Gusperimus
From The Cure For The Needy
Contents |
Gusperimus ((-)-15-deoxyspergualin)
(only marketed in Japan as of 7/1/2009)
Effective Against
A derivative of the antitumor antibiotic spergualin with immunosuppressant activity, Gusperimus inhibits the interleukin-2-stimulated maturation of T cells to the S and G2/M phases and the polarization of the T cells into IFN-gamma-secreting Th1 effector T cells, resulting in the inhibition of growth of activated naive CD4 T cells; this agent may suppress growth of certain T-cell leukemia cell lines.
Cost
Reported Routes of Synthesis
Total synthesis schemes available in following paper Bergeron, R., McManis, J. Total synthesis of (.+-.)-15-deoxyspergualin J. Org. Chem., 1987, 52 (9), pp 1700–1703
The hydrolysis of 7-bromoheptanenitrile (I) with HCl gives the corresponding amide (II), which is treated with Na-N3 in hot DMSO to yield 7-azidoheptanamide (III) (1). The condensation of (III) with 2-hydroxy-2-methoxyacetic acid methyl ester (IV) in hot dichloromethane affords the alpha-hydroxyglycine (V), which is treated with SOCl2 in the same solvent to provide the alpha-chloroglycine (VI). The reaction of (VI) with benzyl alcohol and TEA in dichloromethane furnishes the benzyloxy derivative (VII), which is hydrolyzed at the ester group by means of NaOH in DME to give the carboxylic acid (VIII). The condensation of (VIII) with N1,N4-bis(benzyloxycarbonyl)spermidine (IX) by means of DCC and HOBt in dichloromethane yields the corresponding amide (X), which is reduced at the terminal azido group by means of PPh3 in THF/water, affording the expected primary amine (XI). The condensation of (XI) with the protected isothiourea (XII) in THF affords the protected guanidine derivative (XIII), which is finally deprotected by hydrogenolysis with H2 over Pd(OH)2 in methanol/acetic acid to provide the target compound.
Durand, P.; et al. (-)-15-Deoxyspergualin: A new and efficient enantioselective synthesis which allows the definitive assignment of the absolute configuration. J Org Chem 1998, 63(26): 9723
Durand, P.; et al. A new efficient synthesis of the immunosuppressive agent (±)-15-deoxyspergualin. Tetrahedron 2001, 57(14): 2757
Cost of Starting Materials and Selected Reagents:
7-bromoheptanenitrile from Sigma-Aldrich: 71.7 USD (10g)
Hydrochloric Acid (Molecular Biology Grade, 36.5-38.0%) from Sigma-Aldrich: 46.50 (100 mL)
Sodium Azide from Sigma-Aldrich: 46.9 USD (25g)
Methyl 2-hydroxy-2-methoxy acetate
Thionyl chloride from Sigma Aldrich: 64.4 USD (500mL)
Triethylamine from Sigma-Aldrich: 12 USD (100mL)
(S)-(−)-1-(2-Naphthyl)ethanol from Sigma-Aldrich: 41.1 USD (1 g)
Sodium Hydroxide 10M in H2O from Sigma-Aldrich: 61.60 USD (100 mL)
Dimethoxyethane from : USD (g)
N1,N4-bis (benzyloxycarbonyl) spermidine
- Spermidine from Sigma-Aldrich: 32.2 USD (1 g)
- Benzyl chloroformate from Sigma-Aldrich: 27.6 USD (5g)
N,N′-Dicyclohexylcarbodiimide (DCC) from: 52.1 USD (100g)
1-Hydroxybenzotriazole (HOBt): pricing not available from Sigma-Aldrich
Triphenylphosphine from Sigma-Aldrich: 19 USD (25g)
N,N‘-bis(benzyloxycarbonyl)-S-methylisothiourea
- S-Methylisothiourea hemisulfate salt from Sigma-Aldrich: 17.3 USD (100g)
Palladium hydroxide on carbon (Pearlman's catalyst) from Sigma-Aldrich: 26.50 USD (1g)
Acetic acid from Sigma-Aldrich: 28.8 USD (100 g)
CM Sephadex® C-25 from Sigma-Aldrich: 63 USD (10g)
Sephadex® LH-20 from Sigma-Aldrich: 269.5 USD (50g)
1) By a stepwise conversion of spergualin to DSG in the following sequence: a) Protecting the primary and secondary amines of spergualin with N-(benzyloxycarbonyloxy)suc cinimide to form the N,N'-benzyloxycarbonyl derivative (I); b) protecting the 11-hydroxy group with 3,4-dihydro-2H-pyran to the 11-O tetrahydropyranyl derivative (II); c) converting the 1,5-hydroxy function of (II) to a 1,5-mesylate (III); d) halogenation of (III) with sodium iodide, followed by catalytic hydrogenation, to give 15-deoxy-1-O-tetrahydropyranylspergualin (IV); e) hydrolysis of (IV) with p-toluenesulfonic acid in water to yield 1,5-deoxyspergualin. The overall yield of DSG is 1.8%, based on the amount of spergualin used.
