http://informahealthcare.com/enz ISSN: 1475-6366 (print), 1475-6374 (electronic) J Enzyme Inhib Med Chem, Early Online: 1–4 ! 2014 Informa UK Ltd. DOI: 10.3109/14756366.2014.987137
REVIEW ARTICLE
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High-efficient synthesis and biological activities of allosamidins Gangliang Huang, Daquan Peng, Xinya Mei, Xin Chen, Feng Xiao, and Qilin Tang College of Chemistry, Chongqing Normal University, Chongqing, China
Abstract
Keywords
The pseudo-trisaccharide allosamidin 1 is a potent inhibitor of all family-18 chitinases, and it is confirmed to have insecticidal and antifungal activities. But the synthesis of allosamidins is very difficult, and it is a challengeable subject. Allosamidins were synthesized in solid–liquid phase, total solid-phase and total liquid-phase, respectively. Solid–liquid phase method realizes the partial solid-phase synthesis of allosamidins. Total solid-phase method greatly simplifies the purification process. Total liquid-phase method shortens the synthetic steps of allosamidins. The insecticidal and antifungal activities of allosamidins were also reported herein.
Allosamidins, chitinase inhibitory activities, insecticidal and antifungal activities, synthesis
Introduction The fungal chitinases are used to modify chitins, which are the main component of cell wall. The insect chitinases are utilized to partially degrade the old exoskeletons of insects. So, it indicates that using chitinases as targets can investigate and develop the antifungal agents and biological pesticides (i.e. chitinase inhibitors). Allosamidin 1 is the family-18 chitinase inhibitor, which contains two b-linked N-acetyl-2-amino-2-deoxy-Dallopyranoside building blocks and a residue (namely allosamizoline 2, Figure 1)1. Compound 1 has the unique chemical structure and becomes an attractive molecule, resulting in many total syntheses of allosamidin 1 and its analogues to be reported2–22. The selection of glycosidation method to assemble the building blocks of compound 1 and its analogues causes the substantial difference between any two reported total synthesis methods. Ensuring to produce exclusive b-glycosidic bond is the main aim of these glycosidation methods. Herein, the synthesis, insecticidal and antifungal activities of allosamidins were summarized.
Synthesis of allosamidins Trost’s and Vasella’s groups reported the total synthesis of allosamidin 12–4. They utilized the glycosidation of trichloroacetimidate to couple two N-acetyl-D-allosamine building blocks together, and then the obtained disaccharide donor was regioselectively coupled to the racemic carbsugar analogue. Because of using the racemic reactant, the coupling inevitably produced an unwanted diastereomer. Kuzuhara’s total synthesis of allosamidin 15 involved the glycosidation of ()-allosamizoline derivative and chitobiose
Address for correspondence: Gangliang Huang, College of Chemistry, Chongqing Normal University, Chongqing, 401331, China. Tel: +86 013068336573. Fax: +86 013068336573. E-mail: huangdoctor226@ 163.com
History Received 4 September 2014 Revised 16 October 2014 Accepted 27 October 2014 Published online 4 December 2014
thioglycoside donor, which was promoted with N-iodosuccinimide (NIS). Blattner and co-workers6 investigated the synthesis of allosamidin 1 by glycosylation of acceptor with a trichloroacetimidate donor. The acceptor was aminocyclopentanol, namely, selectively protected allosamizoline 2, which had only one hydroxyl group. Griffith and Danishefsky also reported the total synthesis of allosamidin 17. This method is facile to form the b-linked 2-deoxy-D-allosamine building block. Oligosaccharides can be synthesized by solid-phase method23–26. The excess reactants or by-products may be rapidly removed by filtering in every step of reaction. In this respect, Huang’s group synthesized allosamidin 1 by solid–liquid method27 (Scheme 1). The C-3 hydroxyl group of diol 328 (Scheme 1) was selectively conjugated to a solid support through benzylation by means of stannylene methodology29 to produce dibenzylated unit 4. Glycosidation of a-trichloroacetimidate donor 527 and acceptor 4 provided b-pseudodisaccharide 6. The reaction was promoted with trimethylsilyltrifluromethanesulfonate (TMSOTf). Levulinoyl ester was cleaved with hydrazinium acetate/MeOH to afford acceptor 7. After glycosylation of acceptor 7 with donor 827, Cbz, Wang resin and Bn were removed from the saccharidebound resin in catalytic hydrogenation condition. The resulting mixture was acetylated and then deacetylated to obtain target pseudo-trisaccharide 1. Terayama et al. reported the solution synthesis of N,N0 diacetyl-b-chitobiosylallosamizoline 9 (i.e. allosamidin analogue), which was stereo-selectively synthesized by the coupling reaction of disaccharide thioglycoside building block and allosamizoline 2 derivative building block15. The solid–liquid phase synthesis of compound 9 was also investigated (Scheme 1)30. Allosamidin 1 and N,N0 -diacetyl-b-chitobiosylallosamizoline 9 have been synthesized by combining solid-phase and liquid-phase method from the above-mentioned, but compounds 1 and 9 need
2
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Figure 1. The structures of allosamidin 1 and allosamizoline 2.
