Natural Product Research Vol. 23, No. 1, 10 January 2009, 60–69
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Novel class of hybrid natural products as antidiabetic agents Kanwal Raja*, Namita Misraa, Geetali Pachauria, Mithelesh Sharmaa, Akhilesh Kumar Tamrakarb, Amar Bahadur Singhb, Arvind Kumar Srivastavab, K. Phani Kiranc, C.V. Narasimha Raoc and S.R. Prubhuc a
Medicinal & Process Chemistry Division, Central Drug Research Institute, Lucknow, India; Division of Biochemistry, Central Drug Research Institute, Lucknow, India; cDivision of Crop Chemistry Soil Science, Central Tobacco Research Institute, Rajahmundry, India b
(Received 16 October 2006; final version received 7 February 2007) A number of O-alkylated xanthone, carbazoles and coumarins have been synthesised and screened for their in vitro anti-diabetic activity, such as glucose-6phosphatase, glycogen phosphorylase and alpha glucosidase inhibitors. Compounds which were showing significant percentage inhibition were also tested for in vivo anti-hyperglycemic activity in sucrose loaded normal and streptozotocin (STZ)-induced diabetic rats. These compounds show 22.1, 24.4 and 26.7% and 20.8, 25.0, 20.5% lowering in sucrose loaded normal rats and STZ-induced diabetic rats at a dose of 100 mg kg1. Keywords: glucose-6-phosphatase; glycogen phosphorylase; inhibitors; anti-hyperglycemic activity; solanesol
-glucosidase
1. Introduction Non-insulin dependent diabetes mellitus (NIDDM, type-2 diabetes) is a chronic disease characterised by insulin resistance in liver and peripheral tissues accompanied by defects in -cells. It is the third leading cause of death in the United States after heart disease and cancer; nearly 80–90% of the human population have diabetes and approximately 215 million will be affected worldwide by 2010 (Bennett, 1997). In 2002, $132 billion was spent on diabetes, and per capita expenditure by people with diabetes is 2.4 times that spent by non-diabetic population (American Diabetes Association, 2003). The primary therapy prescribed for type-2 diabetes has been a combination of diet, exercise and oral hypoglycemic agents (Reddy et al., 1999). A variety of pharmacologic agents, including insulin (DeWitt & Hirsch, 2003), glucose-6-phosphatase inhibitors (Ram, Farhanullah, Tripathi, & Srivastava, 2003) (biguanides – metformin), glycogen phosphorylase (Oikonomakos, Kosmopoulou, Chrysina, Leonidas, & Kostas, 2005), inhibitors (acyl ureas), alpha glucosidase inhibitors (Lebovitz, 1998) (acarbose), sulphonylureas (Lebovitz, 1999) (glipzide, chlorpropamide) and thiazolidones (Diamant & Heine, 2003)
*Corresponding author. Email:
[email protected]
ISSN 1478–6419 print/ISSN 1029–2349 online ß 2009 Taylor & Francis DOI: 10.1080/14786410701824940 http://www.informaworld.com
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(troglitazone, rosiglitazone), currently available also have some side effects, such as hypoglycaemia, lactic acidosis, weight gain (Skyler, 2004), and hepatotoxicity (Satyanarayana, Tiwari, Tripathi, Srivastava, Pratap, 2004). Therefore, there still remains a great need for more effective oral anti-diabetic agents. Several herbal formulations, including single plants, are known to exhibit blood sugar lowering activity, and search for new prototype chemical structure for anti-hyperglycemic activity from these can be good leads for further modification. Isolation of 7-acetoxy 4-methyl coumarins from Trigonella foenum – gaaecum (Ajabnoor & Tilmisany, 1988; Riyad, Abdul-Salam, & Mohammad, 