Journal of Zhejiang University SCIENCE B
ISSN 1673-1581(Print), 1862-1783(Online), Monthly

2008   Vol. 9   No. 5   p. 391~400

Synthetic and biological studies on a cyclopolypeptide of plant origin

Rajiv DAHIYA^†, Akhilesh KUMAR

(Department of Pharmaceutical Chemistry, Rajiv Academy for Pharmacy, Mathura 281001, Uttar Pradesh, India)
^†E-mail: rajivdahiya04@yahoo.co.in; rajivdahiya77@rediffmail.com
Received Oct. 16, 2007; revision accepted Mar. 8, 2008

Abstract: Objective: A natural cyclic peptide previously isolated from Citrus medica was synthesized by coupling of tetrapeptide units Boc-Leu-Pro-Trp-Leu-OMe and Boc-Ile-Ala-Ala-Gly-OMe after proper deprotection at carboxyl and amino terminals followed by cyclization of linear octapeptide segment. Methods: Solution phase technique was adopted for the synthesis of cyclooctapeptide—sarcodactylamide. Required tetrapeptide units were prepared by coupling of Boc-protected dipeptides viz. Boc-Leu-Pro-OH and Boc-Ile-Ala-OH with respective dipeptide methyl esters Trp-Leu-OMe and Ala-Gly-OMe. Cyclization of linear octapeptide unit was done by p-nitrophenyl ester method. The structure of synthesized cyclopolypeptide was elucidated by FTIR, ¹H NMR, ¹³C NMR, FABMS spectral data and elemental analysis. The newly synthesized peptide was evaluated for different pharmacological activities including antimicrobial, anthelmintic and cytotoxic activities. Results: Synthesis of sarcodactylamide was accomplished with >78% yield utilizing dicyclohexylcarbodiimide (DCC) as coupling agent. Newly synthesized peptide possessed potent cytotoxic activity against Dalton’s lymphoma ascites (DLA) and Ehrlich’s ascites carcinoma (EAC) cell lines, in addition to moderate anthelmintic activity against earthworms Megascoplex konkanensis, Pontoscotex corethruses and Eudrilus sp. Moreover, cyclopolypeptide displayed good antimicrobial activity against pathogenic fungi Candida albicans and Gram-negative bacteria Pseudomonas aeruginosa, in comparison to standard drugs griseofulvin and ciprofloxacin. Conclusion: Solution phase technique employing DCC and triethylamine (TEA) as base proved to be effective for the synthesis of natural cyclooctapeptide. N-methyl morpholine (NMM) was found to be a better base for the cyclization of linear octapeptide unit in comparison to TEA and pyridine.

Key words: Cyclic octapeptide, Citrus medica var. sarcodactylis, Sarcodactylamide, Peptide synthesis, Anthelmintic activity, Antimicrobial activity, Cytotoxicity
doi:10.1631/jzus.B0720001             CLC number: R91

References:

[1] Akendengue, B., Lemamy, G.J., Bourobou, H.B., Laurens, A., 2005. Bioactive natural compounds from medico-magic plants of Bantu area. Studies Nat. Prod. Chem., 32(12): 803-820.

[2] Bauer, A.W., Kirby, W.M., Sherris, J.C., Turck, M., 1966. Antibiotic susceptibility testing by a standardized single disk method. Am. J. Clin. Path., 45(4):493-496.

[3] Bodanszky, M., Bodanszky, A., 1984. The Practice of Peptide Synthesis. Springer-Verlag, New York, p.78-143.

[4] Dahiya, R., 2007a. Synthesis, characterization and biological evaluation of a glycine-rich peptide—cherimolacy-clopeptide E. J. Chil. Chem. Soc., 52(3):1224-1229.

[5] Dahiya, R., 2007b. Synthesis of a phenylalanine-rich peptide as potential anthelmintic and cytotoxic agent. Acta Pol. Pharm., 64(6):509-516.

[6] Dahiya, R., 2007c. Synthetic and pharmacological studies on longicalycinin A. Pak. J. Pharm. Sci., 20(4):317-323.