J Enzyme Inhib Med Chem, Early Online: 1–4
HO
OH O O
OH O O HO
OH NHAc OH NHAc 1
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Scheme 1. Solid/liquid-phase synthesis of allosamidin 1 and N,N0 -diacetyl-b-chitobiosylallosamizoline 9.
OH
OH HO HO
O N
NMe2
OBn HO HO
O N 3
Bu2SnO HO Wang-chlorinated resin,CsF O NMe2
NMe2
OBn O 4
N
NMe2
OBn 5 or,10TMSOTf LevO O OBn OBn R1 LevO O O O R3 CCl3 O O R2 NHCbz R4 N NMe2 NHCbz NH 5:R1=H,R2=AcO 6:R3=H,R4=AcO 10:R1=AcO,R2=H 11:R3=AcO,R4=H N2H4·HOAc OBn OBn HO O O R5 O O R6 N NMe2 NHCbz 7:R5=H,R6=AcO 12:R5=AcO,R6=H
HO R9 R10
O N 2
AcO R7 R8
OAc O
a. 8or-13,TMSOTf CCl3 b. H2,Pd/C O c. Ac2O,Pyridine NHCbz d. NaOMe,MeOH NH OH OH 8:R7=H,R8=AcO O OH O O O 13:R7=AcO,R8=H R9 HO O NHAc R10 NHAc N NMe2 1:R9=H,R10=HO 9 :R9=HO,R10=H
to be purified by column chromatography for the final three steps. So, the synthetic method for allosamidin 1 and its analogue 9 does not fully utilize the strongpoint of solid-phase synthesis. That is to say, if compounds 1 and 9 are synthesized by solid-phase method for every step, it can simplify the purification process by filtrating and washing to remove excess reactants or by-products. Therefore, the total solid-phase syntheses of allosamidin 1 and N,N0 -diacetyl-b-chitobiosylallosamizoline 9 were investigated (Scheme 2)31,32, and the results were very satisfactory. N,N0 -diacetyl-b-chitobiosylallosamizoline 9 has been synthesized by solid/liquid-phase method and total solid-phase method, respectively. But the synthetic steps are still a little longer, and the yield of this step for introducing solid-phase support is low. Therefore, the allosamidin analogue 9 was also synthesized by total liquid-phase method, which was based on the reported solidphase of allosamidins, but the solid-phase support was not introduced (Scheme 3)33. N,N0 -diacetyl-b-chitobiosylallosamizoline 9 was synthesized in solid–liquid phase, total solid-phase and total liquid-phase, respectively. The main comparison of above-mentioned three methods for synthesizing compound 9 is shown in Table 1. Insecticidal and antifungal activities Allosamidins can inhibit the activity of chitinase, which prevents the ecdysis of insect larvae and pupa as well as separation of fungal microspore mother cells. So, they play the insecticidal and antifungal actions20,34. The pseudo-trisaccharide allosamidin 1 has a competitive inhibitory activity against chitinases at very low concentration. Injection of compound 1 in larvae of the silkworm
Bombyx mori and the armyworm Leucania separata strongly disturbed larval ecdysis and increased mortality rate of these lepidopteran pests. Ecdysis inhibitory activity of allosamidin 1 to larvae of B. mori and L. separata is EI50 ¼ 2 mg and 4 mg, respectively35. EI50 is the 50% ecdysis inhibition. Compound 1 and its derivatives highly increased mortality of the blowfly larvae (Lucilia cuprina) after contact applications or feeding tests20. In the webbing clothes moth Tineola bisselliella, consumption of allosamidin 1 resulted in larval mortality associated with severe morphological alterations (delayed growth and interrupted moulting) that occur during larval development20. Compound 1 also induces aphicidal effects, increases larval mortality and reduces fecundity of the aphid Myzus persicae36. Inhibition of chitinases by allosamidin 1 has been extensively studied due to its high inhibitory activity. Compound 1 and its derivatives, namely, demethylallosamidin, methylallosamidin, glucoallosamidin A, glucoallosamidin B and methyl-N-demethylallosamidin37, were also tested against different human pests and pathogens such as plasmodium38,39 and nematodes40. Allosamidin 1 also possesses antibacterial41 and antifungal activities against the pathogenic fungi42. In Streptomyces species that produce compound 1, this inhibitor favours production of an allosamidininsensitive chitinase, which is necessary for fungi growth43.
