mg, 0.040mmol, 25 %.)
MS (DRAT) m/z 241 [M+H]+, HRMS (DART) Calcd for C11H14FN2O3 [M+H]+:241.0989.
Found: 241.0998
2 7
N Pf TMK
50 µg/mL LB 10 mL
37 °C 50 µg/mL
1 L LB 37 °C OD600 0.60
1 mM IPTG 37 °C 4 6,000 × g
15 4 °C -20 °C
40 mL (25 mM
Tris-HCl buffer pH 7.2 150 mM NaCl) 40
3 3 12,000 rpm 15 4 °C
Talon
(25 mM Tris-HCl buffer pH7.2 150 mM NaCl)
30 (25 mM Tris-HCl buffer pH7.2 150
mM NaCl 10 mM imidazole)
(25 mM Tris-HCl buffer pH7.2 150 mM NaCl 200 mM imidazole)
(50 mM Tris-HCl pH 7.2 0.5 mM phosphoenolpyruvate 40 mM KCl 2 mM MgCl2 2 mM ATP 0.15 mM NADH 2 unit pyruvate kinase 2 unit lactate
dehydrogenase TMP and dGMP ) 1 mL
(Pf TMK) 30°C
335 nm Ki
1 unit 1 1 μmol
v = V
max[S] / (K
m + [S])･････････････(1) 1/v = (K
m / V
max)(1 / [S]) + 1 / V
max･･･(2) K`m = K``
m(1 + [I] / K
i)･･････････････(3)
3 2
(1’R,4’S,5’S)-2-Amino-6-chloro-9-[4’-(1”,2”-diacetoxyethyl)cyclopent-2’-en-1-yl]purine (32)
2-Amino-6-chloropurine (339 mg, 2.0 mmol) dry DMSO (8 mL) Ar NaH (60% pure in mineral oil) (80 mg, 2mmol) 2-amino-6-chloropurine
Na 2 Ar (S)-1-((1S,2R)-2-acetoxy-
cyclopent-3-en-1-yl)ethane-1,2-diyl diacetate (20) (541 mg, 2 mmol), Pd(PPh3)4 (231 mg, 0.2 mmol), PPh3 (52 mg, 0.2 mmol) in dry THF (8 mL)
π-60 oC 24 CHCl3
CHCl3 mineral oil PPh3
AcOEt : hexane = 1 : 2 (20) acetone :
hexane = 1 : 1 (1’R,4’S,5’S)-2-amino-6-chloro-9-[4’-(1”,2”-diacetoxy- ethyl)cyclopent-2’-en-1-yl]purine (32) (301 mg, 40%)
(1S)-1-((1S,4R)-4-(2-Amino-6-hydroxy-1H-purin-9(6H)-yl)cyclopent-2-en-1-yl)ethane-1, 2-diol (33)
(1’R,4’S,5’S)-2-Amino-6-chloro-9-[4’-(1”,2”-diacetoxyethyl)cyclopent-2’-en-1-yl]purine (32) (75 mg) 50v/v% CF3CO2H (5 mL) 2
Toluene CF3CO2H
MeOH (1 mL) 1M NH4OH (1 mL) 2
(CHCl3 ; MeOH
= 4 : 1) (1S)-1-((1S,4R)-4-(2-amino-6-hydroxy-1H-purin-9(6H)- yl)cyclopent-2-en-1-yl)ethane-1,2-diol (33) 42 mg, 77%
1H NMR (CD3OD) δ 1.67 - 1.74 (1H, m, 5’-CH2), 2.71 - 2.76 (1H, m, 5’-CH2), 2.90 - 3.03 (1H, m, 4’-CH), 3.50 - 3.54 (1H, m, 2’’-CH2-O), 3.54 - 3.62 (1H, m, 2’’-CH2-O), 4.57 (1H, br s, 1’-CH-N), 5.45 - 5.52 (1H, m, 1’’-CH-O), 5.85 - 5.88 (1H, m, =CH), 6.20 - 6.26 (1H, m,
=CH), 7.75 (1H, s, 8-H). ; Anal. Calcd. for C12H15N5O3 1/2H2O : C, 50.34; H, 5.63; N, 24.46.
