Structure-activity relationship study on inhibition of fatty acid synthase by xanthones

doi:10.7523/j.issn.2095-6134.2012.6.018

Abstract

Abstract: Fatty acid synthase (FAS), an important enzyme catalyzing the synthesis of long-chain fatty acid in vivo, has been reported to be a potential target for treatment of obesity. We found that xanthones with different functional groups and substituents have different inhibition activities on FAS, and the IC₅₀ values range from 1.24 μmol/L to 1000 μmol/L and above. Structure-activity relationships for these compounds were then analyzed, and some structure-activity rules were established.

Key words: fatty acid synthase, xanthones, inhibitors, structure-activity analysis

CLC Number:

R285.5

QUAN Xiao-Fang, MA Xiao-Feng. Structure-activity relationship study on inhibition of fatty acid synthase by xanthones[J]. , 2012, (6): 841-846.

References

[1] Smith S. The animal fatty acid synthase: one gene, one polypeptide, seven enzymes[J]. FASEB J, 1994, 8(15):1248-1259.
[2] Wakil S J, Stoops J K, Joshi V C. Fatty acid synthesis and its regulation[J]. Annu Rev Biochem, 1983, 52:537-579.
[3] Wakil S J. Fatty acid synthase, a proficient multifunctional enzyme[J]. Biochemistry, 1989, 28(11):4523-4530.
[4] Loftus T M, Jaworsky D E, Frehywot G L, et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors[J]. Science, 2000, 288(5475):2379-2381.
[5] Thupari J N, Landree L E, Ronnett G V, et al. C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity[J]. Proc Natl Acad Sci U S A, 2002, 99(14):9498-9502.
[6] Shu I W, Lindenberg D L, Mizuno T M, et al. The fatty acid synthase inhibitor cerulenin and feeding, like leptin, activate hypothalamic pro-opiomelanocortin (POMC) neurons[J]. Brain Res, 2003, 985(1):1-12.
[7] Wang X, Tian W. Green tea epigallocatechin gallate: a natural inhibitor of fatty-acid synthase[J]. Biochem Biophys Res Commun, 2001, 288(5):1200-1206.
[8] Kao Y H, Hiipakka R A, Liao S. Modulation of endocrine systems and food intake by green tea epigallocatechin gallate[J]. Endocrinology, 2000, 141(3):980-987.
[9] Lee M S, Kim C T, Kim Y. Green tea (-)-epigallocatechin-3-gallate reduces body weight with regulation of multiple genes expression in adipose tissue of diet-induced obese mice[J]. Ann Nutr Metab, 2009, 54(2):151-157.
[10] Nakatani K, Nakahata N, Arakawa T, et al. Inhibition of cyclooxygenase and prostaglandin E2 synthesis by gamma-mangostin, a xanthone derivative in mangosteen, in C6 rat glioma cells[J]. Biochem Pharmacol, 2002, 63(1):73-79.
[11] Suksamrarn S, Suwannapoch N, Ratananukul P, et al. Xanthones from the green fruit hulls of Garcinia mangostana[J]. J Nat Prod, 2002, 65(5):761-763.
[12] Kondo M, Zhang L, Ji H, et al. Bioavailability and antioxidant effects of a xanthone-rich Mangosteen (Garcinia mangostana) product in humans[J]. J Agric Food Chem, 2009, 57(19):8788-8792.
[13] Ngawhirunpat T, Opanasopi P, Sukma M, et al. Antioxidant, free radical-scavenging activity and cytotoxicity of different solvent extracts and their phenolic constituents from the fruit hull of mangosteen (Garcinia mangostana)[J]. Pharm Biol, 2010, 48(1):55-62.
[14] Moongkarndi P, Srisawat C, Saetun P, et al. Protective effect of mangosteen extract against beta-amyloid-induced cytotoxicity, oxidative stress and altered proteome in SK-N-SH cells[J]. J Proteome Res, 2010, 9(5):2076-2086.
[15] Ho C K, Huang Y L, Chen C C. Garcinone E, a xanthone derivative, has potent cytotoxic effect against hepatocellular carcinoma cell lines[J]. Planta Med, 2002, 68(11):975-979.
[16] Nakagawa Y, Iinuma M, Naoe T, et al. Characterized mechanism of alpha-mangostin-induced cell death: caspase-independent apoptosis with release of endonuclease-G from mitochondria and increased miR-143 expression in human colorectal cancer DLD-1 cells[J]. Bioorg Med Chem, 2007, 15(16):5620-5628.
[17] Moongkarndi P, Kosem N, Kaslungka S, et al. Antiproliferation, antioxidation and induction of apoptosis by Garcinia mangostana (mangosteen) on SKBR3 human breast cancer cell line[J]. J Ethnopharmacol, 2004, 90(1):161-166.
[18] Obolskiy D, Pischel I, Siriwatanametanon N, et al.Garcinia mangostana L.: a phytochemical and pharmacological review[J]. Phytother Res, 2009, 23(8):1047-1065.
[19] Jung H A, Su B N, Keller W J, et al. Antioxidant xanthones from the pericarp of Garcinia mangostana (Mangosteen)[J]. J Agric Food Chem, 2006, 54(6):2077-2082.
[20] Jiang H Z, Quan X F, Tian W X,et al. Fatty acid synthase inhibitors of phenolic constituents isolated from Garcinia mangostana[J]. Bioorg Med Chem Lett 2010, 20: 6045-6047
[21] Tian W X, Hsu R Y, Wang Y S. Studies on the reactivity of the essential sulfhydryl groups as a conformational probe for the fatty acid synthetase of chicken liver. Inactivation by 5,5'-dithiobis-(2-nitrobenzoic acid) and intersubunit cross-linking of the inactivated enzyme[J]. J Biol Chem, 1985, 260(20):11375-11387.
[22] Li B H, Ma X F, Wang Y, et al. Structure-activity relationship of polyphenols that inhibit fatty acid synthase[J]. J Biochem, 2005, 138(6):679-685.
[23] Maier T, Jenni S, Ban N. Architecture of mammalian fatty acid synthase at 4.5 A resolution[J]. Science,2006, 311(5765):1258-1262.
[24] Maier T, Leibundgut M, Ban N. The crystal structure of a mammalian fatty acid synthase[J]. Science, 2008, 321(5894):1315-1322.