1988), swerchirin, a xanthone from Swertia chirayta (Asthana, Sharma, Kulshreshtha, & Chatterjee, 1991), and several carbazole alkaloids from the leaves of Murraya koenigii (Joshi, Kamat, & Gawas, 1970; Wang, He, Shan, Hong, & Hao, 2003) are of interest in this contest. Most of these have nuclei that are found appended with one or two isoprene units in one or another form via C– or O– linkage. These prenyl units are an integral part of coenzyme Q and coenzyme Q-10, which is known to facilitate the entry of quinone moiety to hydrocarbon phase of inner mitochondrial membrane. Here we have reported the synthesis of polyprenylated xanthones, coumarins and carbazoles, and their activity profiles for glucose-6-phosphatase (G-6-phosphatase) (Farhanullah, Tripathi, Srivastava, & Ram, 2004), glycogen phosphorylase (Gly phosphorylase) (Wen et al., 2006), and alpha glucosidase (Clessiold & Edwards, 1988) inhibitors. These enzymes represent the key regulatory sites of carbohydrate metabolism and their levels were found to be elevated in diabetes mellitus. Glucose-6-phosphatase (Farhanullah et al., 2004) catalyses the penultimate step of gluconeogenesis. Its inhibitors could decrease hepatic glucose output leading to the lowering of the concentration of plasma glucose. Glycogen phosphorylase catalyses release glucose from glycogen for energy supply. The release of glucose provides the substrate for a number of pathways, e.g. glycolysis or glucose releases to the blood. The activity of this enzyme is significantly higher in cases of diabetes mellitus. Alpha glucosidase (Clessiold & Edwards, 1988), which is a membrane bound enzyme at the epithelium of the small intestine catalyses the cleavage of glucose from disaccharide, is thus responsible for the generation of monosaccharide. 1,3-Dihydroxy xanthone (prepared by the reported method) and swerchirin (isolated from S. chirayta), were selectively alkylated with prenyl, geranyl, farnesyl and solanesyl bromide (prepared from solanesol isolated from tobacco waste) and yielded compounds 1(a)–(c) and 2(a)–(d). Similarly, 4-methyl-7-hydroxy coumarin and 2-hydroxy-3-methylcarbazole were alkylated with solanesyl bromide to give 3a and 4a. In another variation, hemisuccinate of solanesol (5)1 was prepared, appended with 1,3-dihydroxyxanthone and 4-methyl-7-hydroxy coumarins to give respective esters 1e and 3e. In Scheme 3, solanesol bromide was appended with different coumarins and flavones. All these compounds were characterised by spectroscopic data. O-alkylated/esterified compounds are shown in Schemes 1, 2 and 3. The general synthetic route used to synthesise the designated compounds is outlined in Scheme 1. The target compounds, as mentioned in Schemes 1, 2 and 3, were prepared by reacting different alkyl halides with the OH group of xanthones/coumarins in acetone at 60–70 C. In vitro and in vivo anti-hyperglycemic activities of all the compounds are summarised in Tables 1 and 2. The in vitro biological activity of O-alkylated xanthones/coumarin has shown encouraging results (Table 1) against glucose-6-phosphatase (Hubscher & West, 1965), glycogen phosphorylase (Rall, Sutherland & Barthet, 1957), and alpha
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K. Raj et al. OH O
OH O i
HO
R
O
O
1
O
1a-c
OH O
OH O
OH
OR
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i O OCH3
R=
O OCH3
OCH3 2
OCH3
H
a-
2a-d
9
H
b-
i c-
R HO
O
O
O
O
H
2
O d-
H 3
3a
3
i O R
N H
OH
N H 4
4a
Scheme 1. Reagents and conditions: (i) R–Br, dry acetone, K2CO3, 60–70 C.
