Acetylenic Anticancer Agents

Anti-Cancer Agents in Medicinal Chemistry, 2008, 8, 000-000

1

Acetylenic Anticancer Agents A. Siddiq1,* and V. Dembitsky2,* 1 Department of Pharmacology, Faculty of Pharmacy, University of Karachi, Karachi 75270, Pakistan and Chemistry, Moscow 119121, Russia

2

Institute of Biomedical

Abstract: This review is a comprehensive survey of acetylenic anticancer agents obtained from living organisms. Acetylenic metabolites belong to a class of molecules containing triple bond(s). They are found in plants, fungi, microorganisms, and marine invertebrates. Although acetylenes are common as components of terrestrial plants, fungi, and bacteria, it is only within the last 30 years that biologically active polyacetylenes having unusual structural features have been reported from plants, cyanobacteria, algae, invertebrates, and other sources. Naturally occurring aquatic acetylenes are of particular interest since many of them display important biological activities and possess antitumor, antibacterial, antimicrobial, antifungal, phototoxic, HIV inhibitory, and immunosuppressive properties. There is no doubt that they are of great interest, especially for the medicinal chemistry, and/or pharmaceutical industries. This review presents structures and describes cytotoxic activities of more than 300 acetylenic metabolites isolated from living organisms.

Key Words: Acetylenic, polyacetylenes, antitumor, agents, cytotoxic, bacteria, cyanobacteria, algae, invertebrates, fungi, plants, corals, sponges, tunicates, carotenoids, lipopeptides, depsipeptides, fatty acids. INTRODUCTION Natural acetylenic compounds have been isolated from a wide variety of plant species, cultures of higher fungi, and marine invertebrates [1-8]. Many of them display important biological activities, namely antitumor, antibacterial, antimicrobial, antifungal, phototoxic, and other related medicinal properties [9,10]. Currently, about half of all prescribed medicines are extracted or derived from terrestrial plants and microorganisms. Most of the synthetic drugs, it should be noted, were originally inspired by novel compounds discovered in terrestrial organisms [11-13]. Plants have been used worldwide for treatment of various human ailments since antiquity. Their use is still quite prevalent in developing countries in the form of traditional/folkloric medicine. Intensive chemical and pharmacological studies during the last five decades have led in many cases to validation of traditional claims and facilitated identification of the traditional medicinal plants and of their active principles. Biological activities of acetylenes and related compounds from higher plants have been studied intensively in recent years and their activity in various organisms is now well documented. More than 1000 acetylenic metabolites have been isolated and identified from plants, fungi, microorganisms, and marine invertebrates [1-5,14-16]. In the past several decades, natural acetylenic compounds have been isolated from a wide variety of macro- and microalgal species, freshwater and marine cyanobacteria, and other aquatic organisms. Extensive pharmacological screening performed on aquatic species resulted in discovery of novel antitumor agents [1,5,6,17-19]. The purpose of this review is to summarize antitumor and cytotoxic properties of more than 300 acetylenic natural products, belonging to diverse structural classes, including peptides, aliphatic and cyclic polyketides, terpenes, steroids, carotenoids, and lipids. Naturally occurring metabolites possessing an acetylenic unit, as well as polyacetylenes, are of particular interest as many of them display important biological activities, namely antitumor, antibacterial, antimicrobial, antifungal, and others. Their structure and biological activities, modes of action, and future prospects are discussed. This paper is a comprehensive survey of acetylenic anticancer agents that are deemed as naturally occurring.

*Address correspondence to this author at the Department of Pharmacology, Faculty of Pharmacy, University of Karachi, Karachi 75270, Pakistan; E-mail: [email protected] and Institute of Biomedical Chemistry, Moscow 119121, Russia; E-mail: [email protected]