Found: C, 50.31; H, 5.41; N, 24.24.
3 3
(1’R,4’S,5’S)- 6-Chloro-9-[4’-(1”,2”-diacetoxyethyl)cyclopent-2’-en-1-yl]purine (34)
6-Chloropurine (309 mg, 2.0 mmol) dry DMSO (8 mL) Ar NaH
(60% pure in mineral oil) (80 mg, 2mmol) 6-chloropurine Na
2 Ar (S)-1-((1S,2R)-2-acetoxycyclopent-3-en-1-yl)- ethane-1,2-diyl diacetate (20) (541 mg, 2 mmol), Pd(PPh3)4 (231 mg, 0.2 mmol), PPh3 (52 mg, 0.2 mmol) in dry THF (8 mL)
π-60 oC 24 CHCl3
CHCl3 mineral oil PPh3 AcOEt : hexane
= 1 : 2 (20) (145mg) acetone : hexane =1 : 1
(1’R,4’S,5’S)-6-chloro-9-[4’-(1”,2”-diacetoxyethyl)cyclopent-2’-en-1-
yl]purine (34) (34) ether (108 mg, 15%
1H NMR (CDCl3) δ 1.63 - 1.74 (1H, m, 5’-CH2), 2.05 (3H, s, COCH3), 2.08 (3H, s, COCH3), 2.88 - 2.98 (1H, m, 5’-CH2), 3.17 - 3.25 (1H, m, 4’-CH), 4.05 - 4.12 (1H, m, 2’’-CH2-O), 4.33 - 4.38 (1H, m, 2’’-CH2-O), 5.06 - 5.12 (1H, m, 1’-CH-N), 5.77 - 5.84 (1H, m, 1’’-CH-O), 5.97 - 6.02 (1H, m, =CH), 6.23 - 6.26 (1H, m, =CH), 8.18 (1H, s, 8-H), 8.74 (1H, s, 4-H).
(1S)-1-((1S,4R)-4-(6-Hydroxy-1H-purin-9(6H)-yl)cyclopent-2-en-1-yl)ethane-1,2-diol (35)
(1’R,4’S,5’S)- 6-Chloro-9-[4’-(1”,2”-diacetoxyethyl)cyclopent-2’-en-1-yl]purine (34) (80 mg) 50v/v% CF3CO2H (5 mL) 2
toluene CF3CO2H
MeOH (1 mL) 1M NH4OH (1 mL) 2
(CHCl3 : MeOH = 5 : 1)
MeOH (1S)-1-((1S,4R)-4-(6-
hydroxy-1H-purin-9(6H)-yl)cyclopent-2-en-1-yl)ethane-1,2-diol(35) (45 mg, 78%)
mp 280 oC. (dec.) 1H NMR (CD3OD) δ 1.76 (1H, ddd, J =13.7Hz, 6.4Hz, 6.4Hz 5’-CH2), 2.80 (1H, ddd, J =13.7Hz, 8.8Hz, 8.8Hz Hz, 5’-CH2), 3.00 - 3.08 (1H, m, 4’-CH), 3.51 - 3.64 (2H, m, 2’’-CH2-O), 4.82 - 4.90 (1’-CH-N) Overlapped with the H2O Peak , 5.65 - 5.72 (1H, m, 1’’-CH-O), 5.91 - 5.93 (1H, m, =CH), 6.28 - 6.32 (1H, m, =CH), 8.02 (1H, s,
8-H), 8.12 (1H, br s, 2-H).; Anal. Calcd. for C12H14N4O3 2/3H2O : C, 52.55; H, 5.63; N, 20.43. Found: C, 52.50; H, 5.21; N, 20.62.