Conclusion In a word, it proves that the total solid-phase synthesis and its derived liquid-phase synthesis can enhance the synthesis efficiency of allosamidins. These compounds demonstrate
Synthesis and biological activities of allosamidins
DOI: 10.3109/14756366.2014.987137
Scheme 2. Total solid-phase synthesis of N,N0 -diacetyl-b-chitobiosylallosamizoline 9.
OBn
OBn HO HO
HO
a. Bu2 SnO
O N
NMe 2
b.
3
14
O
O N 15
Cl
OBn O
OBn O
O
O
N
NHCbz
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NMe2
a. 10 ,TMSOTf b. N2H 4 ·HOAc HO AcO
O NH2 AcO
OH O
HO HO
O NHAc HO
OH O
O NHAc HO
NMe 2
16
a. 13 TMSOTf , b. H 2 ,Pd/C OH OH O O O O NH 2 N NMe2 17
OAc O
AcO AcO
HO HO
3
a. Ac2O, pyridine b. NH3, MeOH OH OH O O O O NHAc N NMe2 18 OH O NHAc 9
hv OH O HO
O N
NMe2
NO2 Cl O
O
Polystyrene 14 Cl
HO BnO
Table 1. Comparison of three synthetic methods for compound 9.
OBn O
N 19 a.10,TMSOTf b. N2H4·HOAc HO AcO
AcO AcO
OAc O
OBn
OBn O
O NH2 AcO
O BnO NHCbz 20
O HO
NMe2
OH O
O NHAc HO
Number of synthetic steps
Number of column chromatography
Solid/liquid-phase Total solid-phase Total liquid-phase
7 8 6
3 0 6
insecticidal and antifungal activities. The final aim is to screen out high-activity allosamidins.
Declaration of interest
OH O
N NMe2 21 a.Ac2O,pyridine b.NH3,MeOH OH OH O O HO O NHAc 9 N NMe2 NH2
HO HO
Synthetic method of compound 9
O N
a.13,TMSOTf b. H2,Pd/C OH O
Comparison
NMe2
The work was supported by Scientific and Technological Research Program of Chongqing Municipal Education Commission (Grant Nos. KJ1400523 and KJ060805), Natural Science Foundation Project of CQ CSTC (No. cstc2012jjA10101), Chongqing University Students’ Training Project of Innovation and Undertaking (No. 201410637020), Open Foundation from Tertiary College of Chongqing Engineering Research Center of Bioactive Substance and Ministry of Education Engineering Research Center of Active Substance and Biotechnology (No. GCZX2012-2), China. The authors confirm that this article content has no conflict of interest.
References Scheme 3. Total liquid-phase synthesis of N,N0 -diacetyl-b-chitobiosylallosamizoline 9.
1. Sakuda S, Isogai A, Matsumoto S, et al. The structure of allosamidin, a novel insect chitinase inhibitor, produced by Streptomyces Sp. Tetrahedron Lett 1986;27:2475–8.