1871-5206/08 $50.00+.00

ANTICANCER PEPTIDE METABOLITES The ubiquitous tropical cyanobacterium Lyngbya majuscula is a prolific producer of bioactive metabolites, and approximately 30% of all natural products reported from marine cyanobacteria have been isolated from these species [20]. The plethora of structurally diverse secondary metabolites isolated from L. majuscula exhibits a variety of bioactivities including antifeedant, molluscicidal, antiproliferative, and immunosuppressive properties. More than half of the known secondary metabolites of the species are either cyclic or linear lipopeptides, some of them having an acetylenic unit [20]. The linear lipopeptides named apramides A (1), B (2), and G (3) have been isolated from the cytotoxic fraction of L. majuscula collected at Apra Harbor (Guam) [21]. Apramide G showed cytotoxic activity, with IC50 values of 33 ng/mL and 11 ng/mL against KB and LoVo cells, respectively [22]. Four new metabolites have been isolated from L. majuscula collected at Boca del Drago Beach, Bocas del Toro, Panama. These compounds were assigned the trivial names dragonamide (4), pseudodysidenin, dysidenamide, and nordysidenin. Dragonamide exhibited cytotoxic activity against P388, A-549, HT-29, and MEL-28 cells (IC50 > 1 μg/mL) [23]. The first total synthesis of dragonamide was recently reported [24]. Carmabin A (5), a linear lipotetrapeptide, was isolated from the nBuOH extract of L. majuscula. Using the MRC-5 human embryonic lung cell line in the confluent and proliferating states (cytotoxicity assessment assay), curacin A and carmabin produced the following IC50 values: 6.58 μg/mL (crude extract with curacin A), 0.98 μg/mL (fraction with curacin A), 0.003 μg/mL (pure curacin A); 4.8 μg/mL (crude extract with carmabin), 0.6 μg/mL (fraction with carmabin A), and 0.06 μg/mL (pure carmabin A) [25]. Marine depsipeptides are composed of hydroxy and amino acids linked by amide and ester bonds, and many of them showed very promising biological activities, including anticancer, antibacterial, antiviral, antifungal, anti-inflammatory, anti-clotting and antiantherogenic properties. Depsipeptides have shown the greatest therapeutic potential as anticancer agents [26]. A new depsipeptide, malevamide C (6), was isolated from the cyanobacterium Symploca laete-viridis, collected near the south shore of Oahu, Hawaii [27]. At a concentration < 2 μg/mL, this compound was found to be active against P-388, A-549, and HT-29 cancer cells. The malevamide contains some unusual amino and hydroxy acids and several methylated and dimethylated residues. Other unusual moieties include 3-amino-2-methylhexanoic acid and 3-amino-2-methyl-7-octynoic acid. Hexane and butanol extracts of S. hydnoides showed cytotoxic activity against HT-29 human colon cancer cells [27]. © 2008 Bentham Science Publishers Ltd.

2 Anti-Cancer Agents in Medicinal Chemistry, 2008, Vol. 8, No. 2

Siddiq and Dembitsky

H

H

H

H

R O

O

N

O

N

N O

O

O

O

N

N

N

N O

O N

O

O

N

O

NH

N O

N

O

O

N N

N O

O

N

O

O

N

H2N

N O

O N

O O

N

4 Dragonamide

S

H2N

N O

5 Carmabin A

N 3 Apramide G

O

S N

1 Apramide A, R = Me 2 Apramide B, R =H Fig. (1). The linear lipopeptides produced by the ubiquitous tropical cyanobacterium Lyngbya majuscula.

A new series of depsipeptides, antanapeptins A-D, two of them antanapeptin A (7) and D (8) contains acetylenic acid, were isolated from L. majuscula of the Antany Mora collection (Madagascar) [28]. Both metabolites showed moderate cytotoxic activity against neuroblastoma-2A cells in mice. A new cyclodepsipeptide named pitipeptolide A (9), isolated from L. majuscula collected at Piti Bomb Holes (Guam reefs), an area known for its periodic blue-green algal blooms, appears to be unique in this particular collection of Dr Valerie Paul (Smithsonian Marine Station) by the presence of a 2,2-dimethyl-3-hydroxy-7octynoic acid residue [29]. This compound exhibited weak cytotoxicity against LoVo cancer cells, but possessed moderate antimycobacterial activity and stimulated elastase activity. Yanucamides A (10) and B (11) were isolated from lipid extracts of L. majuscula and Schizothrix sp. collected at Yanuca Island (Fiji) [30]. Both compounds contain a unique 2,2-dimethyl-3hydroxy-7-octynoic acid. The first total synthesis of yanucamide A (10) was reported via amide and ester couplings of the key components. This synthesis has established the configuration at the previously ambiguous 3-position, and also revised the stereochemistry at the 22-position, to give 3S,12S,17S,22S for the natural product (10) [31]. Ulongapeptin (12), a cyclic depsipeptide with a -amino acid, 3-amino-2-methyl-7-octynoic acid, was isolated from a Palauan