COOH
OH O
i + HO
H O
O
O
9
5
1
O 9
O
i
+ O
H O
O
9
5
3 O 9 H
O 1e
O COOH
O
O
O
H
HO
OH
O O O
O
O
3e
Scheme 2. Reagents and conditions: (i) DCC, DMAP, dry DCM 0 C.
glucosidase (Lebovitz, 1997). In Schemes 1, 2 and 3, variations in the hydroxyl group were made to access their effect on inhibitory activity. As evident from the screening result of these compounds, the variation in the chain length did not affect the activity profile in glucose-6-phosphatase, and it remains in the range of 16.1–23.2%. Whereas this variation affects the activity profile in glycogen phosphorylase and inhibition goes up to 91.6% by compound 1c followed by 3e (87.5%) and 2b (56.7%), the rest of the compounds remained marginally active. Thus the variation
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H
63
H
Br
O-R1
7 a-f
6
R1
=
7a -
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O O COCH3 CH3 7b O
O
H3COC CH3
OH
7c O MeO
O
OMe
O
7d OMe O 7e -
N 7f -
O
O
Scheme 3. Reagents and conditions: (i) R–OH, dry acetone, K2CO3, 60–70 C.
in chain length plays an important role in glycogen phosphorylase inhibition. All the compounds were also tested for alpha glucosidase inhibition. Solanesol hemisuccinate itself shows 87.9% inhibition against alpha glucosidase and 26.7, 20.5% activity in sucrose loaded normal rats and streptozotocin (STZ)-induced diabetic rats, respectively. When appended, the xanthones/coumarins affected the in vivo activity in 1e and 3e respectively. All the synthesised compounds were evaluated for antihyperglycemic activity in sucrose loaded rats, followed by STZ-induced diabetic rats.
2. Experimental section 2.1. General procedure for the preparation of O-alkylated xanthones/coumarins (Schemes 1 and 3) A mixture of xanthones or coumarins (1.0 g), alkyl halide (1.2 eq.), and potassium carbonate (2.2 eq.) in dry acetone (50 mL) were refluxed for 6–8 h. The reaction mixture was allowed to cool and filtered through a sintered funnel; water (50 mL) was added. The reaction mixture was extracted with chloroform and dried over Na2SO4 to give the crude product, which was purified by column chromatography (hexane/ethyl acetate, 9 : 1, v/v) to give the product.
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Table 1. In vitro anti-hyperglycemic activity of O-alkylated/esters compounds. Percentage inhibition
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Compound
Concentration (mM)
G-6-phosphatase
Gly phosphorylase
-Glucosidase
100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100
16.9 16.1 13.8 23.2 5.5 4.0 3.50 6.30 0.90 4.2 7.2 0.25 9.6 17.1 6.5 4.5
48.6 91.6 10.8 56.7 11.2 18.4 20.8 87.5 16.6 13 11.1 21.0 26.9 26.3 12.8 32.5
31.0 43.1 34.5 42.1 30.9 66.2 5.17 25.8 6.89 87.9 3.8 15.4 3.8 15.3 2.5 2.5
1b 1c 2a 2b 2c 2d 3a 3e 4a 5 7a 7b 7c 7d 7e 7f
Table 2. In vivo antihyperglycemic activity of O-alkylated/esters compounds. Percentage inhibition Compound
Concentration (mg Kg1)
SLM Model
STZ Model
1c 1e 3e 5 Metformin
100 100 100 100 100
19.0 22.1 24.4 26.7 30.0
– 20.8 25.0 20.5 26.0
Note: SLM ¼ sucrose loaded model in normal rats; STZ ¼ streptozotocin-induced diabetic rates.