Journal of Enzyme Inhibition and Medicinal Chemistry Downloaded from informahealthcare.com by University of Otago on 07/02/15 For personal use only.
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2. Maloisel J-L, Vasella A, Trost BM, et al. Synthesis of allosamidin. J Chem Soc Chem Commun 1991;27:1099–101. 3. Maloisel J-L, Vasella A, Trost BM, et al. Synthesis of allosamidin. Helv Chim Acta 1992;75:1515–26. 4. Maloisel J-L, Vasella A. Synthesis of N-acetylallosamine-derived disaccharides. Helv Chim Acta 1992;75:1491–514. 5. Takahashi S, Terayama H, Kuzuhara H. Total synthesis of ()-allosamidin, an insect chitinase inhibitor, employing chitin as a key starting material. Tetrahedron Lett 1992;33:7565–8. 6. Blattner R, Furneaux R, Kemmitt T, et al. Syntheses of the fungicide/insecticide allosamidin and a structural isomer. J Chem Soc Perkin Trans 1994;1:3411–21. 7. Griffith DA, Danishefsky SJ. The total synthesis of allosamidin. Expansions of the methodology of azaglycosylation pursuant to the total synthesis of allosamidin. A surprising enantiotopic sense for a lipase-induced deacetylation. J Am Chem Soc 1996;118:9526–38. 8. Takahashi S, Terayama H, Kuzuhara H. Synthesis of demethylallosamidin, a yeast chitinase inhibitor; use of disaccharide glycosyl donor carrying novel neighboring group. Tetrahedron Lett 1994;35: 4149–52. 9. Trost BM, Van Vranken DL. Flexible strategy to polyfunctional cyclopentanes. A synthesis of mannostatin A. J Am Chem Soc 1991; 113:6317–18. 10. Trost BM, Van Vranken DL. General synthetic strategies toward aminocyclopentitol glycosidase inhibitors. Application of palladium catalysis to the synthesis of allosamizoline and mannostatin A. J Am Chem Soc 1993;115:444–58. 11. Trost BM. A biological catalysis for synthetic efficiency. Pure Appl Chem 1992;64:315–22. 12. Blattner R, Furneaux RH, Lynch GP. Synthesis of allosamidin analogues. Carbohydr Res 1996;294:29–39. 13. Shrader WD, Imperiali B. Synthesis of the glucoallosamidin pseudodisaccharide: use of an efficient Hg(II)-mediated cyclization. Tetrahedron Lett 1996;37:599–602. 14. Takahashi S, Inoue H, Kuzuhara H. Preparation of a highly functionalized cyclopentane derivative suitable for the synthesis of allosamidin analogues. J Carbohydr Chem 1995;14:273–85. 15. Terayama H, Kuzuhara H, Takahashi S, et al. Synthesis of a new allosamidin analog, N,N0 -diacetyl-beta-chitobiosyl allosamizoline and its inhibitory activity against some chitinases. Biosci Biotechnol Biochem 1993;57:2067–9. 16. Takahashi S, Terayama H, Kuzuhara H, et al. Preparation of a demethylallosamidin isomer having an N,N0 -diacetylchitobiosyl moiety and its potent inhibition against yeast chitinase. Biosci Biotechnol Biochem 1994;58:2301–2. 17. Kinoshita M, Sakuda S, Yamada Y. Preparation of N-monoalkyl and O-acyl derivatives of allosamidin, and their chitinase inhibitory activities. Biosci Biotechnol Biochem 1993;57:1699–703. 18. Corbett DF, Dean DK, Robinson SR. Synthesis of pseudodisaccharides related to allosamidin. Tetrahedron Lett 1994;35: 459–62. 19. Takahashi S, Terayama H, Koshino H, et al. Synthesis of a novel azapseudodisaccharide related to allosamidin employing N,N0 diacetylchitobiose as a key starting material. Tetrahedron 1999;55: 14871–84. 20. Blattner R, Gerard PJ, Spindler-Barth M. Synthesis and biological activity of allosamidin and allosamidin analogues. Pestic Sci 1997; 50:312–18. 21. Huang GL, Cheng F. The synthesis of allosamidin and its analogue di-N-acetyl-b-chitobiosyl NAG-thiazoline using the photosensitive o-nitrobenzyl ether tether as linker. Lett Org Chem 2012;9:577–9. 22. Huang GL, Chen Y. Solid-phase synthesis of di-N-acetyl-b-chitobiosyl NAG-thiazoline. Lett Drug Des Discov 2011;8:649–51.