3 4
2-(Trifluoromethyl)-9H-purin-6-ol (36)
4-Amino-5-imidazolecarboxamide hydrochloride (2.0 g, 12 mmol) trifluoroacetamide
(13.6 g, 120 mmol) 180 oC 5 2
ether
ether EtOH
MeOH EtOH 2-(trifluoromethyl)-9H-purin-6-ol (36) (2.14 g, 87%)
2-Trifluoromethyl-6-chloropurine (37)
2-(Trifluoromethyl)-9H-purin-6-ol (36) (1.52 g, 7.4 mmol) dry CH3CN (22 mL) N,N’-dimethylaniline (1.35 g, 11.1 mmol, 1.5 eq) POCl3 (3.43 g, 22.2
mmol, 3 eq.) 95 oC 5
(10 mL) 15
hexane 2-trifluoromethyl-6-chloropurine (37) (1.47 g, 89%)
(S)-1-((1S,4R)-4-(6-Chloro-2-(trifluoromethyl)-9H-purin-9-yl)cyclopent-2-en-1-yl)ethan e-1,2-diyl diacetate (38)
2-Trifluoromethyl-6-chloropurine (37) (222 mg, 1.0 mmol) dry DMSO (5 mL)
Ar NaH (60% pure in mineral oil) (40 mg, 1 mmol) 6-chloro-2-
trifluoromethylpurine Na 2 Ar
1-acetoxy-5-(1,2-diacetoxyethyl)cyclopent-2-ene (270 mg, 1 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol), PPh3 (26 mg, 0.1 mmol) in dry THF (5 mL)
π-Purine Na DMSO 60 oC 24
CHCl3
CHCl3
mineral oil PPh3 AcOEt hexane=1:2
triacetate acetone:hexane=1:1 (S)-1-((1S,4R)-4-(6-chloro-2- (trifluoromethyl)-9H-purin-9-yl)cyclopent-2-en-1-yl)ethane-1,2-diyl diacetate (38)
1H NMR (CDCl3) δ 1.63 - 1.72 (1H, m, 5’-CH2), 2.05 (3H, s, COCH3), 2.08 (3H, s, COCH3), 2.94 - 3.02 (1H, m, 5’-CH2), 3.17 - 3.25 (1H, m, 4’-CH), 4.02 - 4.08 (1H, m, 2’’-CH2-O),
4.32 - 4.38 (1H, m, 2’’-CH2-O), 5.06 (1H, m, 1’-CH-N), 5.88 (1H, m, 1’’-CH-O), 5.98 (1H, m, =CH), 6.26 (1H, m, =CH), 8.35 (1H, s, 8-H).
3 5
2,4-Dichloro-3-nitropyridine (39)
2,4-Dihydroxy-3-nitropyridine (4.73g, 30.2 mmol) POCl3 29 mL 95 oC
17 50 g 30
22 mL 4.51 g, 77%
2-Chloro-4-(p-methoxybenzylamino)-3-nitropyridine (40)
2,4-Dichloro-3-nitropyridine (39) (4.51 g, 23.4 mmol) DMF (40 mL) triethylamine (2.08 g, 20.6 mmol)
p-Methoxybenzylamine (3.3 g, 24.0 mmol) 1
2 200 mL
50 mL 2-Chloro-4-(p-methoxybenzyl
amino)-3-nitropyridine (40) (6.24 g, 91%)
3-Amino-2-chloro-4-(p-methoxybenzylamino)pyridine (41)
2-Chloro-4-(p-methoxybenzylamino)-3-nitropyridine (40) (6.24 g, 21.2 mmol) EtOH (115 mL) Iron powder (6.51 g) H2O (21 mL) HCl (4.6 mL) 95 oC
17
(CH2Cl2:MeOH = 9:1) 3-amino-2-chloro-4-(p-methoxybenzylamino)pyridine (41) (2.93 g, 52.4%)
4-Chloro-1-(p-methoxybenzyl)-1H-imidazo[4,5-c]pyridine (42)
3-Amino-2-chloro-4-(p-methoxybenzylamino)pyridine (41) (2.93 g, 11.1 mmol) triethyl orthoformate (25 mL) acetic anhydride (25 mL) 160 oC 2
(CH2Cl2 : acetone
= 20:1 → 10:1 → 5:1) 4-chloro-1-(p-methoxybenzyl)-1H-imidazo[4,5-c]
pyridine (42) (2.48 g, 82%)