Cheng, CC; Zee-Cheng, RK-Y.; Deoxyspergualin. Drugs of the Future 1987, 12(2) 113
Iwasawa, H.; Kondo, S.; Ikeda, D.; Takeuchi, T.; Umezawa, H. Synthesis of (-)-15-deoxyspergualin and (-)-spergualin-15-phosphate. J Antibiot 1982, 35(12): 1665
Microbial Chemistry Research Foundation. (-)-15-Deoxyspergualin, process for the preparation thereof, and intermediate of the same. US 4525299
Microbial Chemistry Research Foundation. (-)-15-Deoxyspergualin, a process for the preparation of the same, an intermediate of the same, and its use as medicament. EP 0094632
Cost of Starting Materials and Selected Reagents:
Starting Material Spergualin trihydrochloride from Sigma-Aldrich: 180 USD (1 mg)
N-(Benzyloxycarbonyloxy)succinimide from Sigma-Aldrich: 148 USD (100g)
3,4-dihydro-2H-pyran from Sigma-Aldrich: 12.6 USD (5 mL)
p-Toluenesulfonic acid monohydrate from Sigma-Aldrich: 16.9 USD (5g)
Methanesulfonyl chloride from Sigma-Aldrich: 37.6 USD (250 mL)
Sodium Iodide (1 M solution) from Sigma-Aldrich: 35.1 USD (1 mL)
2) By an acid catalyzed condensation of 7-guanidinoheptanamide (IX) with an equivalent amount of glyoxylspermidine (X) in the presence of glutaric acid at 60 C for 8 h. Purification of the reaction mixture gives DSG in 39% yield.
Cheng, CC; Zee-Cheng, RK-Y.; Deoxyspergualin. Drugs of the Future 1987, 12(2) 113
Umeda, Y.; Moriguchi, M.; Kuroda, H.; Nakamura, T. ; Iinuma, H.; Takeuchi, T.; Umezawa, H. Synthesis and antitumor activity of spergualin analogues. I. Chemical modification of 7-guanidino-3-hydroxyacyl moiety. J Antibiot 1985, 38(7): 886
Kondo, S.; Iwasawa, H.; Ikeda, D.; Umeda, Y.; Ikeda, Y.; Iinuma, H.; Umezawa, H. The total synthesis of spergualin, an antitumor antibiotic. J Antibiot 1981, 34(12): 1625
Microbial Chemistry Research Foundation. N-[4-(3-Aminopropyl)-aminobutyl]-2-(omega-guanidino-fatty-acid-amido)-2-substituted-ethanamide and salt thereof. BE 0894651, US 4658058, US 4518532
Microbial Chemistry Research Foundation. N-[4-(3-Aminopropyl)aminobutyl]-2,2-dihydroxyethanamide and process for its synthesis. DE 3217693, GB 2100253
Microbial Chemistry Research Foundation. (S)-7-Guanidino-3-hydroxyheptanamide and its synthesis method. JP 1982188562
Nippon Kayaku Co., Ltd. Purification method of spergualin or its derivatives. JP 1984029652
TaKaRa Shuzo Co., Ltd., Nippon Kayaku Co., Ltd. Method for producing glyoxylspermidine and the use thereof for the production of 15-deoxy spergualin-related compounds. US 4603015, DE 3506330
TaKaRa Shuzo Co., Ltd., Nippon Kayaku Co., Ltd. Spegualin-related nitrile compounds and their preparation method. JP 1985178853
TaKaRa Shuzo Co., Ltd., Nippon Kayaku Co., Ltd. Adduct of omega-guanidino fatty acid amide and glyoxylic acid, and its preparation method. JP 1985178852
Cost of Starting Materials and Selected Reagents:
Glutaric Acid from Sigma-Aldrich: 46.7 USD (100 g)
7-Aminoheptanoic acid from Sigma-Aldrich: 220.5 USD (1g)
S-Methylisothiourea hemisulfate salt from Sigma-Aldrich: 17.3 USD (100g)