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23. Tanaka K, Fujimoto Y, Tanaka S, et al. Combinatorial methods in oligosaccharide synthesis. In: Fraser-Reid B, Tatsuta K, Thiem J, eds. Glycoscience, Part 5. Berlin Heidelberg: Springer-Verlag; 2008: 1205–40. 24. Weishaupt MW, Matthies S, Seeberger PH. Automated solid-phase synthesis of a b-(1,3)-glucan dodecasaccharide. Chem Eur J 2013; 19:12497–503. 25. Kandasamy J, Hurevich M, Seeberger PH. Automated solid phase synthesis of oligoarabinofuranosides. Chem Commun 2013;49: 4453–5. 26. Weishaupt M, Eller S, Seeberger PH. Solid phase synthesis of oligosaccharides. Methods Enzymol 2010;478:463–84. 27. Huang GL, Dai YP. Solid-phase synthesis of allosamidin. Synlett 2010;21:1554–6. 28. Griffith DA, Danishefsky SJ. Total synthesis of allosamidin: an application of the sulfonamidoglycosylation of glycals. J Am Chem Soc 1991;113:5863–4. 29. Huang GL, Yang Q. Efficient synthesis of Wang resin-supported 6-O-benzylallosamizoline. Lett Org Chem 2010;7:396–8. 30. Huang GL. Solid-phase synthesis of di-N-acetyl-b-chitobiosyl allosamizoline. Lett Org Chem 2011;8:625–7. 31. Huang GL, Shu SQ. An efficient synthesis of allosamidin. Synlett 2012;23:1829–31. 32. Huang HL. High-efficiency synthesis of N,N0 -diacetyl-b-chitobiosyl allosamizoline. Lett Drug Des Discov 2013;10:183–5. 33. Huang HL, Liu F, Chen J, et al. Liquid-phase synthesis of N,N0 diacetyl-b-chitobiosyl allosamizoline. Bulg Chem Commun 2014; 46:192–4. 34. Sakuda S, Sakurada M. Preparation of biotinylated allosamidins with strong chitinase inhibitory activities. Bioorg Med Chem Lett 1998;8:2987–90. 35. Sakuda S, Isogai A, Matsumoto S, et al. Search for microbial insect growth regulators. II. Allosamidin, a novel insect chitinase inhibitor. J Antibiot 1987;40:296–300. 36. Saguez J, Dubois F, Vincent C, et al. Differential aphicidal effects of chitinase inhibitors on the polyphagous homopteran Myzus persicae (Sulzer). Pest Manag Sci 2006;62:1150–4. 37. Spindler KD, Spindler-Barth M, Sakuda S. Effect of demethylation on the chitinase inhibitory activity of allosamidin. Arch Insect Biochem Physiol 1997;36:223–7. 38. Tsai YL, Hayward RE, Langer RC, et al. Disruption of Plasmodium falciparum chitinase markedly impairs parasite invasion of mosquito midgut. Infect Immun 2001;69:4048–54. 39. Filho BP, Lemos FJ, Secundino NF, et al. Presence of chitinase and beta-N-acetylglucosaminidase in the Aedes aegypti. A chitinolytic system involving peritrophic matrix formation and degradation. Insect Biochem Mol Biol 2002;32:1723–9. 40. Villago´mez-Castro JC, Calvo-Me´ndez C, Lo´pez-Romero E. Chitinase activity in encysting Entamoeba invadens and its inhibition by allosamidin. Mol Biochem Parasitol 1992;52:53–62. 41. Sampson MN, Gooday GW. Involvement of chitinases of Bacillus thuringiensis during pathogenesis in insects. Microbiology 1998; 144:2189–94. 42. Bortone K, Monzingo AF, Ernst S, et al. The structure of an allosamidin complex with the Coccidioides immitis chitinase defines a role for a second acid residue in substrate-assisted mechanism. J Mol Biol 2002;320:293–302. 43. Suzuki S, Nakanishi E, Ohira T, et al. Chitinase inhibitor allosamidin is a signal molecule for chitinase production in its producing Streptomyces II. Mechanism for regulation of chitinase production by allosamidin through a two-component regulatory system. J Antibiot 2006;59:410–17.
