Flavone-based novel antidiabetic and antidyslipidemic agents

Article

pubs.acs.org/jmc

Flavone-Based Novel Antidiabetic and Antidyslipidemic Agents

Alok K. Verma,^†Himanshu Singh,^†M. Satyanarayana,^†Swayam P. Srivastava,^‡Priti Tiwari,^‡

Amar B. Singh,^‡Anil K. Dwivedi,^§Shio K. Singh,^∥Mukesh Srivastava,^⊥Chandishwar Nath,^#

Ram Raghubir,^#Arvind K. Srivastava,^‡and Ram Pratap*^,†

Divisions of ^†Medicinal & Process Chemistry, ^‡Biochemistry, ^§Pharmaceutics, ^∥Pharmacokinetics & Pharmacodynamics, ^⊥Biometry &

#

Statistics and Pharmacology, Central Drug Research Institute (CSIR), Lucknow−226001, India

S

* Supporting Information

ABSTRACT: The hybrid congeners 62−90 of 6- and 7-

hydroxyﬂavones with aminopropanol have been synthesized

and evaluated for their antidiabetic activity in sucrose-challenged

low-dosed streptozotocin (STZ)-induced diabetic rats and db/db

mice. The optical enantiomers 70a, 70b, 90a, and 90b of two

congeners 70 and 90 exhibiting consistent antidiabetic and

antidyslipidemic activities were also prepared, and their

antidiabetic activity results indicate its association mainly with S

isomers. These compounds also lower cholesterol and TG proﬁles

while improving high-density lipoprotein cholesterol to CHOL

ratio in db/db mice. The bioavailability of compound 70 and its

isomer varies between 27 and 29% whereas that of the more polar compound 90a is poor as determined in rat by oral and

intraperitoneal administrations.

because of the lack of favorable pharmacokinetic property.⁸It

therefore emphasizes the need for structural improvements in

this class of agents. Of the three most potent compounds

shown here, 1 and 2 have the aromatic ring attached with the

INTRODUCTION

The sedentary lifestyle and energy-rich diet in the present

industrialized world is aggressively contributing to a staggering

increase in obesity resulting in insulin resistance. As a result,

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basic pharmacophore but the rings themselves are biologically

there is a steady increase in the pathogenesis of type 2 dia-

betes.¹Prolonged obesity leads to atherogenicity, whereas

nonfunctional. Also the presence of 1,4-substitution patterns

present in compounds 1 and 3 is generally not preferred in

diabetes manifests into chronic macrovascular complications

such as retinopathy and nephropathy. The majority of previous

antiobesity drugs are targeted toward reduction of energy

intake (anorectic drugs) whereas antidiabetic drugs rely on

druggable molecules. The compound 3 has a carbazole moiety

in place of phenyl, which is biologically functional and present

in druglike molecules such as carvedilol.⁹Flavonoids are among

the most ubiquitous groups of polyphenolic compounds in

either an increase in insulin secretion from pancreatic β-cells by

sulphonylureas (e.g., glibenclamide²), an enhancement of

foods of plant origin and exhibit biological activities through

free radical scavenging.¹⁰These properties of ﬂavones led us to

insulin action by PPAR-γ (peroxisome proliferator activated

receptor-γ) agonists³(e.g., rosiglitazone), or a reduction of

utilize them for the synthesis of their hybrids with oxypro-

hepatic glucose production (metformin).⁴The current pharmaco-

panolamine moiety and evaluation of their antidiabetic and

antidyslipidemic activities in animal models, as well as their

logical option for the treatment of obesity is to increase energy

pharmacokinetic and pharmacodynamic properties.

expenditure (thermogenic drugs) by two major hormonal

eﬀectors: β-adrenergic agents and thyroid hormone.⁵In the

RESULTS AND DISCUSSION

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early 1980s, a third β-adrenoceptor (β₃-adrenoceptor) was dis-

Chemistry. The synthesis of 3-amino-2-hydroxypropoxy-

ﬂavones from hydroxylﬂavones is outlined in Scheme 1. The

hydroxylﬂavones were prepared by intramolecular cyclization of

o-hydroxyphenyl-β-diketone, and the latter were prepared from

o-hydroxyacetophenone and ethylbenzoate following the Cushman

and Nagarathnam procedure.¹¹Thus 2,4-dihydoxyaceto-

phenone (4) or 2,5-dihydroxyacetophenone (5) (utilized as

a template of ring A) was treated with an excess of lithium

covered in rodents. The stimulation of this was found to be

associated with marked weight loss as well as antidiabetic pro-

perties, mainly by increasing energy expenditure.^6,7The dual

actions of antiobesity and antidiabetic properties make such

agonists an attractive choice for the development of drugs with this

new mechanism.

Since the discovery of the thermogenic property of the β₃-

adrenergic stimulatory mechanism, several highly selective

noncatecholic agonists of dual actions, e.g., of phenethanol-

amine and phenoxypropanolamine series (Figure 1), were dis-

covered. These agents, however, failed in clinical trials mainly

Received: August 18, 2011

Published XXXX by the American Chemical

Society

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Figure 1. Some thermogenic activators in clinical trials.

a

Scheme 1. Representative Synthetic Route of 3-Amino-2-hydroxypropoxyﬂavones

a

Reagents and conditions: (a) LiHMDS, tetrahydrofuran (THF), −78 °C; (b) Dowex-H⁺, 2-propanol, reﬂux; (c) epichlorohydrin, NaH, DMF,

room temperature (r.t.) or K₂CO₃, 110 °C; (d) amine, methanol, reﬂux; (e) H₂−Pd/C, methanol.

bis(trimethylsilyl)amide (LiHMDS) at −78 °C to generate a

polylithiated anionic intermediate that reacted with ester 10 or

12−19, resulting in the intermediate β-diketones 32−41.¹²The

preparation of ethyl benzoates 16−19 having substitution in

the benzyloxy groups is given in Scheme 2. The additional

benzyl bromides 28−31 used in the protection of hydroxy

groups of ethyl-3,5-dihydroxybenzoate (11) were prepared

from the corresponding benzaldehydes. The β-diketones 32−

41 were cyclized to ﬂavones 42−51 using Dowex H⁺in iso-

propanol. The hydroxylﬂavones 42−47 on treatment with epi-

chlorohydrin in the presence of NaH in dry DMF yielded

epoxyﬂavones 52−57, and heating of ﬂavones 48−51 with epi-

chlorohydrin and anhydrous K₂CO₃in DMF aﬀorded

epoxyﬂavones 58−61. The resulting epoxyﬂavones 52−61 on

treatment with an appropriate amine under reﬂux yielded

desired compounds 62−85. The debenzylation of 62−64, 70,

and 71 was done with Pd−C under H₂atmosphere to obtain

ﬂavones 86−90.

Scheme 2. Representative Synthetic Route O-Benzylated

Benzoic Acid Esters

a

For the synthesis of optical enantiomers, a diﬀerent protocol

used in the synthesis of Atenolol starting with optically active

epichlorohydrin was followed.¹³7-Hydroxyﬂavone 46 was

heated at ∼120 °C with either R- or S-enantiomers of epi-

chlorohydrin to give chlorohydrin intermediates 91a and 91b,

which were then cyclized under basic conditions to provide

epoxyﬂavones 56a and 56b with inversion of stereochemistry

a

Reagents and conditions: (a) NaBH₄, methanol; (b) PBr₃, benzene,

80 °C; (c) K₂CO₃, acetone, NaI, 70 °C.

(Scheme 3). The optically active S- or R-isomer of epoxides

were reﬂuxed with suitable amines to give aminocarbinols 70a,

70b, 71a, and 71b, retaining the epoxide’s conﬁguration. The

B

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a

Scheme 3. Synthetic Route for Optical Enantiomers of 3-Amino-2-hydroxypropoxyﬂavones

a

Reagent and conditions: (a) R-epichlorohydrin or S-epichlorohydrin, 110 °C; (b) aq. NaOH, toluene, triethylbenzylammonium chloride; (c) tert-

butylamine or isopropylamine, methanol, reﬂux; (d) 10% Pd−C, H₂.

debenzylation of 71a and 71b was performed as in the case of

racemic compound to obtain compounds 90a and 90b. All the

puriﬁed optically active enantiomers were checked for their

purity on HPLC column.

Some of the compounds that had promising antihypergly-

cemic activity are 68, 70, 78, 81, 82, 85, and 90, which

exhibited sugar lowering to the extent of ∼17.4, 21.6, 23.2, 22.8,

26.2, 22.1, and 26.9%, respectively, at 5 h post-treatment with

the compounds and ∼19.1, 28.7, 17.2, 11.9, 17.9, 16.2, and

13.2%, respectively, at 24 h post treatment in STZ-S rat model.

The marked antihyperglycemic activity at 24 h in these diabetic

rats showed that these compounds are eﬃcient in the lowering

of blood glucose until 24 h. Compounds 63, 64, 65, 72, 83, and

84 exhibited a lowering of ∼11.8, 12.4, 13.8, 14.3, 12.2, and

14.2%, respectively, and thus had marked lowering of blood

glucose at 5 h but not at 24 h in the STZ-S rat model. The rest

of the compounds were less eﬃcient in the lowering of blood

glucose in the aforementioned model. Therefore, compounds

70, 78, 81, 82, 85, and 90 were identiﬁed as potent blood-

glucose-lowering agents in SLM as well as in STZ-S rat model.

From a structure−activity relationship (SAR) point of view,

these active compounds possess bulky lipophilic substitution on

the B ring of ﬂavones as indicated by 70 and 76−85 and no

bulky attachments at the nitrogen atom. The compounds with

tert-butyl- and isopropylamine functionality are superior in

activity. On the contrary, the molecules reported in the

literature (Figure 1) in general had bulky substitution at the

amino functionality. Further, the oxygen atoms at the 1,3-

positions in the B ring (compounds 70 and 90) seem necessary

because the compounds 86−88 with oxygen atoms at the 1,2-

positions exhibited inferior activity.

Biological Screening. The compounds synthesized above

were tested for their antihyperglycemic and antidyslipidemic

eﬀects. The antihyperglycemic activity was evaluated in arti-

ﬁcially enhanced blood glucose in albino rats called sucrose-

loaded model (SLM) followed by in sucrose-challenged

streptozotocin (STZ-S)-induced pancreatic β-cell damaged

diabetic rats and ﬁnally in C57BL/KsJ-db/db mice models.