marine Lyngbya sp. The compound was cytotoxic against KB cells with an IC50 value of 0.63 μM [32]. Four new depsipeptides have been isolated from the marine cyanobacterium L. semiplena collected from Papua New Guinea. The wewakpeptins represent an unusual arrangement of amino and hydroxy acid subunits compared with known peptides of cyanobacterial origin, and possess a bis-ester, a 2,2-dimethyl-3-hydroxy-7octynoic acid residue. Wewakpeptins A (13) and C (14) were the most cytotoxic among these 4 depsipeptides, with an LC50 value of approximately 0.4 μM for both the NCI-H460 human lung tumor and the mouse neuroblastoma-2A cell lines [33-35]. Guineamide C (15) is a novel cyclic depsipeptide isolated and characterized from a Papua New Guinea collection of L. majuscule [34]. Guineamide C possesses moderate cytotoxicity to a mouse neuroblastoma-2A cell line with an IC50 value of 16 μM. A cyclic depsipeptide, georgamide (16), was isolated from a non-identified cyanobacterium (Australia) [35]. Its constituent units were five amino acid residues (L-Thr, L-Pro, L-Val, N-Me-L-Val, and N-MeL-Phe), as well as two hydroxy carboxylic acids, 2(S)-hydroxy3(R)-methylpentanoic acid and 2,2-dimethyl-3-hydroxy-7-octynoic acid, which are also present in wewakpeptins A and B [35]. The depsipeptides onchidin (17), and onchidin B (18) were isolated from the pulmonate mollusk Onchidium sp. Onchidin contains the -amino acid, 3-amino-2-methyl-7-octynoic acid, and

Acetylenic Anticancer Agents

Anti-Cancer Agents in Medicinal Chemistry, 2008, Vol. 8, No. 2

O N

N O

O

N

O

O

N

O

NH

N

O

O

N NH O O

O

O N

O

NH

O O

O

N N H

N

6 Malevamide C H

O H

O O

N O

NH

O R

O

O HN N

O

O H

N

O

O O

O

O

9 Pitipeptolide A

O

N

O

N H

H

7 Antanapeptin A, R = Me 8 Antanapeptin D, R = H

HN

O

N O

H

N

O

O

O

O

N H

H N

R

O HN

H

HN

O

N O

N

O

O HN

O O

N

O O

H 10 Yanucamide A, R = H 11 Yanucamide B, R = Me

Fig. (2). The cyclic depsipeptide have been isolated from cyanobacterial species.

12 Ulongapeptin

O

3



N N O N

N

O

O

O

O

O

N

O

O

HN

O

O

N

N

N

H N

O

N

O

O O

O O

NH

N H N

H O 13 Wewakpeptin A

O O

H

O

H O 14 Wewakpeptin C

H

O O

N H O

N

O

N

N O

O

O

HN

O

N

O O

H N

OH 15 Guineamide C

N

O

O

NH

O O

O

16 Georgamide H

H

Fig. (3). The cyclic depsipeptide have been isolated from cyanobacterial species. onchidin B, the -hydroxy acid, 3-hydroxy-2-methyl-7-octynoic acid. The onchidins are known to be cytotoxic, but no details were given in regard to this activity [36,37]. Kulolide (19), a cyclic depsipeptide, was isolated from a cephalaspidean mollusk, Philinopsis speciosa [38,39]. Kulolide is made up of five amino acid residues, one each of L-Ala, L-Pro, and N-Me-D-Val and two of L-Val, and two carboxylic acids, L-3-phenyllacetic acid and the unprecedented (R)-3-hydroxy-2,2-dimethyl-7-octynoic acid. Kulolide was active against L-1210 leukemia cells and P388 murine leukemia cells, with IC50 values of 0.7 and 2.1 μg/mL, respectively. Kulolide caused morphological change of rat 3Y1 fibroblast cells at a concentration of 50 μM. In addition to five new depsipeptides related to kulolide-1 (19), further examination of the mollusk Philinopsis speciosa has yielded a linear peptide, pupukeamide, and an unprecedented macrolide, tolytoxin-23-acetate. The chemical makeup suggested that the compounds originate from cyanobacteria, which are transmitted via herbivorous mollusks to P. speciosa [38,39]. Combined extracts [(EtOH and CHCl3/MeOH (1:1)] of the mollusk Philinopsis speciosa yielded kulolide-1 (19), kulolide-2, kulolide-3, kulokainalide-1 (20), kulomo’opunalide-1 (21), kulomo’opunalide2 (22), and tolytoxin 23-acetate. Kulolide-1 (19) caused morphological changes to rat fibroblast cells at a concentration of 50 μM. Less than 0.1% contamination with tolytoxin might account for this activity. Peptides (20-22) showed only moderate cytotoxicity against P388 cells. The unusual cyclodepsipeptide dolastatin 17 (23) was isolated from the Papua New Guinea sea hare Dolabella auricularia (Gas-