REVIEW ARTICLE
Journal of Enzyme Inhibition and Medicinal Chemistry Downloaded from informahealthcare.com by University of Otago on 07/02/15 For personal use only.
High-efficient synthesis and biological activities of allosamidins Gangliang Huang, Daquan Peng, Xinya Mei, Xin Chen, Feng Xiao, and Qilin Tang College of Chemistry, Chongqing Normal University, Chongqing, China
Abstract
Keywords
The pseudo-trisaccharide allosamidin 1 is a potent inhibitor of all family-18 chitinases, and it is confirmed to have insecticidal and antifungal activities. But the synthesis of allosamidins is very difficult, and it is a challengeable subject. Allosamidins were synthesized in solid–liquid phase, total solid-phase and total liquid-phase, respectively. Solid–liquid phase method realizes the partial solid-phase synthesis of allosamidins. Total solid-phase method greatly simplifies the purification process. Total liquid-phase method shortens the synthetic steps of allosamidins. The insecticidal and antifungal activities of allosamidins were also reported herein.
Allosamidins, chitinase inhibitory activities, insecticidal and antifungal activities, synthesis
Introduction The fungal chitinases are used to modify chitins, which are the main component of cell wall. The insect chitinases are utilized to partially degrade the old exoskeletons of insects. So, it indicates that using chitinases as targets can investigate and develop the antifungal agents and biological pesticides (i.e. chitinase inhibitors). Allosamidin 1 is the family-18 chitinase inhibitor, which contains two b-linked N-acetyl-2-amino-2-deoxy-Dallopyranoside building blocks and a residue (namely allosamizoline 2, Figure 1)1. Compound 1 has the unique chemical structure and becomes an attractive molecule, resulting in many total syntheses of allosamidin 1 and its analogues to be reported2–22. The selection of glycosidation method to assemble the building blocks of compound 1 and its analogues causes the substantial difference between any two reported total synthesis methods. Ensuring to produce exclusive b-glycosidic bond is the main aim of these glycosidation methods. Herein, the synthesis, insecticidal and antifungal activities of allosamidins were summarized.
Synthesis of allosamidins Trost’s and Vasella’s groups reported the total synthesis of allosamidin 12–4. They utilized the glycosidation of trichloroacetimidate to couple two N-acetyl-D-allosamine building blocks together, and then the obtained disaccharide donor was regioselectively coupled to the racemic carbsugar analogue. Because of using the racemic reactant, the coupling inevitably produced an unwanted diastereomer. Kuzuhara’s total synthesis of allosamidin 15 involved the glycosidation of ()-allosamizoline derivative and chitobiose
Address for correspondence: Gangliang Huang, College of Chemistry, Chongqing Normal University, Chongqing, 401331, China. Tel: +86 013068336573. Fax: +86 013068336573. E-mail: huangdoctor226@ 163.com
History Received 4 September 2014 Revised 16 October 2014 Accepted 27 October 2014 Published online 4 December 2014
thioglycoside donor, which was promoted with N-iodosuccinimide (NIS). Blattner and co-workers6 investigated the synthesis of allosamidin 1 by glycosylation of acceptor with a trichloroacetimidate donor. The acceptor was aminocyclopentanol, namely, selectively protected allosamizoline 2, which had only one hydroxyl group. Griffith and Danishefsky also reported the total synthesis of allosamidin 17. This method is facile to form the b-linked 2-deoxy-D-allosamine building block. Oligosaccharides can be synthesized by solid-phase method23–26. The excess reactants or by-products may be rapidly removed by filtering in every step of reaction. In this respect, Huang’s group synthesized allosamidin 1 by solid–liquid method27 (Scheme 1). The C-3 hydroxyl group of diol 328 (Scheme 1) was selectively conjugated to a solid support through benzylation by means of stannylene methodology29 to produce dibenzylated unit 4. Glycosidation of a-trichloroacetimidate donor 527 and acceptor 4 provided b-pseudodisaccharide 6. The reaction was promoted with trimethylsilyltrifluromethanesulfonate (TMSOTf). Levulinoyl ester was cleaved with hydrazinium acetate/MeOH to afford acceptor 7. After glycosylation of acceptor 7 with donor 827, Cbz, Wang resin and Bn were removed from the saccharidebound resin in catalytic hydrogenation condition. The resulting mixture was acetylated and then deacetylated to obtain target pseudo-trisaccharide 1. Terayama et al. reported the solution synthesis of N,N0 diacetyl-b-chitobiosylallosamizoline 9 (i.e. allosamidin analogue), which was stereo-selectively synthesized by the coupling reaction of disaccharide thioglycoside building block and allosamizoline 2 derivative building block15. The solid–liquid phase synthesis of compound 9 was also investigated (Scheme 1)30. Allosamidin 1 and N,N0 -diacetyl-b-chitobiosylallosamizoline 9 have been synthesized by combining solid-phase and liquid-phase method from the above-mentioned, but compounds 1 and 9 need
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Figure 1. The structures of allosamidin 1 and allosamizoline 2.