These compounds were also simultaneously evaluated for anti-

dyslipidemic eﬀects in triton-induced dyslipidemic male Wistar,

rats and the activity of the best compounds was then conﬁrmed

in a high-fructose and -fat diet (HFD)-fed hamster model. The

ﬂavone derivatives 70, 90, and their enantiomers found to be

eﬀective in repetitive studies were followed for ED₅₀dose

estimation and pharmacokinetic behaviors.

The compounds 70, 72, 78, 81, 82, 84, 85, and 90 showed

∼29.4, 34.6, 39.1, 51.6, 32.0, 25.9, 32.7, and 29.0% anti-

hyperglycemic activity in SLM rat model, respectively, and

compounds 63, 64, 65, 68, 83, and 89 exhibited a moderate

activity of ∼15.9, 17.9, 23.9, 20.7, 15.7, and 19.1%, respectively.

The rest of the molecules were ineﬃcient in the lowering of

blood glucose in sucrose-loaded rats. These encouraging results

led us to further verify the results in a secondary antidiabetic

animal model of streptozotocin-induced diabetic rats.

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Table 1. 3-Amino-2-hydroxypropoxyﬂavones and Their Antidiabetic and Antidyslipidemic Activity

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Table 1. continued

a

b

SLM and STZ experiments were performed using rats of Wistar and Sprague−Dawley strains, respectively. Lipid-lowering experiments were

performed using Wistar strain of rats. Values are mean % change in 5 animals of a group; signiﬁcance: *p < 0.05 and **p < 0.01; ND = not done; Nil =

insigniﬁcant.

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Figure 2. Comparative eﬀects of metformin with compounds 70, 90, 87, and 71 as well as enantiomers 70a, 70b, 90a, and 90b on blood glucose

lowering in streptozotocin-induced diabetic rats: (a) after 5 h and (b) after 24 h. Values are mean % change in 5 animals of each group; signiﬁcance:

*p < 0.05 and **p < 0.01.

Figure 3. Comparative eﬀects of rosiglitazone, compounds 70 and 90, and their enantiomers on (a) lowering of glucose and (b) improvement of

glucose tolerance in OGTT in db/db mice. Values are mean % change in 5 animals of each group; signiﬁcance: *p < 0.05 and **p < 0.01.

These compounds were also evaluated for the antidyslipi-

demic activity in the triton-induced dyslipidemic rats, and

some of them showed promising activity. Compounds 67, 77,

78, 79, 81, 82, 85, 86, 87, and 90 showed a lowering of ∼28.0,

30.2, 28.2, 26.2, 25.6, 27.2, 26.0, 25.0, 25.0, and 32.0%,

respectively, in TG concentrations of ∼24.0, 12.1, 22.3, 13.5,

20.3, 16.5, 22.2, 24.0, 21.0, and 32%, respectively, in CHOL

levels of ∼26.0, 20.2, 12.6, 24.1, 26.5, 20.8, 11.8, 23.0, 23.0, and

28.0%, respectively, in phospholipid levels as compared to

control dyslipidemic rats. The rest of the compounds had rela-

tively low antidyslipidemic activity.

The compounds 67, 77, 79, 86, and 87 were identiﬁed as

potent antidyslipidemic agents, but these did not lower blood

glucose level either in SLM model or in STZ-S rat model. The

compounds 70, 78, 81, 82, 85, and 90 were identiﬁed as potent

antidyslipidemic as well as antihyperglycemic agents.

Antihyperglycemic Activity of Selected Compounds in STZ

Rats. Figure 2 shows the antihyperglycemic activity proﬁle of

some selected promising compounds 70, 70a, 70b, 90, 87, 71,

90a, and 90b on STZ-induced diabetic rats (Supporting

Information Tables 1, 5, and 10). Oral administration of

these samples at 100 mg/kg of body weight conferred signiﬁcant

inhibition on the blood glucose level in STZ-induced diabetic rats

after sucrose load of 2.5 g/kg of body weight as compared to

vehicle-treated control group. The decline in glucose (area

under curve, AUC) was seen at both 0−5 and 0−24 h after

drug administration. The compounds 70, 70a, 70b, 90, 87, 71,

90a, and 90b were found to exhibit a decline in glucose (AUC)

level ∼22.9, 25.0, 18.1, 22.2, 31.7, 22.1, 22.9, and 16.7%, res-

pectively, at 0−5 h, as compared to the vehicle-treated control

group, whereas the metformin at 100 mg/kg dose showed

∼20.5%. During 0−24 h, the decline was found to be ∼36.3,

36.9, 26.6, 32.1, 12.9, 11.1, 37.4, and 23.5%, respectively,

whereas metformin showed 27.8% decline as compared to the

vehicle-treated control.

Antihyperglycemic Activity in db/db Mice. The data so far

collected reveals that the compounds 70 and 90 exhibited

signiﬁcant and repeated activity and, therefore, were selected

for detailed study in db/db mice. The ﬂavone derivatives 70,

70a, 70b, 90, 90a, and 90b were chosen for detailed study and

were tested in hyperglycemic db/db mice at a lower dose of

25 mg/kg of body weight administered daily for 10 days. The

S-enantiomers 70a and 90a caused a more signiﬁcant decline

in the hyperglycemia by ∼55.4 and 45.6% compared to their

R-enantiomer, which declined the hyperglycemia by ∼34.1 and

28.2%, respectively, whereas the racemic compounds 70 and 90

caused a decline trend of the blood glucose by ∼38.3 and

39.5%, respectively, as compared to the vehicle-treated control

db/db mice (Figure 3a). The standard drug rosiglitazone caused

∼54.3% decline in hyperglycemia of db/db mice as compared to

the vehicle-treated control. Figure 3b shows the antihypergly-

cemic eﬀect of compounds 70, 70a, 70b, 90, 90a, and 90b on

oral glucose tolerance test (OGTT) in db/db mice after 10

consecutive days of treatment. The overnight-fasted db/db mice

were subjected to an oral glucose tolerance test post-3.0 g/kg of

body weight of oral glucose load. The fasting baseline blood

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Figure 4. Comparative eﬀects of standard drug rosiglitazone, compounds 70 and 90, and their enantiomers on (a) lowering of TG and total CHOL,

(b) increase of HDL-C levels in db/db mice, and (c) HDL-C/CHOL ratios in db/db mice. Values are mean % change in 5 animals of each group;

signiﬁcance: *p < 0.05 and **p < 0.01.

glucose values at 0 min were found to be lower in all the treated

groups as compared to the vehicle-treated control group at the

corresponding time. The treatment signiﬁcantly inhibited the

rise in postprandial blood glucose level of db/db mice after

glucose load of 3.0 g/kg of body weight. The treatment with S-

isomer 70a improved the oral glucose tolerance by ∼38.8%

whereas that with the R-isomer 70b showed improvement on

oral glucose by ∼33.3%, and the racemic compound 70 showed

improvement of glucose tolerance by ∼25.9% comparable to

rosiglitazone treatment, which showed improvement on oral

glucose by ∼49.5%. The treatment with 90a showed antihy-

perglycemic eﬀect by ∼29.7%, and that with 90b showed ∼22.4%

antihyperglycemic eﬀect. Racemic compound 90 showed ∼33.2%

antihyperglycemic eﬀect compared to the vehicle-treated db/db

mice.

Eﬀect on Lipid Proﬁle of db/db Mice. The eﬀects of 70, 70a,

70b, 90, 90a, and 90b on plasma lipid proﬁles in db/db mice

were also studied to see further beneﬁts of antidiabetic treat-

ment. Oral administrations of all six compounds at a dose of 25

mg/kg of body weight for the period of 10 consecutive days

signiﬁcantly lowered the plasma TG by ∼20.1, 27.4, 14.1, 14.2,

21.0, and 14.1%, respectively (Figure 4a), while total plasma

CHOL level was decreased by ∼22.3, 30.7, 15.9, 15.3, 27.0, and

11.2%, respectively, whereas the levels of HDL-C were en-

hanced by ∼20.9, 33.2, 8.30, 11.8, 23.1, and 3.59%, respectively

(Figure 4b). Compound 70a displayed better antidyslipidemic

activity as compared to compounds 70 and 70b. Similarly,

compound 90a displayed better antidyslipidemic activity as

compared to 90 and 90b. The antidyslipidemic activities of

these compounds were compared with standard drug rosiglita-

zone. Rosiglitazone also lowered the TG and total CHOL by

∼24.5 and 32.6%, respectively, and enhanced the HDL-C level by

∼6.98% as compared to the vehicle-treated control.

The rosiglitazone and test samples treatment also increased

the HDL-C to CHOL ratio by ∼108.7, 55.7, 92.5, 28.8, 32.1,

68.7, and 16.6%, respectively, as compared to the vehicle-

treated control (Figure 4c).

Eﬀect on Plasma Insulin Level & Body Weight of db/db Mice.

The eﬀect of compounds 70, 70a, 70b, 90, 90a, and 90b on

plasma insulin level in db/db mice after 10 consecutive days of treat-

ment was also studied. Repeated oral gavage of test samples at

an oral dose of 25 mg/kg of body weight caused a signiﬁcant

decrease in plasma insulin levels by ∼30.6, 53.4, 18.0, 22.3,

39.2, and 9.10%, respectively, compared to the vehicle-treated

control group, whereas rosiglitazone treatment declined the

hyperinsulinemia of db/db mice by ∼40.5% as compared to

control (Figure 5). Compound 70a decreased the insulin level

to a greater extent in comparison to the other test compounds

70 and 70b. Similarly, compound 90a displayed a much higher

decrease in plasma insulin level as compared to compounds 90

and 90b. Because these compounds do not increase plasma

insulin level, it therefore can be inferred that the compounds

improve the sensitivity of insulin, which, however, needs to be

further explored.