2.1.1. 1-Hydroxy-3-solanesyl-xanthen-9-one (1a) M.p. 55 C; Ms (FAB): m/z 842 (M þ 2); IR (KBr, cm1): 3408, 2976, 2366, 1652, 1606, 1459, 1355, 1292, 1084, 971, 826; 1H NMR (300 MHz, CDCl3): (ppm) 1.60 (s, 30H,CH3), 2.17 (m, 32H, ¼ CH–CH2 and ¼C (CH3)–CH2), 4.64 (d, J ¼ 6.0 Hz, 2H,O–CH2), 5.13 (t, 8H, CH2–CH¼), 5.51 (t, J ¼ 6.30 Hz, 1H, O–CH2¼CH), 6.36 (d, J ¼ 1.5 Hz, 1H, Ar–H), 6.45 (d, J ¼ 1.8 Hz, 1H, Ar–H), 7.3–7.4 (m, 2H, Ar–H), 7.73 (t, J ¼ 8.1 Hz, 1H, Ar–H), 8.26 (d, J ¼ 8.1 Hz, 1H, Ar–H), 12.7 (s, 1H, Ar–OH). 2.1.2. 1-Hydroxy-3-prenyl-xanthen-9-one (1b) M.p. 136–137 C; Ms (FAB) m/z 297 (Mþ þ 1); IR (KBr, cm1): 3422, 2924, 1567, 1607, 1465, 1299, 1159, 1077; 1H NMR (300 MHz, CDCl3): (ppm) 1.83 (s, 6H, CH3), 4.62 (d, J ¼ 6.0 Hz, 2H, O–CH2), 5.51 (t, 1H, O–CH2–CH¼), 6.37 (d, J ¼ 1.74 Hz, 1H, Ar–H),
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6.45 (d, J ¼ 1.66 Hz, 1H, Ar–H), 7.35–7.45 (m, 2H, Ar–H), 7.74 (t, J ¼ 8.6 Hz, 1H, Ar–H), 8.27 (d, J ¼ 9 Hz, 1H, Ar–H), 12.87 (s, 1H, Ar–OH). 2.1.3. 1-Hydroxy-3-geranyl-xanthen-9-one (1c) M.p. 55–58 C; Ms (FAB) m/z 365 (M þ 1); IR (KBr, cm1): 3416, 2929, 1602, 1463, 1356, 1223, 1158, 1067, 927, 820; 1H NMR (200 MHz, CDCl3): (ppm) 1.58 (s, 9H, ¼ CH–CH3), 2.01–2.16 (m, 4H, –CH2–CH2), 4.61–4.70 (m, 3H, O–CH2 and CH2–CH¼), 5.49 (t, J ¼ 6.30 Hz, 1H, O–CH2–CH), 6.37 (d, J ¼ 2.0 Hz, 1H, Ar–H), 6.45 (d, J ¼ 2.2 Hz, 1H, Ar–H), 7.45–7.37 (m, 2H, Ar–H), 7.71 (t, J ¼ 8.60, 1H, Ar–H), 8.27 (d, J ¼ 9.40 Hz, 1H, Ar–H), 12.8 (s, 1H, Ar–OH). 2.1.4. 8-Hydroxy-3,5-dimethoxy-1-solanesyl-xanthen-9-one (2a) Ms (FAB) m/z 900 (Mþ), 924 (M þ 1 þ Na); IR (Neat, cm1): 3435, 2924, 2341, 1607, 1492, 1445, 1352, 1251, 1110, 1066, 959, 817; 1H NMR (300 MHz, CDCl3): (ppm) 1.597 (s, 30H, CH3), 2.18 (m, 32H, ¼ CH–CH2 and ¼C (CH3)–CH2), 3.91 (s, 3H, –OCH3), 3.96 (s, 3H, –OCH3), 4.78 (d, J ¼ 6.0 Hz, 2H, O–CH2), 5.12 (m, 8H, CH2–CH¼), 5.58 (m, 1H, O–CH2–CH¼), 6.36 (d, J ¼ 9 Hz, Ar–H,), 6.61 (d, J ¼ 9 Hz, Ar–H), 6.70 (d, J ¼ 9 Hz, 1H, Ar–H), 7.19 (d, J ¼ 9 Hz, 1H, Ar–H), 12.2 (s, 1H, Ar–OH). 2.1.5. 