4-Chloro-1H-imidazo[4,5-c]pyridine (43)
4-Chloro-1-(p-methoxybenzyl)-1H-imidazo[4,5-c]pyridine (42) (2.4 g, 8.8 mmol) trifluoroacetic acid (11.0 mL) 80 oC 2
CHCl3
CHCl3
acetone AcOEt
CHCl3 : MeOH = 5 : 1 5
CHCl3 PMB
CHCl3 : MeOH = 10 : 1 4-chloro-1H- imidazo[4,5-c]pyridine (43) (0.811 g, 60%)
(S)-1-((1S,4R)-4-(4-Chloro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopent-2-en-1-yl)ethane-1, 2-diyl diacetate (44)
4-Chloro-1H-imidazo[4,5-c]pyridine (43) (307 mg, 2 mmol) dry DMSO (8 mL) NaH (60% pure in mineral oil) (136 mg, 3.4 mmol, 1.7 eq.) Ar
2 Na Ar (S)-1-((1S,2R)-2-acetoxy-
cyclopent-3-en-1-yl)ethane-1,2-diyl diacetate (20) (541 mg, 2 mmol), PPh3 (73 mg, 0.28 mmol, 0.14 eq.), Pd(PPh3)4 (324 mg, 0.28 mmol, 0.14 eq.) in dry THF (8 mL)
π- Deazapurine Na DMSO 60 oC
24
AcOEt:hexane=1:2 Ph3P acetone : hexane = 1 : 1 9- coupling product TLC (44)
(S)-1-((1S,4R)-4-(4-chloro-1H-imidazo[4,5-c]pyridin- 1-yl)cyclopent-2-en-1-yl)ethane-1,2-diyl diacetate (44) (39 mg, 47%)
(S)-1-((1S,4R)-4-(4-Chloro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopent-2-en-1-yl)ethane-1, 2-diol (45)
(S)-1-((1S,4R)-4-(4-chloro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopent-2-en-1-yl)ethane-1,2-diyl diacetate (44) (80 mg) 50v/v%CF3CO2H (3 mL) 2
Toluene CF3CO2H
MeOH (1 mL), 1M NH4OH (1 mL) 2 TLC (CHCl3 : MeOH = 10 : 1)
(S)-1-((1S,4R)-4-(4-chloro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopent-2 -en-1-yl)ethane-1,2-diol (45) (42mg 66%)
MS (m/z): 279 (M+), 281 ([M+2]+).
3 6
2 7
1) , 2005.
(http://jsp.tm.nagasaki-u.ac.jp/modules/tinyd3/content/complete.pdf)
2) 2010, 56, 139-145.
3) W. Peters, British Medical Bulletin, 1982, 38(2): 187-192.
4) (WHO) 2011 7
5) (1993) . , .
6) (1993) . , , [ ]
(1) , , , pp.211-226.
7) AIM Developing Team (1994) An estimation of climatic change effects on malaria.
AIM Interim Paper, August 12, 1994, Tsukuba.
8) , , , 2004.
9) 1995
10) K. Tanabe, T. Mita, T. Jombart, et al. Curr Biol. 2010 Jul 27;20(14):1283-9.
11) 2 :
1 :
12) 5
13)
14) IDWR 2010 38 15)
(http://www.biken.osaka-u.ac.jp/biken/BioScience/page02/index_02.html) 16) CDC Travelers’ Health, 2010
(http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-2/malaria.aspx) 17) Vol. 81, No. 7, 1999
18) E. D. Clercq, Nucleosides Nucleotides, 1998, 17, 625-634.
19) L. Agrofoglio, E. Suhas, R. Condom, S. R. Challand, R. A. Earl and R.Guedj, Tetrahedron, 1994, 50, 10611-10670.
20) Hiraoka, H. Satake, S. Iguchi, A. Matsuda, T. Ueda and Y. Wataya, Biochem. Biophys.