The eﬀect of these compounds on body weight was also

studied, and it has been observed that, in the db/db mice

treated with S-enantiomer 70a, there was a signiﬁcant decline

(28.2%) in the body weight when compared to the control,

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whereas compounds 70, 70b, 90, 90a, and 90b did not show

any signiﬁcant change in body weight. In the same set of ex-

periments, rosiglitazone led to an increase in the body weight

by 18.3% as compared to control.

developing insulin resistance and type 2 diabetes. Our results

are in accord with previous reports that HFD-fed hamsters

shared some common features of type 2 diabetes, that is,

obesity, dyslipidemia, and usually hypertension. In the present

study, experiments were carried out to investigate the

antidyslipidemic eﬀects of ﬂavone derivatives in the HFD-fed

dyslipidemic hamster model. Feeding of high-fructose diet to

these hamsters caused an alteration of the plasma lipid proﬁle

(Supporting Information Tables 11, 12, and 13). Figure 7

Figure 5. Comparative eﬀects of rosiglitazone, compounds 70 and 90,

and their enantiomers on the lowering of plasma insulin levels in db/db

mice. Values are mean % change in 5 animals of each group; signiﬁcance:

*p < 0.05 and **p < 0.01.

Figure 7. Antidyslipidemic activity proﬁle of 70 and 90. Data is given

as % change with reference to HFD control of six hamsters per group.

Signiﬁcance: ***p < 0.001, **p < 0.01, *p < 0.05 as compared to

HFD control.

Dose-Dependent Antidiabetic Activity of 70a and 90a in

db/db Mice. The S-enantiomers 70a and 90a were also

evaluated to ascertain the lowest dose required for antidiabetic

activity in db/db mice. Figure 6a shows the eﬀects at doses of 1,

3, 10, 25, and 100 mg/kg on oral glucose tolerance in

overnight-fasted db/db mice. After 2 h post-administration of

compound 70a, it exhibited ∼21.5, 35.1, 39.9, 44.6, and 59.4%

improvement in glucose tolerance 0−2 h (AUC), respectively,

whereas compound 90a had ∼12.0, 19.7, 30.7, 41.1, and 49.2%

improvement in glucose tolerance 0−2 h (AUC), respectively.

Figure 6b shows the eﬀect of compounds 70a and 90a on

postprandial blood glucose proﬁle at doses of 1, 3, 10, 25, and

50 mg/kg after 10 consecutive days of treatment. It was evident

that the average decline on postprandial blood glucose was

∼14.8, 22.1, 28.8, 38.3, 39.1% for compound 70a whereas it

was ∼12.1, 27.1, 31.2, 31.6, and 35.4% for 90a, respectively. On

the basis of these data, the ED₅₀of compound 70a was

estimated to be ∼1.72 mg/kg.

presents the antidyslipidemic proﬁle of ﬂavone derivatives 70

and 90 at the dose of 100 mg/kg in HFD-fed Syrian golden

hamsters. Compounds 70 and 90 caused signiﬁcant lowering of

TG level by ∼61.5 and 48.9%, CHOL level by ∼22.9 and

13.8%, and LDL-C concentration by ∼61.9 and 47.7%,

respectively. Compounds 70 and 90 also displayed a marked

elevation of ∼20.0 and 14.9%, respectively, in the level of HDL-

C, i.e., good cholesterol, which is beneﬁcial and desirable. The

antidyslipidemic proﬁles of compounds 70 and 90 were

compared to the standard lipid-lowering drug fenoﬁbrate at

the same doses, which caused ∼53.4% lowering in TG con-

centration, ∼16.8% lowering in cholesterol level, and ∼56.3%

lowering in low-density lipoprotein level. Fenoﬁbrate treatment

also caused ∼16.2% increase in the HDL-C level. The com-

pounds 70, 90, and fenoﬁbrate treatment also caused lowering

in the body weight, but the eﬀect of 70 was found to be greater

as compared to 90 and fenoﬁbrate. The antidyslipidemic activity

found after treatment with 70 was more promising than that with

ﬂavone 90 or the standard drug fenoﬁbrate (Figure 7). Therefore,

Antidyslipidemic Proﬁle of Compounds 70, 70a, 70b, and

90 in Hamsters. Obesity is associated with an increased risk of

Figure 6. Dose-dependent (a) glucose tolerance in OGTT and (b) lowering of postprandial glucose by 70a and 90a in db/db mice. Values are mean

% change in 5 animals of a group; signiﬁcance: *p < 0.05 and **p < 0.01.

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they were selected for further study in HFD-fed hamsters along

with optical enantiomers 70a and 70b at the dose of 25 mg/kg.

The antidyslipidemic activities of compounds 70a and 70b

were compared with that of standard drug fenoﬁbrate at the

same doses, i.e., 25 mg/kg (Figure 8). The compounds 70, 70a,

of 10, 30, and 100 mg/kg) exhibited a dose-dependent eﬀect.

Compound 70a at 10 mg/kg dose lowered the TG, CHOL,

LDL-C, glycerol, and nonesteriﬁed free fatty acid (NEFA)

levels and was calculated to be ∼21.2, 13.8, 21.1, 14.4, and

13.1%, respectively. Elevation of ∼9.37% in HDL-C and ∼13.2%

increase in lipoprotein lipase activity were observed at this dose.

After 7 days after treatment of 70a at 30 mg/kg, there was a

marked decrease in the TG (39.8%), CHOL (27.2%), LDL-C

(34.6%), glycerol (25.7%), and NEFA levels (26.3%). An increase

in the HDL-C level (21.0%) and an elevation in the lipoprotein

lipase (LPL) activity were observed as compared to HFD control

(31.2%). The compound 70a at 100 mg/kg showed a sharp

decrease in the TG (76.3%), CHOL (50.7%), LDL-C (68.4%),

glycerol (50.5%), and NEFA levels (59.1%). A marked increase in

HDL-C level (27.9%) and a marked elevation in LPL activity

(69.7%) were observed as compared to HFD control. The standard

drug fenoﬁbrate treatment at the dose of 30 mg/kg showed a

reduction in TG (30.2%), CHOL (18.5%), LDL-C (32.3%),

glycerol (22.1%), and NEFA levels (22.2%). Increases in HDL-C

(9.68%) and LPL activity (24.7%) were also observed after

treatment of fenoﬁbrate. The interesting feature of com-

pound 70a was an increase in the level of good cholesterol,

i.e., HDL-C. HFD-fed hamsters showed a decrease of LPL

activity. Treatment with compound 70a caused an increase of

LPL activity.

Figure 8. Antidyslipidemic activity of 70, 70a, and 70b. Data is given

as % change with reference to HFD control of six hamsters per group.

Signiﬁcance: ***p < 0.001, **p < 0.01, *p < 0.05 as compared to

HFD control.

and 70b showed triglyceride-lowering activity of ∼22.2, 34.7,

and 8.40%, respectively. These compounds also caused

lowering of ∼15.3, 24.4, and 5.52%, respectively, in CHOL

level and lowering of ∼23.3, 30.1, and 9.78%, respectively, in

LDL-C on post-treatment with 70, 70a, and 70b. The

treatment with these compounds also caused an increase in

the HDL-C level, which was calculated to be ∼13.3, 20.5, and

7.08%, respectively. The lipid-lowering activity of the

fenoﬁbrate was found to be ∼25.5, 17.5, and 26.8% lowering

in triglyceride, cholesterol, and LDL-C levels at the same dose.

Fenoﬁbrate treatment also caused elevation in HDL-C level of

∼11.2%. These enantiomers and fenoﬁbrate showed body-

weight-reducing activity, which was found to be ∼8.89, 14.3,

3.73, and 6.78% after treatment, respectively.

Compound 70a exhibited antidyslipidemic property in a

similar manner as fenoﬁbrate. Fenoﬁbrate treatment at the

same dose signiﬁcantly lowered the level of TG and LDL-C and

also resulted in an increase of LPL activity.

The epidemiological studies suggest that the consumption of

HFD is linked with obesity, which in turn causes development

of hyperinsulinemia resulting in type 2 diabetes. The reversal of

dyslipidemia and eﬀect on body weight was therefore studied in

a hamster model with compound 70a at diﬀerent doses (Figure 10).

It was clear from Figure 8 that 70a showed better anti-

dyslipidemic activity than 70, 70b, and fenoﬁbrate at the dose

of 25 mg/kg. Finally, compound 70a was followed for the dose-

dependent study in HFD-fed dyslipidemic hamsters and was

found to correct dyslipidemia in a dose-dependent manner. It

was evident from Figure 9 that the compound 70a (at the doses

Figure 10. Dose-dependent body-weight-reducing activity of 70a in

HFD-fed dyslipidemic golden hamsters.

Compound 70a displayed ∼7.38, 10.2, and 12.5% reduction in

body weight of the treated hamsters at 10, 30, and 100 mg/kg

doses, respectively, whereas fenoﬁbrate displayed 10.2%

reduction in body weight at 30 mg/kg dose after 7 days of

treatment.

Pharmacokinetic Study of Compounds 70, 70a, and 90a.

The pharmacokinetic parameters were evaluated from plasma

concentration−time proﬁle in Sprague−Dawley male rats (Table 2).¹⁴

After oral dose administration of compounds 70, 70a, and 90a,

the elimination half-lives (t_1/2) were found to be 19.56, 19.83,

and 3.97 h, respectively. The plasma clearances (Cl) of these

compounds were found to be 3.42, 3.75, and 3.27 L/h/kg,

Figure 9. Dose-dependent antidyslipidemic proﬁle of 70a. Data is

given as % change with reference to HFD control of six hamsters per

group. Signiﬁcance: ***p < 0.001, **p < 0.01, *p < 0.05 as compared

to HFD control.

I

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a

Table 2. Pharmacokinetic Parameter Studies on Compounds 70, 70a, and 90a

compd.

route

oral

C_max(ng/mL)

T_max(h)

Cl (L/h/kg)

MRT (h)

V_d(L/kg)

AUC (ngh/ml)

t_1/2(h)

bioavailability (%)

29.48

70

60.93

998.21

70.30

8.00

3.42

3.65

3.75

3.72

3.27

3.30

43.20

22.77

30.26

13.50

5.96

96.73

69.41

107.41

50.26

16.18

16.20

3469.28

2717.5

1798.22

666.00

39.50

19.56

16.30

19.83

10.10

3.39

70

intravenous

oral

70a

90a

8.00

0.33

27.00

0.52

intravenous

oral

523.00

21.17

intravenous

1813.00

4.90

756.00

4.83

(200 MHz, CDCl₃): δ 7.30 (s, 2H, arom. −CH), 4.38 (q, J = 7.1 Hz,

2H, −OCH₂), 3.91 (s, 9H, −OCH₃), 1.40 (t, J = 7.1 Hz, 3H, −CH₃).