8-Hydroxy-3,5-dimethoxy-1-prenyl-xanthen-9-one(2b) M.p. 159–160 C; Ms (FAB) m/z 356(Mþ); IR (KBr, cm1): 3403, 2938, 1602, 1491, 1440, 1389, 1359, 1106, 1062, 960, 819; 1H NMR (200 MHz, CDCl3): (ppm) 1.78 (s, 3H, CH3). 1.82 (s, 3H, CH3), 3.90 (s, 3H, –OCH3,) 3.95 (s, 3H, –OCH3), 4.73 (d, J ¼ 6Hz, 2H, O–CH2), 5.58 (m, 1H, ¼ CH), 6.35 (d, J ¼ 2.4 Hz, 1H, Ar–H), 6.60 (d, J ¼ 2.4 Hz, 1H, Ar–H), 6.69 (d, J ¼ 9 Hz, Ar–H), 7.19 (d, J ¼ 9 Hz, Ar–H). 2.1.6. 1-Geranyl-8-hydroxy-3,5-dimethoxy-xanthen-9-one (2c) M.p. 97–98 C; Ms (FAB) m/z 425 (M þ 1); IR (KBr, cm1): 3440, 2922, 2852, 1601, 1490, 1444, 1352, 1382, 1242, 1160, 965, 762; 1H NMR (200 MHz, CDCl3): (ppm) 1.55 (s, 6H, CH3), 1.60 (s, 3H, CH3), 2.11 (m, 4H, CH2–CH2), 3.89 (s, 3H, –OCH3), 3.94 (s, 3H, –OCH3), 4.77 (d, J ¼ 6.0 Hz, 2H, O–CH2), 5.15 (t, 1H, –CH2–CH¼), 5.45 (t, 1H,OCH2– CH¼), 6.34 (d, J ¼ 9 Hz, Ar–H), 6.60 (d, J ¼ 9 Hz, Ar–H), 6.69 (d, J ¼ 9.0 Hz, 1H, Ar–H), 7.14 (d, J ¼ 9.0 Hz, 1H, Ar–H), 12.66 (s, 1H, Ar–OH). 2.1.7. 8-Hydroxy-3,5-dimethoxy-1-farnesyl-xanthen-9-one (2d) Ms(FAB) m/z 474 (M – OH); IR (Neat, cm1) 3437, 2927, 2852, 1607, 1492, 1446, 1246, 1112, 964, 761; 1H NMR (200 MHz, CDCl3): (ppm) 1.58 (s, 12H, CH3), 2.02 (m, 4H, CH2–CH2), 2.12 (m, 4H, CH2–CH2), 3.89 (s, 3H, –OCH3), 3.94 (s, 3H, –OCH3), 4.77 (d, J ¼ 6.0 Hz, 2H, O–CH2), 5.10 (m, 2H, –CH2–CH¼), 5.57 (t, 1H, OCH2–CH¼), 6.34 (d, J ¼ 9 Hz, 1H, Ar–H), 6.59 (d, J ¼ 9 Hz, Ar–H), 6.69 (d, J ¼ 9.0 Hz, 1H, Ar–H), 7.18 (d, J ¼ 9.0 Hz, 1H, Ar–H), 12.66 (s, 1H, Ar–OH). 2.1.8. 7-Solanesyl-4-methyl-chromen-2-one (3a) M.p. 60–63 C; Ms (FAB) m/z 789 (M þ 1), 811 (M þ Na); IR (KBr, cm1): 3431, 2938, 1602, 1491, 1440, 1389, 1359, 1106, 1062, 960, 819; 1H NMR (200 MHz, CDCl3): (ppm)
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1.597 (s, 30H, CH3), 2.114 (m, 32H, ¼ CH–CH2 and ¼C (CH3)–CH2), 2.394 (s, 3H, ¼C–CH3), 4.61 (d, 2H, J ¼ 6.6 Hz, 2H O–CH2), 5.111 (t, 8H, CH2–CH¼), 5.509 (t, 1H, O–CH2–CH¼), 6.12 (s, 1H, –C (O)–CH¼), 6.83 (d, J ¼ 2.2 Hz, 1H, Ar–H), 6.88 (d, J ¼ 2.4 Hz, 1H, Ar–H), 7.5 (d, J ¼ 6.8 Hz, 1H, Ar–H).
