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Prolyl Endopeptidase Inhibitors from Syzygium Samarangense (Blume) Merr

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Prolyl Endopeptidase Inhibitors from Syzygium Samarangense (Blume) Merr Prolyl Endopeptidase Inhibitors from Syzygium samarangense (Blume) Merr. & L. M. Perry Evangeline C. Amor*,a, Irene M. Villasen˜ ora, Amsha Yasinb, and M. Iqbal Choudharyb a Institute of Chemistry, College of Science, University of the Philippines, Diliman 1101 Quezon City, Philippines. Fax: (632)9205427. E-mail: [email protected] b International Center for Chemical Sciences at HEJ Research Institute of Chemistry, University of Karachi, Karachi 75270, Pakistan * Author for correspondence and reprint requests Z. Naturforsch. 59c,86Ð92 (2004); received May 14/July 18, 2003 Compounds isolated from the hexane extract of the leaves of Syzygium samarangense (Blume) Merr. & L. M. Perry were tested for inhibitory activity against the following serine proteases: trypsin, thrombin and prolyl endopeptidase. The compounds were identified as an intractable mixture of α-carotene and -carotene (1), lupeol (2), betulin (3), epi-betulinic acid (4), 2Ј,4Ј-dihydroxy-6Ј-methoxy-3Ј-methylchalcone (5), 2Ј-hydroxy-4Ј,6Ј-dimethoxy-3Ј- methylchalcone (6), 2Ј,4Ј-dihydroxy-6Ј-methoxy-3Ј,5Ј-dimethylchalcone (7), 2Ј,4Ј-dihydroxy- 6Ј-methoxy-3Ј-methyldihydrochalcone (8) and 7-hydroxy-5-methoxy-6,8-dimethylflavanone (9). Hydrogenation of compounds 5, 6 and 7 yielded compound 8,2Ј-hydroxy-4Ј,6Ј-dime- thoxy-3Ј-methyldihydrochalcone (10) and 2Ј,4Ј-dihydroxy-6Ј-methoxy-3Ј,5Ј-dimethyldihy- drochalcone (11), respectively. The hydrogenated products of compounds 6 and 7 were also tested for enzyme inhibitory activity. In addition, -sitosterol (12) and -d-sitosterylglucoside (13) were also isolated. This is the first report of the isolation of compounds 1Ð6, 8 and 13 from this plant. Compounds 3Ð8 and 10 exhibited significant and selective inhibition against prolyl endopeptidase among three serine proteases. This is the first report of this kind of activity for all these compounds. Key words: Syzygium samarangense, Prolyl Endopeptidase, Flavonoids Introduction ration and degradation of proline containing pep- tide hormones and neuropeptides, which are sug- Syzygium samarangense (Blume) Merr. & L. M. gested to participate in learning and memory Perry (Myrtaceae) is locally known in the Philip- processes such as vasopressin, substance P, thy- pines as “makopa”. The plant has been reported rotropin-releasing hormone (TRH), angiotensin, to have antibacterial (Santos, 1981), antidiabetic LH-RH neurotensin, angiotensin II, oxytocin and (Nonaka et al., 1992) and immunostimulant (Sri- bradykinin. Currently, new drugs are required that vastava et al., 1995) activities. Compounds pre- can improve memory and learning or delay the viously isolated from this plant include mearn- neurodegenerative process in conditions such as sitrin, 2Ј-C-methyl-5Ј-O-galloylmyricetin-3-O-α-l- Alzheimer’s disease. Inhibitors of prolyl endopep- rhamnopyranoside, desmethoxymatteucinol (Nair tidase may improve memory by blocking the me- et al., 