Ethyl-3,5-dihydroxybenzoate (11). Yield 75%; mp 128−130 °C;

MS (FAB): 183 (M + 1); IR (KBr): 3496, 1819, 1687 cm⁻¹; ¹H NMR

(200 MHz, DMSO-d₆): δ 9.89 (s, 2H, −OH), 7.06 (d, J = 2.2 Hz, 2H,

arom. −CH), 6.69 (t, J = 2.2 Hz, 1H, arom. −CH), 4.48 (q, J = 7.1 Hz,

2H, −OCH₂), 1.52 (t, J = 7.1 Hz, 3H, −CH₃).

respectively. The oral bioavailabilities of compounds 70, 70a,

and 90a on these parameters were estimated to be ∼29.48,

27.00, and 0.52%, respectively, in accordance with their dose-

normalized AUC. After oral dosing of both racemic com-

pound 70 and its S-enantiomer 70a, it appears that the

absorption was slow as plasma concentrations peaked at 8 h

after dose. Multiple peaks were observed in plasma concentration−

time proﬁle after oral dose. It may be due to enterohepatic

recycling, selective and diﬀerential absorption from the gastro-

intestinal tract, formation of depot on the intestinal wall, and

variation in gastrointestinal motility. The higher values of MRT

and elimination half-life (t_1/2) after oral and intravenous doses

indicate that compound 70 was retained for longer periods of

time and had slow elimination from the body. The oral

bioavailability of both racemic compound 70 and its S-enantiomer

70a were nearly similar with values of ∼29.48 and 27.0%,

respectively.

Ethyl-3,4-dimethoxybenzoate (13). Dimethylsulfate (16.4 mL,

130 mmol) and 20% NaOH (in excess) were added dropwise to a

solution of 3,4-dihydroxybenzoic acid (6, 20.0 g, 130 mmol) in ethanol

(250 mL) over a period of 3 h, and the reaction mixture was further

stirred at room temperature for 3 h. During this process, esteriﬁcation

also occurred due to the acid generated in situ from dimethyl sulfate.

The solvent was removed, and the residue was taken in water and

extracted with ether. The combined ethereal layers were washed with

saturated NaHCO₃solution, dried (Na₂SO₄), and ﬁltered, and the

solvent was removed to aﬀord the required product ethyl-3,4-

dimethoxybenzoate (7). Yield 24.5 g (90%); oil; MS (FAB): 211

(M + 1); IR (KBr): 1974, 1712 cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ

7.68 (d, J = 8.4 Hz, 1H, arom. −CH), 7.55 (s, 1H, arom. −CH), 6.88

(d, J = 8.4 Hz, 1H, arom. −CH), 4.36 (q, J = 7.1 Hz, 2H, −OCH₂),

3.93 (s, 3H, −OCH₃), 3.89 (s, 3H, −OCH₃), 1.39 (t, J = 7.1 Hz, 3H,

−CH₃).

CONCLUSION

■

Thus, these ﬂavones show signiﬁcant antihyperglycemic as well

as antidyslipidemic eﬀects and possess hyperinsulinemia

reversal activity with moderate reduction in body weight, with

the S-enantiomer of both compounds being the most active.

The ﬂavonoid derivatives 70 and 90 thus oﬀer promising leads

to develop as drug molecules for the management of type 2

diabetes.

Ethyl-3,5-dimethoxybenzoate (15). Yield 94%; oil; MS (FAB):

1

211 (M + 1); IR (KBr): 1970, 1716 cm⁻¹; H NMR (200 MHz,

CDCl₃): δ 7.18 (d, J = 2.3 Hz, 2H, arom. −CH), 6.64 (d, J = 2.3 Hz,

1H, arom. −CH), 4.36 (q, J = 7.1 Hz, 2H, −OCH₂), 3.82 (s, 6H,

−OCH₃), 1.39 (t, J = 7.1 Hz, 3H, −CH₃).

Typical Procedure for Benzylation of Hydroxy Ethyl

Benzoates. Ethyl-3,5-dibenzyloxybenzoate (14). To a solution

of ethyl-3,5-dihydroxybenzoate (11, 16.8 g, 92 mmol) in dry

acetone (350 mL) were added K₂CO₃(27.6 g, 200 mmol) and

benzyl bromide (23.8 mL, 200 mmol), and the reaction mixture

was stirred at room temperature for ∼9 h. On completion of

the reaction, it was ﬁltered. The excess reagent and solvent

were removed to get the crude product 14, which was puriﬁed

by column chromatography. Yield 74%; mp 63−65 °C; MS

EXPERIMENTAL SECTION

■

¹H NMR spectra were recorded at 200 or 300 MHz as mentioned

using Perkin-Elmer DPX 200 MHz or Bruker Avance DRX-300

spectrometer. Chemical shifts (δ) are quoted in ppm, referenced

internally to CDCl₃at 77.0 ppm. All coupling constants (J) are given

in Hz. Low- and high-resolution electrospray ionization (ESI) MS was

carried out using a Bruker (U.S.A.) Daltronics BioApex II with a 7T

superconducting magnet and an analytical ESI source. The purity of

the compounds is veriﬁed by the HPLC performed on Chira Sphere

NT (250 mm × 0.4 mm, 5 μm, Merck) column using a solvent

mixture of hexane/isopropanol/methanol/ammonia (in a ratio of

60:40:5:0.5 mL) at the ﬂow rate of 2 mL/min and a peak detection at

240 nm under UV.

1

(FAB): 363 (M + 1); IR (KBr): 1824, 1708 cm⁻¹; H NMR

(200 MHz, CDCl₃): δ 7.34−7.35 (m, 10H, −Ph), 7.30 (d, J =

2.3 Hz, 2H, arom. −CH), 6.79 (t, J = 2.2 Hz, 1H, arom. −CH),

5.07 (s, 4H, −OCH₂), 4.36 (q, J = 7.1 Hz, 2H, −OCH₂), 1.38

(t, J = 7.1 Hz, 3H, −CH₃).

Ethyl-3,4-dibenzyloxybenzoate (12). Yield 76%; mp 68−69 °C;

MS (FAB): 363 (M + 1); IR (KBr): 1889, 1707 cm⁻¹; ¹H NMR (200

MHz, CDCl₃): δ 7.65 (s, 1H, arom. −CH), 7.63 (dd, J = 8.7 Hz, 1.7

Hz, 1H, arom. −CH), 7.48−7.25 (m, 10H, −Ph), 6.91 (d, J = 8.3 Hz,

1H, arom. −CH), 5.19 (s, 2H, −OCH₂), 5.18 (s, 2H, −OCH₂), 4.31

(q, J = 7.1 Hz, 2H, −OCH₂), 1.35 (t, J = 7.1 Hz, 3H, −CH₃).

General Procedure to Prepare Substituted Benzyloxyethyl

Benzoates 16−19. In an ice-cooled solution of substituted

benzaldehydes 20−23 (10 mmol) in dry methanol (100 mL), pellets

of sodium borohydride (20 mmol) were added under stirring at room

temperature for 2−6 h. On completion of the reaction, the solvent was

removed followed by the addition of water to precipitate the crude

products, which were ﬁltered, washed, and dried. The resulting benzyl

alcohols 24−27 (5 mmol) were taken in benzene and cooled in ice

water followed by the addition of PBr₃(6 mmol). The reaction

mixture was then reﬂuxed for 6−10 h. On completion of the reaction,

it was decomposed by slow addition of water and extracted with

General Procedure for Esteriﬁcation. Concentrated sulphuric

acid (2−3 mL) was added dropwise to a solution of required benzoic

acid (6−8, 123 mmol) in absolute ethanol (250 mL), and the reaction

mixture was reﬂuxed for ∼8 h. Solvent was removed and the residue

was taken up in water and extracted with diethyl ether. The combined

ethereal layers were washed with NaHCO₃solution, water, and brine.

It was dried over Na₂SO₄and ﬁltered, and the solvent was removed to

get ethyl benzoates 9−11, which crystallized to get puriﬁed esters.

Ethyl-3,4-dihydroxybenzoate (9). Yield 82%; mp 133−134 °C;

1

MS (FAB): 183 (M+1); IR (KBr): 3498, 3471, 1819, 1685 cm⁻¹; H

NMR (200 MHz, DMSO-d₆): δ 7.20 (d, J = 1.9 Hz, 1H, arom. −CH),

7.15 (dd, J = 8.2 Hz, 2.0 Hz, 1H, arom. −CH), 6.65 (d, J = 8.2 Hz, 1H,

arom. −CH), 4.04 (q, J = 7.1 Hz, 2H, −OCH₂), 1.09 (t, J = 7.1 Hz,

3H, −CH₃).

Ethyl-3,4,5-trimethoxybenzoate (10). Yield 75%; mp 56−57 °C;

1

MS (FAB): 241 (M + 1); IR (KBr): 1967, 1708 cm⁻¹; H NMR

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Journal of Medicinal Chemistry

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benzene. The organic layer was dried (Na₂SO₄) and the solvent was

removed to obtain the crude products 28−31.

(d, J = 8.5 Hz, 1H, H-5), 6.97 (dd, J = 8.5 Hz, 1.7 Hz, 1H, H-2′), 6.83

(d, J = 1.7 Hz, 1H, H-6′), 6.43 (d, J = 8.5 Hz, 1H, H-6), 6.34 (s, 1H,

H-8), 6.30 (dd, J = 9.7 Hz, 2.0 Hz, 1H, H-5′), 6.08 (s, 1H, H-3), 3.35

(s, 3H, −OCH₃), 3.32 (s, 3H, −OCH₃).