Res. Commun., 1986, 3, 1114-1121.
21) Y. Saso, E. M. Conner, B. R. Teegarden and C. S. Yuan, J. Pharmacol. Exp. Ther., 2001, 296, 106-112.
22) J. A. Wolos, K. A. Frondorf, G. F. Babcock, S. A. Stripp and T. L. Bowlin, Cell.
Immunol., 1993, 149, 402-408.
23) Herdewijn, P.; Clercq, E. D.; Balzarini, J.; Vanderhaeghe, H. J. Med. Chem., 1985, 28,
550-555.
24) M. S. Wolfe and R. T. Borchardt, J. Med. Chem., 1991, 34, 1521-1530.
25) S. Liu, M. S. Wolfe and R. T. Borchardt, Antivairal Res., 1992, 19, 247-265.
26) M. Nakanishi, The Pharmaceutical Society of Japan, 2007, 127(6) 977-982 27) J. L. Palmar and R. H. Abeles, J. Biol. Chem, 1979, 254, 1217-1226.
28) P. M. Ueland, Pharmacol. Rev., 1982, 34, 223-253.
29) D. J. T. Porter and F. L. Boyd, J. Biol. Chem, 1991, 266, 21616-21625.
30) Kloor, D.; Osswald, H. Trends Pharmacol Sci. 2004, 25, 294-297.
31) C. S. Yuan, Y. Saso, E. Lazarides, R. T. Borchardt and M. J. Robins, Exp. Opin. Ther.
Patent, 1999, 9, 1197-1206
32) Y. Kitade, A. Kozaki, T.Miwa and M. Nakanishi, Tetrahedron, 2002, 58, 1271-1277.
33) Y. Kitade, H. Kojima, F. Zulfiqor, K. Hye-Sook and Y. Wataya, Bioorg. Med. Che,.
Lett., 2003, 13, 3963-3965.
34) T. Ando, M. Iwata, F. Zulfiqar, T. Miyamoto, M. Nakanishi and Y. Kitade, Bioorg.
Med. Chem., 2008, 16, 3809-3815.
35) N. Tanaka, M. Nakanishi, Y. Kusakabe, K. Shiraiwa, S. Yabe, Y. Ito, Y. Kitade and K.
T. Nakamura, J. Mol. Biol., 2004, 343, 1007-1017.
36) Y. Kitade, T. Ando, T. Yamaguchi, A. Hori, M. Nakanishi and Y. Ueno, Bioorg. Med.
Chem., 2006, 14, 5578-5583.
37) J. L. Whittingham, J. Carrero-Lerida, J. A. Brannigan, L. M. Ruiz-Perez, A. P. G. Silva, M. J. Fogg, A. J. Wilkinson, I. H. Gilbert, K. S. Wilson and D. Gonzalez-Pacanowska, J. Biochem., 2010, 428, 499-509.
38) M. Kandeel, Y. Kitade, J. Biochem., 2008, 144, 245-250.
39) M. Kandeel, T. Ando, Y. Kitamura, M. Abdel-aziz and Y. Kitade, Parasitology, 2009, 136, 12-25.
40) A. Kato, Y. Yasuda, Y. Kitamura, M. Kandeel, Y. Kitade, Parasitol. Int., 2012, 61, 501-503.
41)
42) Organic Synthesis, Coll. Vol. V, 444
43) A. Lubineau, J. Auge and N. Lubin, Tetrahedron Lett., 1991, 32 (51), 7529-7530.
44) R. A. MacKeith, R. McCague, H. F. Olivo, S. M. Roverts, S. J. C. Taylor and H. Xiong, Bioorg. Med. Chem., 1994, 2 (6), 387-394.
45) H. Kapeller, C. Marschner, M. Weibenbancher and H. Griengl, Tetrahedron, 1998, 54, 1439-1456.
46) R. A. MacKeith, R. McCague, H. F. Olivo, C. F. Palmer, S. M. Roberts, J. Chem. Soc.,