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2.1.9. 2-Solanesyl-3-methyl-9H-carbazole (4a) Ms (FAB) m/z 839 (M þ Na); 1H NMR (200 MHz, CDCl3): (ppm) 1.60 (s, 30H, CH3), 2.17 (m, 32H, ¼ CH–CH2 and ¼C (CH3)–CH2), 4.64 (d, J ¼ 6.0 Hz, 2H, O–CH2), 5.51 (t, J ¼ 6.30 Hz, 1H, O–CH2 ¼ CH), 5.13 (t, 8H, CH2–CH¼), 6.87 (s, 1H, Ar–H), 7.2 (m, 2H, Ar–H), 7.3 (m, 2H, Ar–H), 7.78 (s, 1H, Ar–H), 7.9 (d, 1H, Ar–H), 10.11 (s, 1H, N–H). 2.1.10. 8-Acetyl-7-solanesyl-chromen-2-one (7a) Ms (FAB) m/z 839 (M þ Na); IR 3423, 2927, 1715, 1601, 1357, 1076, 773; 1H NMR (200 MHz,CDCl3): (ppm) 1.597 (s, 30H, CH3), 2.114 (m, 32H, ¼ CH–CH2 and ¼C (CH3)– CH2), 2.96 (s, 3H, C(O)CH3), 4.61 (d, 2H, J ¼ 6.6 Hz, 2H, O–CH2), 5.111 (t, 8H, CH2– CH¼), 5.509 (t, 1H, O–CH2–CH¼), 6.25 (d, J ¼ 9.5 Hz, 1H, C(O)–CH), 6.85 (d, J ¼ 8.6 Hz, 1H, Ar–H), 7.41(d, J ¼ 8.6 Hz, 1H, Ar–H), 7.61 (d, J ¼ 9.5 Hz, 1H, C(O)–CH ¼ CH–). 2.1.11. 8-Acetyl-7-solanesyl-4-methyl-chromen-2-one (7b) Ms (FAB) m/z 853 (Mþ þ Na); IR (KBr, cm1): 3428, 2965, 1733, 1600, 1366, 1087, 775; 1 H NMR (200 MHz, CDCl3: (ppm) 1.597 (s, 30H, CH3), 2.114 (m, 32H, ¼ CH–CH2 and ¼C (CH3)–CH2), 2.39 (s, 3H, ¼ C–CH3), 2.96 (s, 3H, C(O)CH3), 4.61 (d, J ¼ 6.6 Hz, 2H, O–CH2), 5.111 (t, 8H, CH2–CH¼), 5.509 (t, 1H, O–CH2–CH¼), 6.14 (s, 1H, C(O)–CH¼), 6.87 (d, J ¼ 8.8 Hz, 1H, Ar–H), 7.54 (d, J ¼ 8.8 Hz, 1H, Ar–H). 2.1.12. 7-Solanesyl-3-(2-hydroxy-ethyl)-4-methyl-chromen-2-one (7c) Ms (FAB) m/z 963 (M þ Na); IR (KBr, cm1) 3433, 2922, 2855, 1708, 1609, 1445, 1384, 1285, 1248, 1169, 1091, 1004; 1H NMR (200 MHz, CDCl3): (ppm) 1.590 (s, 3H, ¼C– CH3), 1.597 (s, 30H, CH3), 2.114 (m, 32H, ¼CH–CH2 and ¼C (CH3)–CH2), 2.94 (t, 2H, O–CH2–CH2), 3.85 (t, 2H, O–CH2), 4.61 (d, J ¼ 6.6 Hz, 2H, O–CH2), 5.111 (t, 8H, CH2– CH¼), 5.509 (t, 1H, O–CH2–CH¼), 6.81 (d, J ¼ 2.3 Hz, 1H, Ar–H), 6.87 (dd, J ¼ 8.8/ 2.3 Hz, 1H, Ar–H), 7.51 (d, J ¼ 8.8 Hz, 1H, Ar–H). 