In an ice-cooled solution of 3,5-dihydroxybenzoic acid (8, 10 mmol)

in absolute ethanol, thionyl chloride (15 mmol) was added dropwise

under stirring. On completion of the reaction, the solvent was re-

moved followed by extraction with chloroform, dried (Na₂SO₄), and

concentrated to obtain crude product 11. The resulting ethyl-3,5-

dihydroxybenzoate (11, 10 mmol) in dry acetone, anhydrous K₂CO₃

(30 mmol), substituted benzyl bromide 28−31 (22 mmol) prepared

above, and sodium iodide (2 mmol) was reﬂuxed for 4−6 h. On

completion of the reaction, K₂CO₃was ﬁltered, and the solvent was

removed. The residue was taken in chloroform, washed with water,

and dried (Na₂SO₄), and the solvent was removed to get crude

products, which were puriﬁed by column chromatography on silica gel.

Ethyl-3,5-bis(2-chlorobenzyloxy)benzoate (16). Yield 52%;

mp 65 °C; ES-MS: 432 (M + 1); C₂₅H₂₆O₄; FT-IR(KBr): 1698, 1600,

7-Hydroxy-3′,4′,5′-trimethoxyﬂavone (45). Yield 82%; mp 284−

1

286 °C; MS (FAB): 329 (M + 1); IR (KBr): 3408, 1630 cm⁻¹; H

NMR (200 MHz, DMSO-d₆): δ 7.86 (d, J = 8.7 Hz, 1H, H-5), 7.29 (s,

2H, H-2′ and H-6′), 7.03 (d, J = 1.8 Hz, 1H, H-8), 6.96 (s, 1H, H-3),

6.92 (d, J = 8.9 Hz, 1H, H-6), 3.89 (s, 6H, −OCH₃), 3.79 (s, 3H,

−OCH₃).

3′,5′-Dibenzyloxy-7-hydroxyﬂavone (46). Yield 81%; mp 248−

249 °C; MS (FAB): 451 (M + 1); IR (KBr): 3452, 1620 cm⁻¹;

¹H NMR (200 MHz, DMSO-d₆): δ 7.84 (d, J = 8.7 Hz, 1H, H-5),

7.52−7.28 (m, 10H, −Ph), 7.23 (d, J = 1.9 Hz, 2H, H-2′, and H-6′),

6.98 (d, J = 2.0 Hz, 1H, H-8), 6.89 (s, 1H, H-3), 6.89 (dd, J = 8.6 Hz,

2.1 Hz, 1H, H-6), 6.82 (s, 1H, H-4′), 5.14 (s, 4H, −OCH₂).

3′,5′-Dimethoxy-7-hydroxyﬂavone (47). Yield 59%; mp 267−

268 °C; MS (FAB): 299 (M + 1); IR (KBr): 3405, 1602 cm⁻¹; ¹H NMR

(200 MHz, DMSO-d₆): δ 10.82 (s, 1H, −OH), 7.89 (d, J = 8.7 Hz,

1H, H-5), 7.17 (d, J = 2.0 Hz, 2H, H-2′, and H-6′), 7.03 (d, J = 1.9 Hz,

1H, H-8), 6.95 (s, 1H, H-3), 6.94 (dd, J = 7.2 Hz, 2.0 Hz, 1H, H-6),

6.71 (s, 1H, H-4′), 3.85 (s, 6H, OCH₃).

1

1452 cm⁻¹; H NMR (200 MHz, CDCl₃): δ 7.54 (m, 2H, arom. −CH);

7.38 (m, 8H, arom. −CH); 6.82 (d, 1H, J = 2.2 Hz, arom. −CH); 5.16

(s, 4H, −OCH₂); 4.35 (q, 2H, −OCH₂); 1.39 (t, 3H, −CH₃).

Ethyl-3,5-bis(2-methylbenzyloxy)benzoate (17). Yield 51%; mp

77 °C; ES-MS: 391 (M + 1), C₂₅H₂₆O₄; FT-IR(KBr): 1711, 1600, 1445 cm⁻¹;

¹H NMR (300 MHz, CDCl₃): δ 7.27 (d, 2H, J = 2.2 Hz, arom. −CH);

7.24 (m, 6H, arom. −CH); 6.85 (d, 1H, J = 2.2 Hz, arom. −CH);

5.08 (s, 4H, −OCH₂); 4.40 (q, 2H, J = 6.9 Hz, −OCH₂); 2.41 (s, 6H,

−CH₃); 1.43 (t, 3H, J = 6.7 Hz, −CH₃).

3′, 5′-bis(2″-Chlorobenzyloxy)-7-hydroxyﬂavone (48). Yield 81%;

mp 176 °C; ESMS: 519 (M + 1); 521 (M + 3); ¹H NMR (200 MHz,

CDCl₃): δ 8.01 (d, 1H, J = 8.4 Hz, H-5); 7.41 (s, 1H); 7.56 (m, 6H,);

7.33 (d, 1H, J = 4.4 Hz); 7.15 (s, 1H); 6.91 (d, 2H); 6.78 (s; 1H,

H-6′); 6.68 (s, 1H, H-3); 6.35 (d, 1H, J = 4.4 Hz, H-4′); 5.23 (s, 4H,

−OCH₂).

Ethyl-3,5-bis(4-methylbenzyloxy)benzoate (18). Yield 58%; mp

1

85 °C; ESMS: 391(M + 1); H NMR (300 MHz, CDCl₃): δ 7.20−

7.32 (m, 10H, arom. −CH); 6.77 (d, 1H, J = 2.2 Hz, arom. −CH);

5.01 (s, 4H, −OCH₂); 4.34 (q, 2H, J = 6.9 Hz, −OCH₂); 1.37 (t, 3H,

−CH₃); 2.35 (s, 6H, −CH₃).

3′,5′-bis(2″-Methylbenzyloxy)-7-hydroxyﬂavone (49). Yield 71%;

1

mp 195 °C; ES-MS: 479 (M + 1); H NMR (200 MHz, CDCl₃): δ

8.05 (d, J = 8.4 Hz, 1H, H-5′); 7.43 (m, 6H, −Ph, H-2′, and H-6′); 6.95

(s, 1H, H-6); 7.16 (s, 4H, −Ph); 6.69 (s, 1H, H-4′); 5.09 (s, 4H,

−OCH₂); 2.73 (s, 6H, −CH₃).

Ethyl-3,5-bis(3,5-dichlorobenzyloxy)benzoate (19). Yield 61%; mp

115 °C; ESMS: 501(M + 1), ¹H NMR (200 MHz, CDCl₃): δ 7.53 (d,

2H, J = 1.8. Hz, arom. −CH); 7.47 (s, 1H, arom. −CH); 7.43 (s, 1H,

arom. −CH); 7.23(d, 4H, J = 2.1 Hz, arom. −CH); 6.70 (s, 1H, arom.

−CH); 5.02 (s, 4H, −OCH₂); 4.38 (q, 2H, −OCH₂); 1.44 (t, 3H,

−CH₃).

3′,5′-bis(4″-Methylbenzyloxy)-7-hydroxyﬂavone (50). Yield 74%;

1

mp 205 °C; ES-MS: 479 (M + 1); H NMR (200 MHz, CDCl₃): δ

8.04 (d, J = 4.5 Hz, 1H, H-5); 7.23−7.39 (m, 9H); 7.19 (m, 4H); 7.01

(d, J = 1.9 Hz, 2H, −CH); 6.93 (m, 2H); 6.77 (m, 1H); 6.66 (s, 1H,

H-3); 5.06 (s, 4H, −OCH₂); 2.37 (s, 6H, −CH₃).

Typical Procedure for the Preparation of 6- or 7-

Hydroxyﬂavones 42−51. A solution of LiHMDS (20% in THF,

217.5 mL, 260 mmol) was added dropwise to a well-stirred and cooled

(at −78 °C) solution of 2,4-dihydroxyacetophenone (4) or 2,5-

dihydroxyacetophenone (5, 9.88 g, 65 mmol) in THF (150 mL)

during ∼30 min under nitrogen atmosphere. The reaction mixture was

stirred for 1 h at this temperature and subsequently at −30 °C for 2 h.

It was again cooled to −78 °C, and a solution of ethyl benzoates (10

or 12−19, 65 mmol) in THF (100 mL) was added over a period of 30

min. It was further stirred at room temperature overnight and poured

into ice water containing hydrochloric acid. It was extracted with

chloroform, dried (Na₂SO₄), and ﬁltered, and the solvent was removed

to aﬀord β-diketone intermediates 32−41. The residue was reﬂuxed

with Dowex-H⁺(8 g) in 2-propanol for 3−4 h. The solvent was

removed under reduced pressure, and the residue was suspended in

hot DMF to dissolve the product. Dowex-H⁺was ﬁltered, the solvent

was removed, and the solid product was washed with cold MeOH (3 ×

200 mL) to aﬀord ﬂavones 42−51.

3′,4′-Dibenzyloxy-6-hydroxyﬂavone (42). Yield 44%; mp 196−

197 °C; MS (FAB): 451 (M + 1); IR (KBr): 3419, 1621 cm⁻¹; ¹H NMR

(200 MHz, DMSO-d₆): δ 10.08 (s, 1H, −OH), 7.75 (s, 1H, H-8), 7.69

(d, J = 8.7 Hz, 1H, H-7), 7.63 (s, 1H, H-3), 7.55−7.22 (m, 13H, H-2′,

H-5′, H-5, and -Ph), 6.94 (s, 1H, H-6′), 5.30 (s, 2H, −OCH₂), 5.27 (s, 2H,

−OCH₂).

3′,4′-Dibenzyloxy-7-hydroxyﬂavone (43). Yield 24 g (89%); mp

245−247 °C; MS (FAB): 451 (M + 1); IR (KBr): 3426, 1607 cm⁻¹;

¹H NMR (200 MHz, DMSO-d₆): δ 10.79 (s, 1H, −OH), 7.86 (d, J =

3′,5′-bis(3″,5″-Dichlorobenzyloxy)-7-hydroxyﬂavone (51). Yield

55%; mp 225 °C; ES-MS: 589 (M + 1); ¹H NMR (300 MHz, CDCl₃):

δ 8.01 (d, J = 8.1 Hz, 1H, H-5); 7.40 (m, 4H, −Ph); 7.18 (m, 6H,

−Ph); 6.72 (m, 2H, H-4′, and H-8); 6.37 (m, 1H, H-6); 6.28 (s, 1H,

H-3); 5.01 (s, 4H, −OCH₂).