[7] Dahiya, R., 2008. Synthesis, spectroscopic and biological investigation of cyclic octapeptide: cherimolacyclopeptide G. Turk. J. Chem., 32(2):205-215.

[8] Dahiya, R., Pathak, D., 2006a. Synthetic studies on a natural cyclic tetrapeptide—halolitoralin C. J. Pharm. Res., 5(3): 69-73.

[9] Dahiya, R., Pathak, D., 2006b. Cyclic peptides: new hope for antifungal therapy. Egypt. Pharm. J. (NRC), 5(2): 189-199.

[10] Dahiya, R., Pathak, D., 2007a. First total synthesis and biological evaluation of halolitoralin A. J. Serb. Chem. Soc., 72(2):101-107.

[11] Dahiya, R., Pathak, D., 2007b. Synthesis, characterization and biological evaluation of halolitoralin B—a natural cyclic peptide. Asian J. Chem., 19(2):1499-1505.

[12] Dahiya, R., Kaur, K., 2007. Synthetic and biological studies on natural cyclic heptapeptide: segetalin E. Arch. Pharm. Res., 30(11):1380-1386.

[13] Dahiya, R., Kaur, K., 2008. Synthetic and pharmacological investigation of segetalin C as a novel antifungal and cytotoxic agent. Arzneim. Forsch., 58(1):29-34.

[14] Dahiya, R., Pathak, D., Himaja, M., Bhatt, S., 2006. First total synthesis and biological screening of hymenamide E. Acta Pharm., 56(4):399-415.

[15] Garg, L.C., Atal, C.K., 1963. Anthelmintic activity of Myrsine africana. Indian J. Pharm. Sci., 59:240-245.

[16] Kumarasamy, Y., Nahar, L., Cox, P.J., Jaspars, M., Sarker, S.D., 2003. Bioactivity of secoiridoid glycosides from Centaurium erythraea. Phytomedicine, 10(4):344-347.

[17] Kuttan, R., Bhanumathy, P., Nirmala, K., George, M.C., 1985. Potential anticancer activity of turmeric (Curcuma longa). Cancer Lett., 29(2):197-202.

[18] Lago, J.H.G., Chaves, M.H., Ayres, M.C.C., Agripino, D.G., Young, M.C.M., 2007. Evaluation of antifungal and DNA-damaging activities of alkaloids from branches of Porcelia macrocarpa. Planta Med., 73(3):292-295.

[19] Marston, A., Maillard, M., Hostettmann, K., 1993. Search for antifungal, molluscicidal and larvicidal compounds from African medicinal plants. J. Ethnopharmacol., 38(2-3): 209-214.

[20] Matsumoto, T., Nishimura, K., Takeya, K., 2002. New cyclic peptides from Citrus medica var. sarcodactylis SWINGLE. Chem. Pharm. Bull., 50(6):857-860.

[21] Morel, A.F., Maldaner, G., Ilha, V., Missau, F., Silva, U.F., Dalcol, I.I., 2005. Cyclopeptide alkaloids from Scutia buxifolia Reiss and their antimicrobial activity. Phytochemistry, 66(21):2571-2576.

[22] Nogueira, M.A., de Oliveira, J.S., Ferraz, S., 1996. Nematicidal hydrocarbons from Mucuna aterrima. Phytochemistry, 42(4):997-998.

[23] Pathak, D., Dahiya, R., 2003. Cyclic peptides as novel antineoplastic agents: a review. J. Sci. Pharm., 4(4):125-131.

[24] Svangård, E., Göransson, U., Hocaoglu, Z., Gullbo, J., Larsson, R., Claeson, P., Bohlin, L., 2004. Cytotoxic cyclotides from Viola tricolor. J. Nat. Prod., 67(2):144-147.

[25] Wele, A., Zhang, Y., Brouard, J.P., Pousset, J.L., Bodo, B., 2005. Two cyclopeptides from the seeds of Annona cherimola. Phytochemistry, 66(19):2376-2380.