1999), 4Ј,6Ј-dihydroxy-2Ј-methoxy-3Ј,5Ј-di- tabolism of endogenous neuropeptides and have methylchalcone, methyl 3-epi-betulinate, oleanolic possible potential as antiamnesiac drugs (Tezuka acid, jacoumaric acid, ursolic acid, arjunolic acid et al., 1999; Yoshimoto et al., 1987). In fact, it has (Srivastava et al., 1995), samarangenin A and sa- been hailed as a new class of memory enhancing marangenin B (Nonaka et al., 1992). drugs (De Nanteuil et al., 1998). Prolyl endopeptidase (PEP) is a post-proline There are two known kinds of PEP inhibitors, cleaving enzyme (EC 3.4.21.26). It was first iso- peptidic inhibitors (De Nanteuil et al., 1998; Feher lated from the human uterus as an oxytocin-inacti- et al., 1999; Hermecz and Kanai, 2000) and non- vating enzyme, specifically cleaving the peptide peptidic inhibitors (Christner et al., 1998; Lee bond at the carbonyl side of proline residues (Te- et al., 2000; Inamori et al., 1997; Fan et al., 1999, zuka et al., 1999). In the central nervous system, 2000, 2001). Peptidic inhibitors are known to con- PEP has been playing an important role in matu- tain an electrophilic center such as an alpha-keto 0939Ð5075/2004/0100Ð0086 $ 06.00 ” 2004 Verlag der Zeitschrift für Naturforschung, Tübingen · http://www.znaturforsch.com · D E. C. Amor et al. · Prolyl Endopeptidase Inhibitors 87 beta-amide group and this group is considered to All compounds except 9 showed significant in- be an active center. Non-peptidic inhibitors, on the hibitory activity against PEP while compounds 3Ð other hand, are further grouped into two types. 10 did not exhibit significant inhibitory activity One type contains either a catechol or pyrogallol against thrombin and trypsin and therefore are group and the second type, none. In the former, specific inhibitors for PEP. the catechol or pyrogallol group is believed to be Flavonoids with PEP inhibitory activity have responsible for its PEP inhibition (Fan et al., 1999). been reported. Of the 20 flavonoids tested con- Most PEP inhibitors reported are synthetic and taining the flavone, flavonol, flavanone and flava- only a few of the natural inhibitors are from plant nol skeletons, luteolin and quercetin (flavones) ex- sources (Tezuka et al., 1999). This study explores hibited potent PEP inhibitory activity with an IC50 the PEP inhibitory activity of compounds from S. of 0.17 and 0.19 ppm, respectively (Lee et al., samarangense. 1998). In addition, flavans (Fan et al., 1999, 2001) were also reported to have PEP inhibitory activity. A catechol or pyrogallol moiety in ring C and a 7- Results and Discussion OH group in flavones are believed to be responsi- Several compounds were isolated from the he- ble for the observed activity. The tested flavonoids xane extract of the leaves of S. samarangense and in this research work having a chalcone (5, 6 and their structures (Fig. 1) elucidated through 7), dihydrochalcone (8, 10 and 11) and a flavanone spectral analyses and by comparison with the liter- (9) skeleton do not contain a catechol nor a pyro- ature. These were identified as mixture of α- and gallol moiety in ring C and are less potent than -carotene (1), lupeol (2), betulin (3), epi-betulinic luteolin or quercetin. However, the inhibitory acid (4), 2Ј,4Ј-dihydroxy-6Ј-methoxy-3Ј-methyl- activities of the active compounds are comparable, chalcone (5), 2Ј-hydroxy-4Ј,6Ј-dimethoxy-3Ј-me- if not greater than other natural non-peptidic in- Ј Ј Ј Ј Ј hibitors that contain a pyrogallol or catechol moi- thylchalcone (6), 2 ,4 -dihydroxy-6 -methoxy-3 ,5 - µ dimethylchalcone (7), 2Ј,4Ј-dihydroxy-6Ј-methoxy- ety. For example, 8 (IC50 = 12.5 m or 3.55 ppm) 3Ј-methyldihydrochalcone (8) and 7-hydroxy-5- contains no catechol moiety and yet is more active methoxy-6,8-dimethylflavanone (9). Hydrogena- than orientin (IC50 = 38.5 ppm), which has a cate- tion of compounds 5, 6 and 7 yielded compound chol moiety (Lee et al., 1998). It is more active 8,2Ј-hydroxy-4Ј,6Ј-dimethoxy-3Ј-methyldihydro- Ј Ј Ј chalcone (10) and 2 ,4 -dihydroxy-6 -methoxy- 13 Ј Ј Table I. C NMR chemical shift data of compound 5 3 ,5 -dimethyldihydrochalcone (11), respectively. and 7. In addition, -sitosterol (12) and -d-sitosterylglu- coside (13) were also isolated. This is the first re- C Compound 5 Compound 7 port of the isolation of compounds 1Ð6, 8 and 13 in C3D6O at 125 MHz in CDCl3 at 125 MHz (ppm) (ppm) from this plant. The 13C NMR chemical shifts for compound 5 are reported for the first time and 1 136.4 135.3 those of compound 7 are also reported because 2 129.0 128.9 of differences with that reported in the literature 3 129.7 128.4 4 130.7 130.2 (Srivastava et al., 1995). These are summarized in 5 129.7 128.4 Table I. 6 129.0 128.9 Among the compounds, compound 2 was pre- 142.3 142.9 α viously reported to be a competitive inhibitor of 128.6 126.7 C=O 193.1 193.4 trypsin and chymotrypsin with Ki values of 22 and 1Ј 104.4 106.6 8 µm, respectively (Rajic et al., 2000). In addition, 2Ј 166.4 162.0 compound 13 has been reported to exhibit PEP 3Ј 106.0 109.0 inhibitory activity with IC of 27.5 ppm (Lee 4Ј 161.8 159.3 50 5Ј 91.5 109.0 et al., 1998). 6Ј 163.3 158.8 Ð Ј Compounds 3 11 were then tested for inhibi- 6 -OCH3 56.1 62.3 Ј tory activities against three serine proteases tryp- 3 -CH3 7.36 8.2 Ј sin, thrombin and prolyl endopeptidase as de- 5 -CH3 Ð 7.6 Ј scribed previously (Rahman et al., 2002). The 2 -OH Ð 4Ј-OH Ð results are summarized in Table II. 88 E. C. Amor et al. · Prolyl Endopeptidase Inhibitors CH 3 CH3 H C 2 H2C CH3 C HO O R CH3 CH3 CH CH COOH 3 3 A B CH H C 3 CH3 3 HO HO O O H3C H C CH 3 3 H3C CH3 2 3 4 9 R = CH3 CH2OH OH O OH O H3C 2' H3C 2' α 3' 1' α 3' 1' A A 4' 6' β 4' 6' β R2 O 5' O R2 O 5' O C C 1 1 R CH3 R CH3 5 6 7 8 10 11 1 R1 = H H CH R = H H CH3 3 2 R2 = H CH H R = H CH3 H 3 Fig. 1. Structures of compounds 2Ð11: lupeol (2); betulin (3); epi-betulinic acid (4); 2Ј,4Ј-dihydroxy-6Ј-methoxy-3Ј- methylchalcone (5); 2Ј-hydroxy-4Ј,6Ј-dimethoxy-3Ј-methylchalcone (6); 2Ј,4Ј-dihydroxy-6Ј-methoxy-3Ј,5Ј-dimeth- ylchalcone (7); 2Ј,4Ј-dihydroxy-6Ј-methoxy-3Ј-methyldihydrochalcone (8); 7-hydroxy-5-methoxy-6,8-dimethylflava- none (9); 2Ј-hydroxy-4Ј,6Ј-dimethoxy-3Ј-methyldihydrochalcone (10); 2Ј,4Ј-dihydroxy-6Ј-methoxy-3Ј,5Ј-dimethyldi- hydrochalcone (11).
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