Typical Procedure for 6- or 7-(2,3-Epoxypropoxy)ﬂavones.

To a well-stirred solution of 7-hydroxyﬂavone 42−47 (17.8 mmol) in

dry DMF (200 mL), NaH (50%, 125 mmol) was added at 0−5 °C,

and after 30 min of stirring an excess of epichlorohydrin (107 mmol)

was added and the solution was again stirred at room temperature

overnight. The reaction mixture was concentrated under reduced

pressure, diluted with water, and extracted with chloroform. The

combined organic layers were dried (Na₂SO₄), ﬁltered, and evaporated

to dryness. The crude products 52−57 were puriﬁed by column

chromatography over silica gel (100−200 mesh).

3′,4′-Dibenzyloxy-6-(2,3-epoxypropoxy)ﬂavone (52). Yield 81%;

mp 147−149 °C; MS (FAB): 507 (M + 1); IR (KBr): 1610 cm⁻¹; ¹H

NMR (200 MHz, CDCl₃): δ 7.57−7.29 (m, 15H, arom. −CH), 7.02

(d, J = 8.6 Hz, 1H, H-4′), 6.66 (s, 1H, H-3), 5.25 (s, 4H, −OCH₂),

4.39 (dd, J = 11.0 Hz, 2.6 Hz, 1H, −OCH₂), 3.98 (dd, J = 11.0 Hz,

6.0 Hz, 1H, −OCH₂), 3.40−3.39 (m, 1H, −OCH), 2.93 (t, J = 4.5 Hz,

4.5 Hz, 1H, −OCH₂), 2.78 (dd, J = 4.8 Hz, 2.6 Hz, 1H, −OCH₂).

3′,4′-Dibenzyloxy-7-(2,3-epoxypropoxy)ﬂavone (53). Yield 86%;

mp 168−170 °C; MS (FAB): 507 (M + 1); IR (KBr): 1639 cm⁻¹; ¹H

NMR (200 MHz, CDCl₃): δ 8.12 (d, J = 8.7 Hz, 1H, H-5), 7.50−7.32

(m, 12H, arom. −CH), 7.04−6.93 (m, 3H, H-2′, H-6′, and H-3), 6.61

(s, 1H, H-4′), 5.24 (s, 4H, −OCH₂), 4.38 (dd, J = 11.1 Hz, 2.9 Hz, 1H,

−OCH₂), 4.05 (dd, J = 11.1 Hz, 5.8 Hz, 1H, −OCH₂), 3.42−3.40 (m,

1H, −OCH), 2.96 (t, J = 4.5 Hz, 4.5 Hz, 1H, −OCH₂), 2.80 (dd, J =

4.8 Hz, 2.6 Hz, 1H, −OCH₂).

8.6 Hz, 1H, H-5), 7.68 (s, 1H, C-2′), 7.60 (d, J = 8.8 Hz, 1H, C-6′),

7.51−7.30 (m, 10H, −Ph), 7.18 (d, J = 8.5 Hz, 1H, H-6), 6.98 (s, 1H,

C-6), 6.91 (d, J = 8.8 Hz, 1H, C-8), 6.83 (s, 1H, H-3), 5.26 (s, 2H,

−OCH₂), 5.21 (s, 2H, −OCH₂).

3′,4′-Dimethoxy-7-hydroxyﬂavone (44). Yield 52%; mp 263−

265 °C; MS (FAB): 299 (M + 1); IR (KBr): 3452, 1625 cm⁻¹;

¹H NMR (200 MHz, CDCl₃+ DMSO-d₆): δ 9.83 (s, 1H, −OH), 7.32

3′,4′-Dimethoxy-7-(2,3-epoxypropoxy)ﬂavone (54). Yield 74%;

mp 148−149 °C; MS (FAB): 355 (M + 1); IR (KBr): 1632 cm⁻¹; ¹H

K

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NMR (200 MHz, CDCl₃): δ 8.13 (d, J = 9.5 Hz, 1H, H-5), 7.73 (dd,

J = 8.5 Hz, 2.0 Hz, 1H, H-8), 7.35 (d, J = 1.9 Hz, 1H, H-6), 7.00 (dd,

J = 7.1 Hz, 2.3 Hz, 1H, H-2′), 6.99 (d, J = 2.2 Hz, 1H, H-6′), 6.97

(d, J = 8.5 Hz, 1H, H-5′), 6.68 (s, 1H, H-3), 4.39 (dd, J = 11.1 Hz,

2.9 Hz, 1H, −OCH₂), 4.05 (dd, J = 11.1 Hz, 5.8 Hz, 1H, −OCH₂),

3.98 (s, 3H, −OCH₃), 3.96 (s, 3H, −OCH₃), 3.44−3.40 (m, 1H,

−OCH), 2.96 (t, J = 4.5 Hz, 4.5 Hz, 1H, −OCH₂), 2.81 (dd, J = 4.8

Hz, 2.6 Hz, 1H, −OCH₂).

7-(2,3-Epoxypropoxy)-3′,4′,5′-trimethoxyﬂavone (55). Yield 83%;

mp 187−188 °C; MS (FAB): 385 (M + 1); IR (KBr): 1651 cm⁻¹; ¹H

NMR (200 MHz, CDCl₃): δ 8.14 (d, J = 9.3 Hz, 1H, H-5), 7.10 (s,

2H, H-2′, and H-6′), 7.02 (d, J = 7.6 Hz, 1H, H-8), 7.00 (s, 1H, H-6),

6.70 (s, 1H, H-3), 4.39 (dd, J = 11.0 Hz, 2.8 Hz, 1H, −OCH₂), 3.98

(dd, J = 11.0 Hz, 5.7 Hz, 1H, −OCH₂), 3.43−3.39 (m, 1H, −OCH),

3.96 (s, 6H, −OCH₃), 3.93 (s, 3H, −OCH₃), 2.97 (t, J = 4.5 Hz, 4.2

Hz, 1H, −OCH₂), 2.82 (dd, J = 4.7 Hz, 2.2 Hz, 1H, −OCH₂).

3′,5′-Dibenzyloxy-7-(2,3-epoxypropoxy)ﬂavone (56). Yield 79%;

mp 172−173 °C; MS (FAB): 507 (M + 1); IR (KBr): 1640 cm⁻¹; ¹H

NMR (200 MHz, CDCl₃): δ 8.13 (d, J = 8.7 Hz, 1H, H-5), 7.47−7.34

(m, 10H, arom. −CH), 7.11 (d, J = 2.2 Hz, 2H, H-2′, and H-6′), 7.00

(dd, J = 10.9 Hz, 2.1 Hz, 1H, H-4′), 6.97 (d, J = 1.9 Hz, 1H, H-8), 6.77

(d, J = 2.0 Hz, 1H, H-6), 6.69 (s, 3H, H-3), 5.10 (s, 4H, −OCH₂),

4.38 (dd, J = 11.1 Hz, 2.8 Hz, 1H, −OCH₂), 4.04 (dd, J = 11.1 Hz, 5.8

Hz, 1H, −OCH₂), 3.41−3.40 (m, 1H, −OCH), 2.95 (t, J = 4.5 Hz, 4.5

Hz, 1H, −OCH₂), 2.80 (dd, J = 4.8 Hz, 2.6 Hz, 1H, −OCH₂); ¹³C

NMR: δ 177.9, 163.8, 162.9, 160.7, 158.1, 136.7, 133.9, 129.1, 128.6,

127.9, 127.5, 118.2, 115.1, 108.1, 106.0, 105.4, 101.7, 70.8, 69.7, 50.2,

44.9.

3′,5′-Dimethoxy-7-(2,3-epoxypropoxy)ﬂavone (57). Yield 72%;

mp 181−182 °C; MS (FAB): 355 (M + 1); IR (KBr): 1630 cm⁻¹; ¹H

NMR (200 MHz, CDCl₃): δ 8.14 (dd, J = 8.3 Hz, 0.77 Hz, 1H, H-5),

7.04−6.99 (m, 4H, H-2′, H-6′, H-8, and H-6), 6.73 (s, 1H, H-3), 6.61

(t of dd, J = 2.2 Hz, 2.2 Hz, 2.2 Hz, 1H, H-4′), 4.39 (dd, J = 11.1 Hz,

2.9 Hz, 1H, −OCH₂), 4.06 (dd, J = 11.1 Hz, 5.8 Hz, 1H, −OCH₂),

3.87 (s, 6H, −OCH₃), 3.44−3.39 (m, 1H, −OCH), 2.96 (t, J = 4.5 Hz,

4.5 Hz, 1H, −OCH₂), 2.80 (dd, J = 4.8 Hz, 2.6 Hz, 1H, −OCH₂).

To a well-stirred solution of substituted 7-hydroxyﬂavone 48−

51 (17.8 mmol), an excess of epichlorohydrin was added as

well as anhydrous K₂CO₃(54 mmol), and the reaction mixture

was heated at 100−110 °C for 2−6 h. K₂CO₃was ﬁltered, and

the residue was taken in chloroform, washed with water, and the

organic layer was dried (Na₂SO₄). The solvent was removed, and

the product was puriﬁed by column chromatography to aﬀord

(300 MHz, CDCl₃): δ 7.96 (d, J = 7.8 Hz, 1H, H-5); 7.61 (d, J = 2.0

Hz, 2H, H-2′, and H-6′); 7.41 (m, 2H, H-3, and H-4′); 7.12 (m, 4H,

−Ph); 6.69 (d, J = 2.2 Hz, 2H, −Ph); 6.60 (m, 1H, H-8); 6.50 (s, 1H,

H-6); 4.90 (s, 4H, −OCH₂); 3.96 (m, 2H, −OCH₂and −OCH); 3.85

(m, 1H, −OCH₂); 2.82 (m, 1H, −OCH₂); 2.56 (m, 1H, −OCH₂).

Typical Procedure for Epoxide Ring-Opening by Amines.

A solution of 7-epoxyﬂavone (52−61, 4.9 mmol) and corresponding

amine (9.8 mmol) in dry methanol or absolute ethanol (150 mL) was

reﬂuxed for 6 h. The solvent was removed, and the products were

puriﬁed by column chromatography to 6- or 7-(3-amino-2-hydroxypro-

poxy)ﬂavones 62−85.