J Enzyme Inhib Med Chem, Early Online: 1–4
HO
OH O O
OH O O HO
OH NHAc OH NHAc 1
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Scheme 1. Solid/liquid-phase synthesis of allosamidin 1 and N,N0 -diacetyl-b-chitobiosylallosamizoline 9.
OH
OH HO HO
O N
NMe2
OBn HO HO
O N 3
Bu2SnO HO Wang-chlorinated resin,CsF O NMe2
NMe2
OBn O 4
N
NMe2
OBn 5 or,10TMSOTf LevO O OBn OBn R1 LevO O O O R3 CCl3 O O R2 NHCbz R4 N NMe2 NHCbz NH 5:R1=H,R2=AcO 6:R3=H,R4=AcO 10:R1=AcO,R2=H 11:R3=AcO,R4=H N2H4·HOAc OBn OBn HO O O R5 O O R6 N NMe2 NHCbz 7:R5=H,R6=AcO 12:R5=AcO,R6=H
HO R9 R10
O N 2
AcO R7 R8
OAc O
a. 8or-13,TMSOTf CCl3 b. H2,Pd/C O c. Ac2O,Pyridine NHCbz d. NaOMe,MeOH NH OH OH 8:R7=H,R8=AcO O OH O O O 13:R7=AcO,R8=H R9 HO O NHAc R10 NHAc N NMe2 1:R9=H,R10=HO 9 :R9=HO,R10=H
to be purified by column chromatography for the final three steps. So, the synthetic method for allosamidin 1 and its analogue 9 does not fully utilize the strongpoint of solid-phase synthesis. That is to say, if compounds 1 and 9 are synthesized by solid-phase method for every step, it can simplify the purification process by filtrating and washing to remove excess reactants or by-products. Therefore, the total solid-phase syntheses of allosamidin 1 and N,N0 -diacetyl-b-chitobiosylallosamizoline 9 were investigated (Scheme 2)31,32, and the results were very satisfactory. N,N0 -diacetyl-b-chitobiosylallosamizoline 9 has been synthesized by solid/liquid-phase method and total solid-phase method, respectively. But the synthetic steps are still a little longer, and the yield of this step for introducing solid-phase support is low. Therefore, the allosamidin analogue 9 was also synthesized by total liquid-phase method, which was based on the reported solidphase of allosamidins, but the solid-phase support was not introduced (Scheme 3)33. N,N0 -diacetyl-b-chitobiosylallosamizoline 9 was synthesized in solid–liquid phase, total solid-phase and total liquid-phase, respectively. The main comparison of above-mentioned three methods for synthesizing compound 9 is shown in Table 1. Insecticidal and antifungal activities Allosamidins can inhibit the activity of chitinase, which prevents the ecdysis of insect larvae and pupa as well as separation of fungal microspore mother cells. So, they play the insecticidal and antifungal actions20,34. The pseudo-trisaccharide allosamidin 1 has a competitive inhibitory activity against chitinases at very low concentration. Injection of compound 1 in larvae of the silkworm
Bombyx mori and the armyworm Leucania separata strongly disturbed larval ecdysis and increased mortality rate of these lepidopteran pests. Ecdysis inhibitory activity of allosamidin 1 to larvae of B. mori and L. separata is EI50 ¼ 2 mg and 4 mg, respectively35. EI50 is the 50% ecdysis inhibition. Compound 1 and its derivatives highly increased mortality of the blowfly larvae (Lucilia cuprina) after contact applications or feeding tests20. In the webbing clothes moth Tineola bisselliella, consumption of allosamidin 1 resulted in larval