Ammonium hydroxide solution (28% in H2O) from Sigma-Aldrich: 25.7 USD (5mL)
Spermidine from Sigma-Aldrich: 32.2 USD (1 g)
2,2-diethoxyacetic Acid not available from Sigma-Aldrich
The synthesis of racemic 15-deoxyspergualin and tritium-labeled compound has been described: The oxidation of N-(3-hydroxypropyl) carbamic acid tert-butyl ester (I) with pyridinium chlorochromate in dichloromethane gives N-(3-oxopropyl) carbamic acid tert-butyl ester (II), which is condensed with 4 - (triphenylphosphonium) butyrate (III) by means of lithium bis (trimethylsilyl) amide in THF yielding 7 - (tert-butoxycarbonylamino)-4-heptenoic acid (IV). The esterification of (IV) with N-hydroxysuccinimide (V) by means of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole affords the corresponding ester (VI), which is treated with ammonia in methanol giving the corresponding amide (VII). The hydrolysis of (VII) with HCl in ethyl acetate yields 7-amino-4-heptenamide (VIII), which is treated with 3,5-dimethylpyrazole-1-carboxamidine (IX) and K2CO3 in methanol affording 7-guanidino-4-heptenamide (X). The reduction of (X) gives 7-guanidinoheptanamide (XI), which is finally condensed with glyoxylspermidine (XII) by means of glutaric acid in hot water. The tritium-labeled compound can also be obtained in the same way by performing the reduction of heptenamide ( X) with tritium gas.
Cook, DJ; Tepper, MA; Saulnier, MG; Dischino, DD; Synthesis of tritium labeled (? 15-deoxyspergualin trihydrochloride. J Label Compd Radiopharm 1993, 33(2) 137
Cost of Starting Materials and Selected Reagents:
3-(Boc-amino)-1-propanol from Sigma-Aldrich: 51.2 USD (10mL)
Pyridinium chlorochromate from Sigma-Aldrich: 23 USD (25g)
4-(triphenylphosphonium) butyrate
Lithium bis(trimethylsilyl)amide from Sigma-Aldrich: 21.9 USD (10g)
N-hydroxysuccinimide from Sigma-Aldrich: 36.6 USD (25g)
N,N′-Dicyclohexylcarbodiimide (DCC) from Sigma-Aldrich: 52.1 USD (100g)
1-Hydroxybenzotriazole (HOBt): pricing not available from Sigma-Aldrich
Hydrochloric Acid (Molecular Biology Grade, 36.5-38.0%) from Sigma-Aldrich: 46.50 (100 mL)
3,5-Dimethyl-1-pyrazolylformaminidium nitrate from Sigma-Aldrich: 30.5 USD (5g)
Potassium carbonate from Sigma-Aldrich: 35.6 USD (100g)
Spermidine from Sigma-Aldrich: 32.2 USD (1 g)
Glutaric acid from Sigma-Aldrich: 46.7 USD (100g)
Description: The synthesis of [14C]-labeled 15-deoxyspergualin trihydrochloride has been reported: The condensation of [14C]-labeled S-methylisothiourea (I) with 7-aminoheptanoic acid (II) by means of NaOH in water gives 7-guanidinoheptanoic acid ( III), which is treated with Dowex 50W resin (H + form) in refluxing methanol yielding the corresponding methyl ester (IV). The reaction of (IV) with concentrated NH4OH affords the amide (V), which is finally condensed with glyoxyloxyspermidine (VI ) by means of glutaric acid in hot water (60 C), and purified by chromatography over Sephadex CM-25 (Na + form).