2.1.13. 2-(3,4-Dimethoxy-phenyl)-8-solanesyl-6-methoxy-chromen-4-one (7d) Ms (ESMS) m/z 942 (M þ Na); IR (KBr) 3428, 2927, 2839, 2363, 1634, 1603, 1357, 1262, 1161, 1026, cm1; 1H NMR (200 MHz, CDCl3): (ppm) 1.597 (s, 30H, CH3), 2.114 (m, 32H, ¼ CH–CH2 and ¼C (CH3)–CH2), 3.89 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 4.61 (d, 2H, J ¼ 6.6 Hz, 2H, O–CH2), 5.111 (t, 8H, CH2–CH¼), 5.509 (t, 1H, O–CH2–CH¼), 6.32 (d, J ¼ 2.0 Hz, 1H, Ar–H), 6.51 (d, J ¼ 2.0 Hz, 1H, Ar–H), 6.52 (s, 1H, C(O)–CH¼), 6.92 (d, J ¼ 8.5 Hz, 1H, Ar–H), 7.29 (d, J ¼ 1.7 Hz, 1H, Ar–H), 7.47 (dd, J ¼ 1.8/8.7 Hz, 1H, Ar–H). 2.1.14. 6-Solanesyl-quinolin (7e) Ms (FAB) m/z 963 (M þ Na); IR (KBr, cm1) 3424, 2923, 2852, 1598, 1443, 1360, 1224, 1165, 1001, 837, 773; 1H NMR (200 MHz, CDCl3): (ppm) 1.597 (s, 30H, CH3), 2.114
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(m, 32H, ¼ CH–CH2 and ¼C (CH3)–CH2), 4.61 (d, 2H, J ¼ 6.6 Hz, 2H O–CH2), 5.111 (t, 8H, CH2–CH¼), 5.509 (t, 1H, O–CH2–CH¼), 6.98 (s, 1H, Ar–H), 7.45 (m, 2H, Ar–H), 8.1(m, 2H, Ar–H), 8.7 (m, 1H, Ar–H).
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2.1.15. 4-Solanesyl-chromen-2-one (7f) Ms (ESMS) m/z 797 (M þ Na); IR (KBr,cm1): 3428, 2854, 1730, 1621, 1448, 1379, 1240, 1185, 1105, 1031; 1H NMR (200 MHz, CDCl3): (ppm) 1.597 (s, 30H, CH3), 2.114 (m, 32H, ¼ CH–CH2 and ¼C (CH3)–CH2), 4.61(d, J ¼ 6.6 Hz, 2H, O–CH2), 5.111 (t, 8H, CH2–CH¼), 5.509 (t, 1H, O–CH2–CH¼), 5.64 (s, 1H C(O)–CH¼), 7.20 (d, J ¼ 7.4 Hz, 1H, Ar–H), 7.29((d, J ¼ 8.7 Hz, 1H, Ar–H), 7.50 (d, J ¼ 7.0 Hz, 1H, Ar–H), 7.81 (d, J ¼ 6.6 Hz, 1H, Ar–H).