tropoda, Orthogastropoda, Aplysiidae) and found to contain an acetylenic -amino acid, designated dolayne. Dolastatin 17 exhibited significant human cancer cell growth inhibitory activity (GI50 0.45-0.74 μg/mL range) [40,41]. ANTICANCER AROMATIC METABOLITES Capillin (24) was isolated from Artemisia capillaries (fragrant wormwood), and its inhibitory activity on carcinogenic EpsteinBarr virus demonstrated [42-44]. Capillin, capillol (25) and capillene (26) were obtained from extracts of Artemisia scoparia (redstem wormwood) [45,46], from aerial parts of Artemisia variabilis [47] and from the essential oil of Santolina rosmarinifolia (Holy flax, Compositae) [48]. Concentrations (1-10μM) of capillin (24) from Artemisia monosperma inhibited cell proliferation on four human tumor cell lines: colon carcinoma HT29, pancreatic carcinoma MIA PaCa-2, epidermoid carcinoma of the larynx HEp-2 and lung carcinoma A549 by inducing DNA fragmentation and cell death [49]. The oil content increased in the aerial parts of Artemisia scoparia from the rosette stage to budding (from 0.21 to 2.5%) and flowering (0.23 to 2.6%). Concomitantly the capillene (26) content increased from 42.4 to 79.8% and that of capillin (24) decreased from 45.0 to 4.4% [50]. The capillene and capillin were the main components in both the roots and leaves of Artemisia capillaris growing at riverside sites [51]. Syntheses of capillin and related compounds have been reported [52-56]. Bioassay-directed fractionation of the dried roots of Asparagus cochinchinensis led to the isolation of some active compounds [57-



O H N HN

O

O

H

O

O

N

O

O

O

O

N

O

O

H

O

NH

O

N H

O 17 Onchidin O N

O

O

N

N

O

O

H N

H

O O

O

HN

O

O

O O

O

N

O

H

O

O

O

O

N H N

H

O

O

O

O

O

N O

O

19 Kulolide

18 Onchidin B

H N

N O

O

HN

O

O

O O

NH

O

O

O

N

O

H N

N

O

O

O

H

N O

O

O

N

N

O 20 Kulokainalide 1

21 Kulomo'opunalide 1 H

O O

O

O

N

NH

O

O O

N

O O

N

O

O

N

H N

O

O

NH

O O

N

NH

O O

H

22 Kulomo'opunalide 2

Fig. (4). The cyclic depsipeptide from marine mollusks.

23 Dolastatin 17

H

5



59], including a new acetylenic derivative, 3’’-methoxyasparenydiol (27), and asparenydiol (28). These compounds demonstrated moderate cytotoxicities in a panel comprised of KB, Col-2, LNCaP, Lu-1, and HUVEC cells, with IC50 values ranging from 4 to 20 μg/mL (Table 1). Table 1.

Cytotoxic Activities of Compounds Isolated from Asparagus Cochinchinensis (IC50 , μg/mL)

Compound

A

B

C

D

E

F

27

12.0

>20

>20

19.7

>20

20

>20

19.8

>20

3.0

3.7

267

1.3

0.1

0.1

0.6

0.8

268

>3.0

>3.0

>3.0

>3.0

>3.0

269

1.4

0.1

0.2

1.2

1.2

Doxorubicin

0.1

0.2

0.2

0.2

0.9

A549; human lung carcinoma; SK-OV-3; human ovarian cancer; SK-MEL-2; human skin cancer; XF498; human CNS cancer; HCT15; human colon cancer.