Reference: Dischino, DD; Synthesis of carbon-14 labeled (? 15-deoxyspergualin trihydrochloride. J Label Compd Radiopharm 1995, 36(11) 1097
Obtained from http://www.chemdrug.com/ Specific, translated page page available here
Cost of Starting Materials and Selected Reagents:
S-Methylisothiourea hemisulfate salt from Sigma-Aldrich: 17.3 USD (100g)
7-Aminoheptanoic acid from Sigma-Aldrich: 220.5 USD (1g)
Sodium Hydroxide 10M in H2O from Sigma-Aldrich: 61.60 USD (100 mL)
Dowex® 50W X8 (p.a., H+-form, strongly acidic, 20-50 mesh) from Sigma-Aldrich: 247.5 USD (100g)
Methanol from Sigma-Aldrich: 21.5 USD (100mL)
Ammonium hydroxide solution (28% in H2O) from Sigma-Aldrich: 25.7 USD (5mL)
Spermidine from Sigma-Aldrich: 32.2 USD (1 g)
Glutaric Acid from Sigma-Aldrich: 46.7 USD (100 g)
Scheme 1. Reagents and conditions: a CbzCl, 1N NaOH, CH2Cl2, H2O, rt, 2 days, 97%; b 7-aminoheptanoic acid, NaHCO3, THF, H2O, 65°C, 6 h, 81%; c (i) NHS, DCC, CH3CN, THF, rt, 16 h and (ii) NH3, DMF, rt, 2 h, 87%; d methyl glyxolate, THF, 40°C, 20 h, 89%; e Ac2O, pyridine, CH2Cl2; f R-α-methyl benzyl alcohol, EtAlCl2, Hunig's base, CH2Cl2, 0°C to rt, 10 h, 74% two steps; g 0.1N LiOH, THF, H2O, rt, 2 h, 93%; h PPA, TEA, CH2Cl2, 0°C, 1 h, 94%; i (i) H2, Pd/C; Pd(OH)2/C, 2N AcOH/MeOH, rt, 20 h, (ii) CM-Sephadex C-25 and (iii) Sephadex LH-20
Cost of Starting Materials and Selected Reagents:
Sodium Hydroxide 10M in H2O from Sigma-Aldrich: 61.6 USD (100 mL)
Benzyl chloroformate from Sigma-Aldrich: 27.6 USD (5g)
7-Aminoheptanoic acid from Sigma-Aldrich: 220.5 USD (1g)
N-Hydroxysuccinimide (NHS) from Sigma-Aldrich: 36.6 USD (25g)
N,N′-Dicyclohexylcarbodiimide (DCC) from Sigma-Aldrich: 52.1 USD (100g)
Acetonitrile from Sigma-Aldrich: 42.3 USD (100mL)
Methyl glyxolate ???
Pyridine from Sigma-Aldrich: 66.5 USD (100mL)
Acetic Anhydride (Ac2O) from Sigma-Aldrich: 16.2 USD (5g)
α-Methylbenzyl alcohol from Sigma-Aldrich: 86 USD (1 kg)
Ethylaluminum Dichloride from Sigma-Aldrich: 106 USD (100g)
N,N-Diisopropylethylamine (Hunig's Base) from Sigma-Aldrich: 65.7 USd (100 mL)
Lithium Hydroxide from Sigma-Aldrich: 42.3 USD (100g)
Triethylamine from Sigma-Aldrich: 12 USD (100 mL)
Palladium hydroxide on carbon from Sigma-Aldrich: 26.5 USD (1g)
Acetic acid from Sigma-Aldrich: 28.8 USD (100 g)
CM Sephadex® C-25 from Sigma-Aldrich: 63 USD (10g)
Sephadex® LH-20 from Sigma-Aldrich: 269.5 USD (50g)