2.2. General procedure for the preparation of esterified xanthones/coumarins (Scheme 2) A mixture of xanthones or coumarins (1.0 g), solanesol hemisuccinate (1.5 eq.), DCC (2 eq.), and a catalytic amount of DMAP in dry DCM (50 mL) was stirred at 0 C for 6–8 h. The reaction mixture was concentrated on rotavapour, ether was added, DCU was separated through filtration, washed with ether filtrate, concentrated and was purified by column chromatography (hexane/chloroform, 2 : 8; v/v) to give the product. 2.2.1. Succinicacid-1-hydroxy-9-oxo-9H-xanthen-3-yl ester-3,7,11,15,19,23,27,31, 35-nonamethylhexatriaconta-2,6,10,14,18,22,26,30,34-nonaenylester (1e) M.p. 52–55 C; Ms (FAB) m/z 963 (Mþ þ Na); IR (KBr, cm1): 3405, 2924, 1739, 1605, 1440, 1353, 1198, 1156, 990, 859; 1H NMR (200 MHz, CDCl3): (ppm) 1.50 (s, 30H, CH3), 2.07 (m, 32H, ¼ CH–CH2 and ¼C (CH3)–CH2), 2.79 (t, J ¼ 6.8 Hz, 2H, C (O)–CH2), 2.93 (t, J ¼ 6.8 Hz, 2H), C (O)–CH2), 4.68 (d, J ¼ 8.0 Hz, 2H, O–CH2), 5.1 (t, 8H, CH2–CH¼), 5.40(t, J ¼ 6.2 Hz, 1H, O–CH2–CH¼), 6.58 (d, J ¼ 2.0 Hz, 1H, Ar–H), 6.78 (d, J ¼ 2.0 Hz, 1H, Ar–H), 7.3–7.48 (m, 2H, Ar–H), 7.78 (t, J ¼ 7.0 Hz, 1H, Ar–H), 8.29 (d, J ¼ 7.8 Hz, 1H, Ar–H), 12.7 (s, 1H, Ar–OH). 2.2.2. Succinicacid-4-methyl-2-oxo-2H-chromen-7-yl-ester3,7,11,15,19,23,27,31, 35-nonamethylhexatriaconta-2,6,10,14,18,22,26,30,34-nonaenylester (3b) M.p. 50–55 C; Ms (FAB) m/z 911 (M þ Na); IR (KBr, cm1): 3445, 2969, 2852, 2170, 1770, 1732, 1613, 1444, 1383, 1154, 982,797; 1H NMR (300 MHz, CDCl3): (ppm) 1.6 (s, 30H, CH3), 2.0 (m, 32H, ¼ CH–CH2 and ¼C (CH3)–CH2), 2.4 (s, 3H, ¼ C–CH3), 2.7 (t, J ¼ 6.0 Hz, 2H, O–C (O)–CH2), 2.9 (t, J ¼ 6.0 Hz, 2H, O–C (O)–CH2), 4.6 (d, J ¼ 6.0 Hz, 2H, O–CH2), 5.1 (t, 8H, CH2–CH¼), 5.3 (t, 1H, O–CH2–CH¼), 6.2 (s, 1H, C (O)–CH¼), 7.0 (d, J ¼ 3.0 Hz, 1H, Ar–H), 7.1 (dd, J ¼ 9.0/3.0 Hz, 1H, Ar–H), 7.6 (d, J ¼ 9.0 Hz, 1H, Ar–H).
Acknowledgements Two of the authors, Geetali Pauchari and K. Phani Kiran, are thankful to ICAR New Delhi for financial support, and also Ms. Veena Mehrotra for technical support.
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Note 1. Synthesis of solanesol hemisuccinate (5) – Succinic anhydride (1eq.), and DMAP (1eq.) were added to the stirred solution of solanesol (1eq.) in dry pyridine (100 mL) and the whole was stirred at room temperature for 6 h. On completion, excess pyridine was removed in vacuo and the residue was extracted with chloroform (3 100 mL) and washed with water. Combined organic layer was dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated to give a thick residue which was purified through flash column chromatography. Elution with ethyl acetate: hexane (4 : 96; v/v) gave the desired compound which was then crystallized with methylene chloride: methanol at 10 C.
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