3′,4′-Dibenzyloxy-6-[3-tert-butylamino-2-hydroxypropoxy]-

ﬂavone (62). Yield 89%; mp 156−157 °C; MS (FAB): 580 (M + 1);

1

IR (KBr): 3404, 1621 cm⁻¹; H NMR (200 MHz, CDCl₃): δ 7.51−

7.26 (m, 15H, −Ph), 6.97 (d, J = 8.9 Hz, 1H, −Ph), 6.62 (s, 1H, H-3),

5.22 (s, 2H, −OCH₂), 5.20 (s, 2H, −OCH₂), 4.26−4.22 (m, 1H,

−OCH₂), 4.14−4.10 (m, 2H, −OCH₂and −OCH), 3.07−2.86 (m,

2H, −NCH₂), 1.29 (s, 9H, −CH₃). Elemental analysis: calculated for

C₃₆H₃₇NO₆: C = 74.59; H = 6.43; N = 2.42; found: C = 74.61; H =

6.62; N = 2.36.

3′,4′-Dibenzyloxy-7-[3-tert-butylamino-2-hydroxypropoxy]-

ﬂavone (63). Yield 85%; mp 159−61 °C; MS (FAB): 580 (M + 1); IR

(KBr): 3400, 1633 cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 8.08 (d, J =

8.7 Hz, 1H, H-5), 7.50−7.28 (m, 12H, −Ph), 7.02−6.93 (m, 3H,

−Ph), 6.60 (s, 1H, H-3), 5.23 (s, 4H, −OCH₂), 4.10−3.98 (m, 1H,

−OCH₂and −OCH), 2.90 (dd, J = 5.9 Hz, 3.8 Hz, 1H, −OCH₂), 2.71

(dd, J = 5.9 Hz, 7.3 Hz, 1H, −NCH₂), 2.47 (m, 1H, −NCH₂), 1.14 (s,

9H, −CH₃). Elemental analysis: calculated for C₃₆H₃₇NO₆: C = 74.59;

H = 6.43; N = 2.42; found: C = 73.36; H = 6.62; N = 2.39.

3′,4′-Dibenzyloxy-7-[3-isopropylamino-2-hydroxypropoxy]-

ﬂavone (64). Yield 87%; mp 177−179 °C; MS (FAB): 566 (M + 1);

IR (KBr): 3423, 1635 cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 8.02 (d,

J = 8.5 Hz, 1H, H-5), 7.70−7.32 (m, 12H, −Ph), 7.11−6.98 (m, 3H,

−Ph), 6.64 (s, 1H, H-3), 5.24 (s, 2H, −OCH₂), 5.23 (s, 2H, −OCH₂),

4.14−4.09 (m, 3H, −OCH₂and −OCH), 3.05 (m, 1H, −NCH₂),

2.92−2.68 (m, 2H, −NCH₂and −NCH), 1.09 (d, J = 6.2 Hz, 6H,

−CH₃). Elemental analysis: calculated for C₃₅H₃₅NO₆: C = 74.32; H =

6.24; N = 2.48; found: C = 74.46; H = 6.19; N = 2.36.

3′,4′-Dimethoxy-7-[3-isopropylamino-2-hydroxypropoxy]ﬂavone

(65). Yield 83%; mp 144−145 °C; MS (FAB): 414 (M + 1); IR (KBr):

3410, 1634 cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 8.03 (d, J = 9.5 Hz,

1H, H-5), 7.51 (dd, J = 8.5 Hz, 1.7 Hz, 1H, H-2′), 7.36 (d, J = 1.7 Hz,

1H, H-8), 6.96−6.92 (m, 3H, −Ph), 6.74 (s, 1H, H-3), 4.18−4.12 (m,

3H, −OCH₂and −OCH), 3.97 (s, 3H, −OCH₃), 3.96 (s, 3H,

−OCH₃), 3.10−2.75 (m, 3H, −NCH₂and −NCH), 1.23 (d, J = 6.3

Hz, 6H, −CH₃). Elemental analysis: calculated for C₂₃H₂₇NO₆: C =

66.81; H = 6.58; N = 3.39; found: C = 66.67; H = 6.65; N = 3.53.

3′, 4′-Dimethoxy-7-[3-(4-phenylpiperazin-1-yl)-2-

hydroxypropoxy]ﬂavone (66). Yield 94%; mp 191−193 °C; MS

58−61.

3′,5′-bis(2-Chlorobenzyloxy)-7-(2,3-epoxypropoxy)ﬂavone (58).

Yield 79%; mp 135 °C; ESMS: 575 (M + 1), 577 (M + 3); ¹H

NMR (200 MHz, CDCl₃): δ 8.01 (d, 1H, J = 8.4 Hz, H-5); 7.41 (s,

1H); 7.56 (m, 6H, −Ph); 7.33 (d, J = 4.4 Hz, 1H, −Ph); 7.15 (s, 1H,

H-4′); 6.91 (d, 2H, −Ph); 6.78 (s; 1H, H-3); 6.68 (s, 1H, H-8); 6.35

(d, J = 4.4 Hz, 1H, H-6); 5.22 (s, 4H, −OCH₂); 4.42 (dd, J = 5.6 Hz,

1H, −OCH₂); 4.07 (dd, J = 5.6 Hz, 1H, −OCH₂); 3.42 (m, 1H,

−OCH); 2.87 (m, 1H, −OCH₂); 2.82 (m, 1H, −OCH₂).

1

(FAB): 517 (M + 1); IR (KBr): 3416, 1627 cm⁻¹; H NMR (200

MHz, CDCl₃): δ 8.16 (d, J = 9.5 Hz, 1H, H-5), 7.54 (dd, J = 8.3 Hz,

2.1 Hz, 1H, H-2′), 7.34 (d, J = 1.9 Hz, 1H, H-8), 7.31−7.23 (m, 2H,

−Ph), 7.04−6.87 (m, 6H, −Ph), 6.70 (s, 1H, H-3), 4.21−4.16 (m, 3H,

−OCH₂and −OCH), 3.99 (s, 3H, −OCH₃), 3.97 (s, 3H, −OCH₃),

3.28 (t, J = 4.8 Hz, 4H, −CH₂), 2.90−2.71 (m, 2H, −NCH₂), 2.71 −

2.65 (m, 4H, −CH₂). Elemental analysis: calculated for C₃₀H₃₂N₂O₆:

C = 69.75; H = 6.24; N = 5.42; found: C = 69.96; H = 6.57; N = 5.51.

3′,4′,5′-Trimethoxy-7-[3-tert-butylamino-2-hydroxypropoxy]-

ﬂavone (67). Yield 84%; mp 119−120 °C; MS (FAB): 458 (M + 1);

IR (KBr): 3403, 1631 cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 8.11 (d,

J = 9.5 Hz, 1H, H-5), 7.10 (m, 2H, H-6, and H-8), 7.02−6.99 (m, 2H,

H-2′, and H-6′), 6.70 (s, 1H, H-3), 4.14−4.11 (m, 3H, −OCH₂and

−OCH), 3.96 (s, 6H, −OCH₃), 3.93 (s, 3H, −OCH₃), 2.86−2.81 (m,

2H, −NCH₂), 1.14 (s, 9H, −CH₃). Elemental analysis: calculated for

C₂₅H₃₁NO₇: C = 65.63; H = 6.83; N = 3.06; found: C = 65.47; H =

6.77; N = 3.12.

3′,5′-bis(2-Methylbenzyloxy)-7-(2,3-epoxypropoxy)ﬂavone (59).

Yield 67%; mp 115 °C; ESMS: 535 (M + 1), FT-IR(KBr): 1644,

1603, 1440 cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 8.10 (d, J = 8.4 Hz

1H, H-5); 7.21 (m, 6H, −Ph);7.41 (d, J = 5.2 Hz, 2H, −Ph); 7.13

(d, J = 2.0 Hz, 2H, −Ph); 7.02 (d, J = 2.2 Hz, 1H, −Ph); 6.78 (d, J =

2.0 Hz, 1H, −Ph); 6.73 (s, 1H, H-3); 5.07 (s, 4H, −OCH₂); 4.35 (d,

J = 2.6 Hz, 1H, −OCH₂); 4.06 (d, J = 6.0 Hz, 1H, −OCH₂); 3.41 (m,

1H, −OCH); 2.93 (d, J = 4.2 Hz, 2H, −OCH₂); 2.40 (s, 6H, −CH₃).

3′,5′-bis(4-Methylbenzyloxy)-7-(2,3-epoxypropoxy)ﬂavone (60).

Yield 55%; mp 128 °C; ESMS: 535 (M + 1); FT-IR(KBr): 1643,

1603, 1443 cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 8.15 (d, J = 8.7 Hz,

1H, H-5); 7.11−7.36 (m, 10H, −Ph); 6.76 (m, 1H, −Ph); 6.70 (s, 1H,

−H-3); 5.06 (s, 4H, −OCH₂); 4.41 (dd, J = 8.3 Hz, 3.0 Hz, 1H,

−OCH₂); 4.0 (m, 2H, −OCH₂and −OCH); 2.96 (m, 1H, −OCH₂),

2.81 (m, 1H, OCH₂), 2.37 (s, 6H, −CH₃).

3′,4′,5′-Trimethoxy-7-[3-isopropylamino-2-hydroxypropoxy]-

ﬂavone (68). Yield 65%; mp 106−107 °C; MS (FAB): 444 (M + 1);

IR (KBr): 3394, 1631 cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 8.09 (d,

J = 9.5 Hz, 1H, H-5), 7.10 (m, 2H, H-6, and H-8), 7.10−6.99 (m, 2H,

H-2′, and H-6′), 6.71 (s, 1H, H-3), 4.16−4.09 (m, 3H, −OCH₂and

3′,5′-bis(3,5-Dichlorobenzyloxy)-7-(2,3-epoxypropoxy)ﬂavone

(61). Yield 81%; mp 105 °C; ES-MS: 645 (M + 1); ¹H NMR

L

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−OCH), 3.96 (s, 6H, −OCH₃), 3.93 (s, 3H, −OCH₃), 2.95−2.82 (m,

3H, −NCH₃and −NCH), 1.14 (d, J = 6.2 Hz, 6H, −CH₃). Elemental

analysis: calculated for C₂₄H₂₉NO₇: C = 65.00; H = 6.59; N = 3.16;

found: C = 65.16; H = 6.47; N = 3.31.