H N

HO3S

31

O H N

O HO

OAc

O O

251 Taurospongin A

252 Callyspongamide A H

HO

H

H

253 Callyspongenol A

254 Callyspongenol B

H H OH

HO

OH

255 Callyspongenol C

256 Siphonochalynol

Fig. (33). Cytotoxic lipophilic compounds from several marine sponges.

OH

O O

257 Stellettic acid A

O

258

O R

OH

O

O

260 Title acid, R = H 261 NSC 300263, R = Me

O

Br

Br

O O

HO

O

Br

Br

263

Br

Br

O

O

259

262

HO

Fig. (34). Cytotoxic lipophilic compounds from several marine sponges.

Acetylenic enol ethers of glycerols, including bioactive compounds (270-275), have been isolated from a sponge of the genus Petrosia. Compounds 270 and 272 exhibited weak cytotoxicity against a human leukemia cell-line (K-562) [340]. Bioactivities of glyceryl enol ether compounds 270, 271 and 273, of the yne-diene series, exhibited weak cytotoxicity against the human leukemia cell-line K-562 (LC50 9.2, 57, 29 g/mL, for 270, 271 and 272, respectively), while 273-275, possessing the yne-ene group, were less active (LC50 > 100 g/mL). The genus Montipora (phylum Cnidaria) is very rich in acetylenic compounds and many of them were shown to be cytotoxic and/or to possess antifungal and antibacterial properties. Two polyacetylene carboxylic acids, montiporic acids A (276) and B (277), have been isolated from the eggs of the scleractinian coral M. digi-

tata [341]. They exhibited antimicrobial activity against Escherichia coli and cytotoxicity towards P-388 murine leukemia cells. Montiporic acids A and B were not only antibacterial against Escherichia coli, but also cytotoxic against P-388 murine leukemia cells, with IC50values of 5 and 12 μg/mL, respectively. Coral metabolites (278-286) and four known diacetylenes (276,277) have been isolated from the methanolic extract of the stony coral Montipora sp. [342]. The compounds exhibited significant cytotoxicity against a small panel of human solid tumor cell lines (Table 17). Compounds (278-270) appear to share a common 2,4-diyne moiety as a biosynthetic precursor. Compounds (271275) are similar to (262-286) in having a diyne group, but the position is different. 2,4-Diynes are encountered more frequently in corals, and this may raise a question of the origin of (287-291). The


H


OH

264 Petrocortyne A H

OH

12 HO

H

12 H

265 Petrocortyne D

OH H

OH

OH

12 H

266 Petrocortyne E

OH H

OH

12 OH H

267 Petrocortyne F

OH

H

OH

12 OH H

OH

268 Petrocortyne G H

OH OH

12 269 Petrocortyne H H

OH

Fig. (35). Cytotoxic lipophilic compounds from a sponge of the genus Petrosia.

isolated compounds have been tested for cytotoxicity against a small panel of human cancer cell lines (Table 18), and most of them were found to be cytotoxic. Compound 287 showed significant cytotoxicity against human skin cancer and human ovarian cancer cell lines. In general, diacetylenes with the -hydroxy ketone functionality (287-289) were found to be more active. The trans-isomer (290) was more active than the cis-isomer (291), as in the case of

montiporyne A-D. Montiporyne A (292), an analog of 291, showed significant cytotoxicity towards human solid tumor cell lines. Montiporyne A (292) showed significant cell cycle inhibition in the HCT116 cell. Montiporyne A-F (292-297, respectively), with cytotoxic activities against human solid tumor cell lines SK-OV-3, SKMEL-2, XF498, and HCT15, have been isolated from the stony coral Montipora sp. by other researchers (Table 19) [343].



R

R O

O HO

HO

H

O

H

HO

OH

OH

33

R

H OH

272

270 R = Me 271 R = H

273 R = R1 = H 274 R = Me, R1 = H 275 R = H, R1 = Me

Fig. (36). Acetylenic enol ethers of glycerols (or plasmalogens) from sponge of the genus Petrosia. Table 18.