mortality associated with severe morphological alterations (delayed growth and interrupted moulting) that occur during larval development20. Compound 1 also induces aphicidal effects, increases larval mortality and reduces fecundity of the aphid Myzus persicae36. Inhibition of chitinases by allosamidin 1 has been extensively studied due to its high inhibitory activity. Compound 1 and its derivatives, namely, demethylallosamidin, methylallosamidin, glucoallosamidin A, glucoallosamidin B and methyl-N-demethylallosamidin37, were also tested against different human pests and pathogens such as plasmodium38,39 and nematodes40. Allosamidin 1 also possesses antibacterial41 and antifungal activities against the pathogenic fungi42. In Streptomyces species that produce compound 1, this inhibitor favours production of an allosamidininsensitive chitinase, which is necessary for fungi growth43.
Conclusion In a word, it proves that the total solid-phase synthesis and its derived liquid-phase synthesis can enhance the synthesis efficiency of allosamidins. These compounds demonstrate
Synthesis and biological activities of allosamidins
DOI: 10.3109/14756366.2014.987137
Scheme 2. Total solid-phase synthesis of N,N0 -diacetyl-b-chitobiosylallosamizoline 9.
OBn
OBn HO HO
HO
a. Bu2 SnO
O N
NMe 2
b.
3
14
O
O N 15
Cl
OBn O
OBn O
O
O
N
NHCbz
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NMe2
a. 10 ,TMSOTf b. N2H 4 ·HOAc HO AcO
O NH2 AcO
OH O
HO HO
O NHAc HO
OH O
O NHAc HO
NMe 2
16
a. 13 TMSOTf , b. H 2 ,Pd/C OH OH O O O O NH 2 N NMe2 17
OAc O
AcO AcO
HO HO
3
a. Ac2O, pyridine b. NH3, MeOH OH OH O O O O NHAc N NMe2 18 OH O NHAc 9
hv OH O HO
O N
NMe2
NO2 Cl O
O
Polystyrene 14 Cl
HO BnO
Table 1. Comparison of three synthetic methods for compound 9.
OBn O
N 19 a.10,TMSOTf b. N2H4·HOAc HO AcO
AcO AcO
OAc O
OBn
OBn O
O NH2 AcO
O BnO NHCbz 20
O HO
NMe2
OH O
O NHAc HO
Number of synthetic steps
Number of column chromatography
Solid/liquid-phase Total solid-phase Total liquid-phase
7 8 6
3 0 6
insecticidal and antifungal activities. The final aim is to screen out high-activity allosamidins.
Declaration of interest
OH O
N NMe2 21 a.Ac2O,pyridine b.NH3,MeOH OH OH O O HO O NHAc 9 N NMe2 NH2
HO HO
Synthetic method of compound 9
O N
a.13,TMSOTf b. H2,Pd/C OH O
Comparison
NMe2
The work was supported by Scientific and Technological Research Program of Chongqing Municipal Education Commission (Grant Nos. KJ1400523 and KJ060805), Natural Science Foundation Project of CQ CSTC (No. cstc2012jjA10101), Chongqing University Students’ Training Project of Innovation and Undertaking (No. 201410637020), Open Foundation from Tertiary College of Chongqing Engineering Research Center of Bioactive Substance and Ministry of Education Engineering Research Center of Active Substance and Biotechnology (No. GCZX2012-2), China. The authors confirm that this article content has no conflict of interest.
References Scheme 3. Total liquid-phase synthesis of N,N0 -diacetyl-b-chitobiosylallosamizoline 9.
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