Cytotoxic Activities (ED 50 μg/mL) of Compounds Against Human Solid Tumor Cells

Compound

A549

SK-OV-3

SK-MEL-2

XF498

HCT15

278

>30

>30

>30

>30

>30

279

6.31

7.50

7.97

7.72

8.30

280

6.26

4.88

4.68

4.96

4.47

281

>30

20.52

>30

>30

25.61

282

>30

>30

>30

>30

>30

283

13.78

9.79

9.56

10.78

12.93

284

5.48

4.63

4.45

5.59

5.90

285

3.90

3.23

3.94

5.26

3.32

286

22.73

17.94

25.08

16.88

24.05

287

4.17

1.81

1.40

3.70

3.73

288

4.97

3.85

3.74

3.87

3.42

289

4.91

3.34

3.52

4.45

4.18

290

6.39

3.52

4.21

5.50

4.56

291

>30

5.23

4.61

29.16

11.30

Key to cell lines used: A549 = human lung cancer; SK-OV-3 = human ovarian cancer; SK-MEL-2 = human skin cancer; XF498 = human CNS cancer; HCT15 = human colon cancer.

Table 19.

In Vitro Cytotoxicities (ED50 , μg/mL) of Montiporynes Against Human Solid Tumor Cells

Compound

A549

SK-OV3

SK-MEL2

XF498

HCT15

292

>50

3.2

1.4

1.9

3.7

293

>50

2.5

1.5

3.2

5.2

294

>50

25.9

42.6

>50

>50

295

>50

45.1

43.1

>50

>50

296

>50

>50

>50

>50

>50

297

>50

29.2

36.7

31.3

45.1

Cisplatin

0.6

0.9

0.7

0.6

0.6

A549: human lung cancer; SK-OV-3: human ovarian cancer; SK-MEL-2: human skin cancer; XF498: human CNS cancer; HCT15: human colon cancer. Compounds were assayed in two separate batches.

Many species of tunicata produce bioactive compounds [345]. Callysponginol sulfate A (298), a sulfated C24 acetylenic fatty acid from the marine sponge Callyspongia truncata, is a membrane type 1 matrix metalloproteinase (MT1-MMP) inhibitor. Compound 298 inhibited MT1-MMP with an IC50 value of 15.0 μg/mL [346], and sodium 1-(12-hydroxy)octadecanyl sulfate was isolated from a marine tunicate as a matrix metalloproteinase 2 (MMP2) inhibitor [347]. This compound inhibited MMP2 with an IC50 value of 9.0 μg/mL. Four cytotoxic straight-chain polyacetylenic alcohols (299-302) were isolated from a marine ascidian (Phyllum Chordata, subphyl-

lum Urochordata) collected off Vigo, along the Atlantic coast of northwestern Spain [348]. This is the first finding of acetylenic lipids from an organism belonging to phylum Chordata. CONCLUSIONS Intensive searches for new classes of pharmacologically potent agents produced by bacteria, cyanobacteria, micro- and macroalgae, marine and freshwater invertebrates, plants, and fungi have resulted in the discovery of dozens of compounds possessing high cytotoxic activities. However, only a limited number of them have been tested in pre-clinical and clinical trials. One of the reasons is a



O

OH

O

OH

O 276 Montiporic acid A

O

OH O

O

277 Montiporic acid B Na

O

287 OH

O

OH

O 288

O Na

O

O

O

278

O Na

289 O

O

O

279

O

290 O

O

O

Z or E

280

H

O O

291 O

281

O Z or E

O HO

282

292 Montiporyne A E 293 Montiporyne B Z

O HN

HO

HO HO

294 Montiporyne C E 295 Montiporyne D Z

283

O

284

296 Montiporyne E O

285

286 297 Montiporyne F Fig. (37). Cytotoxic lipophilic compounds from the stony coral Montipora sp.

OH O O HO

298 Callysponginol sulfate A S

O O

OH R 299 R = H 300 R = OH

H OH

R H

Fig. (38). Cytotoxic lipophilic compounds from the ascidia species.

301 R = H 302 R = OH



limited supply of the active ingradients from the natural sources. However, the pre-clinical and clinical development of many terrestrial and aquatic derived natural products into pharmaceuticals is often hampered by a limited supply from the natural source. Total synthesis is of vital importance in these situations, allowing for the production of useful quantities of the target compound for further biological evaluation.

[39]

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Received: December 4, 2006

Revised: January 11, 2007

Accepted: February 12, 2007

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