3′, 5′-Dimethoxy-7-[3-(4-phenylpiperazin-1-yl)-2-

hydroxypropoxy]ﬂavone (75). Yield 84%; mp 195−196 °C; MS

1

(FAB): 517 (M + 1); IR (KBr): 3417, 1633 cm⁻¹; H NMR (200

MHz, DMSO-d₆): δ 7.97 (d, J = 8.8 Hz, 1H, H-5), 7.40 (d, J = 1.9 Hz,

1H, H-8), 7.24 (d, J = 1.9 Hz, 2H, H-2′, and H-6′), 7.20 (d, J = 7.9 Hz,

2H, −Ph), 7.12 (dd, J = 8.9 Hz, 1.9 Hz, 1H, −Ph), 7.04 (s, 1H, H-6),

6.93 (d, J = 8.2 Hz, 2H, −Ph), 6.80 (d, J = 7.1 Hz, 1H, H-4′), 6.74 (s,

1H, H-3), 4.25−4.09 (m, 3H, −OCH₂and −OCH), 3.87 (s, 6H,

−OCH₃), 3.13 (t, J = 6.5 Hz, 4H, −CH₂), 2.63 (d, J = 4.5 Hz, 2H,

−NCH₂), 2.47−2.43 (m, 4H, −CH₂). Elemental analysis: calculated

for C₃₀H₃₂N₂O₆: C = 69.75; H = 6.24; N = 5.42; found: C = 69.61;

H = 6.53; N = 5.61.

3′,4′,5′-Trimethoxy-7-[3-(4-phenylpiperazin-1-yl)-2-

hydroxypropoxy]ﬂavone (69). Yield 85%; mp 170−171 °C; MS

1

(FAB): 547 (M + 1); IR (KBr): 3406, 1635 cm⁻¹; H NMR (200

MHz, CDCl₃): δ 8.13 (d, J = 9.5 Hz, 1H, H-5), 7.27 (t, J = 7.9 Hz, 2H,

H-6, and H-8), 7.10 (m, 2H, H-2′, and H-6′), 7.04−7.01 (m, 2H,

−Ph), 6.95−6.87 (m, 3H, −Ph), 6.70 (s, 1H, H-3), 4.21−4.12 (m, 3H,

−OCH₂and −OCH), 3.95 (s, 6H, −OCH₃), 3.93 (s, 3H, −OCH₃),

3.23 (t, J = 4.6 Hz, 4H, −CH₂), 2.87−2.83 (m, 2H, −NCH₂), 2.68−

2.65 (m, 4H, −OCH₂). Elemental analysis: calculated for

C₃₁H₃₄N₂O₇: C = 68.12; H = 6.27; N = 5.12; found: C = 68.26;

H = 6.37; N = 5.41.

3′,5′-Dibenzyloxy-7-[3-tert-butylamino-2-hydroxypropoxy]-

ﬂavone (70). Yield 93%; mp 170−171 °C; MS (FAB): 580 (M + 1);

IR (KBr): 3428, 1648 cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 8.02 (d,

J = 8.8 Hz, 1H, H-5), 7.59−7.33 (m, 10H, −Ph), 7.13 (d, J = 1.9 Hz,

2H, H-2′, and H-6′), 7.07 (s, 1H, H-8), 7.01 (dd, J = 9.8 Hz, 2.0 Hz,

1H, H-6), 6.76 (s, 1H, H-4′), 6.71 (s, 1H, H-3), 5.12 (s, 4H, −OCH₂),

4.57−4.54 (m, 1H, −OCH₂), 4.27−4.16 (m, 2H, −OCH₂and

−OCH), 3.24 (d, J = 10.5 Hz, 1H, −NCH₂), 3.05 (t, J = 10.6 Hz, 1H,

−NCH₂), 1.45 (s, 9H, −CH₃); ¹³C NMR: δ 178.3, 163.5, 163.2, 160.7,

158.1, 136.8, 133.9, 129.0, 128.6, 127.9, 127.5, 118.3, 115.2, 108.0,

105.9, 101.5, 72.9, 70.8, 67.5, 54.0, 45.3, 28.1. Elemental analysis:

calculated for C₃₆H₃₇NO₆: C = 74.59; H = 6.43; N = 2.42; found: C =

74.44; H = 6.35; N = 2.51.

3′,5′-Dibenzyloxy-7-[3-isopropylamino-2-hydroxypropoxy]-

ﬂavone (71). Yield 79%; mp 173−174 °C; MS (FAB): 566 (M + 1);

IR (KBr): 3431, 1637 cm⁻¹; ¹H NMR (200 MHz, CDCl₃): δ 8.05 (d, J

= 8.6 Hz, 1H, H-5), 7.59−7.34 (m, 10H, −Ph), 7.15 (d, J = 1.8 Hz,

2H, H-2′, and H-6′), 7.06 (s, 1H, H-8), 7.03 (d, J = 9.4 Hz, 1H, H-6),

6.78 (s, 1H, H-4′), 6.71 (s, 1H, H-3), 5.13 (s, 4H, −OCH₂), 4.14−4.11

(m, 3H, −OCH₂and −OCH), 3.18−3.16 (m, 1H, −NCH₂), 2.93−

2.79 (m, 2H, −NCH₂and −NCH), 1.11 (d, J = 6.2 Hz, 6H, −OCH₃);

¹³C NMR δ 177.9, 163.8, 162.9, 160.6, 158.1, 136.7, 133.9, 128.9,

128.5, 127.8, 127.1, 118.1, 115.3, 108.0, 105.8, 105.3, 101.5, 71.7, 70.7,

68.4, 49.8, 49.3, 23.1, 23.0. Elemental analysis: calculated for

C₃₅H₃₅NO₆: C = 74.32; H = 6.24; N = 2.48. found: C = 74.16;

H = 6.17; N = 2.29.

3′,5′-bis(2-Chlorobenzyloxy)-7-[3-tert-butylamino-2-

hydroxypropoxy]ﬂavone (76). Yield 52%; mp 160 °C; ¹H NMR (200

MHz, CDCl₃): δ 8.14 (d, J = 9.5 Hz, 1H, H-5); 7.57 (d, 2H, J = 4.9

Hz, H-2′,and H-6′); 7.57 (m, 4H, −Ph); 7.19 (m, 4H, −Ph); 7.05 (m,

2H, H-4′,and H-3); 6.78 (d, J = 1.4 Hz, 2H, H-6,and H-8); 5.22 (s, 4H,

−OCH₂); 4.11(m, 3H, −OCH₂); 2.98 (m, 1H, N−CH₂), 2.88 (m,

1H, N−CH₂); 1.16 (s, 9H, −CH₃). ES-MS: 648 (M + 1), 650 (M + 3);

HRMS: calc. for C₃₆H₃₆Cl₂NO₆= 648.1920; obtained: 648.1925.

3′,5′-bis(2-Chlorobenzyloxy)-7-[3-isopropylamino-2-

hydroxypropoxy]ﬂavone (77). Yield 58%, mp 155 °C; ¹H NMR (200

MHz, CDCl₃): δ 8.07 (d, J = 8.9 Hz, 1H, H-5); 7.67 (s, 1H); 7.61

(d, J = 4.0 Hz, 2H, H-2′, and H-6′); 7.57 (m, 5H, −Ph); 7.19 (m, 2H,

H-3, H-4′); 7.05 (m, 2H, H-6, and H-8); 6.80 (d, J = 9.6 Hz, 2H,

−Ph); 5.24 (s, 4H, −OCH₂); 4.33 (m, 1H, −OCH₂), 4.18 (m, 2H,

−OCH₂); 2.98 (m, 1H, N−CH₂), 2.88 (m, 2H, N−CH₂and N−CH);

1.28 (d, J = 5.7 Hz, 6H, −CH₃). ES-MS: 634 (M + 1), 636 (M + 3);

HRMS: calc. for C₃₅H₃₄Cl₂NO₆= 634.1763; obtained = 634.1781.

3′,5′-bis(2-Methylbenzyloxy)-7-[3-tert-butylamino-2-

hydroxypropoxy]ﬂavone (78). Yield 61%; mp 175 °C; FT-IR (KBr):

1633, 1601 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 8.03 (d, J = 3.6 Hz,

1H, H-5); 7.41 (d, J = 4.2 Hz, 2H, H-2′, and H-6′); 7.31 (m, 6H,

−Ph); 7.13 (m, 2H, −Ph); 7.00 (m, 2H, H-3, and H-4′); 6.74 (m, 2H,

H-6, and H-8); 5.06 (s, 4H, −OCH₂); 4.54 (m, 1H, −OCH₂); 4.14

(m, 2H, −OCH₂and OCH); 3.37 (m, 1H, N−CH₂); 3.01 (m, 1H,

N−CH₂); 2.40 (s, 6H, −CH₃); 1.47 (d, 9H, −CH₃); ¹³C NMR (75

MHz, CDCl₃+ CD₃OD): δ 159.2, 135.4, 132.9, 129.2, 127.5, 127.2,

125.8, 124.8, 104.1, 103.7, 67.7, 63.9, 55.7, 48.2, 43.5, 24.5, 17.7; ES-

MS: 607 (M + 1); HRMS calc. for C₃₈H₄₁NO₆= 608.3010; obtained =

608.3015.

3′,5′-bis(2-Methylbenzyloxy)-7-[3-isopropylamino-2-

3′,5′-Dibenzyloxy-7-[3-(4-phenylpiperazin-1-yl)-2-

hydroxypropoxy]ﬂavone (79). Yield 65%; mp 235 °C; FT-IR (KBr):

1

3405, 1637, 1600 cm⁻¹; H NMR (200 MHz, CDCl₃+ CD₃OD): δ

hydroxypropoxy]ﬂavone (72). Yield 94%; mp 168−170 °C; MS

1

(FAB): 669 (M + 1); IR (KBr): 3389, 1634 cm⁻¹; H NMR (200

8.05 (d, J = 8.4 Hz, 1H, H-5); 7.29 (d, J = 2.2 Hz, 2H, H-2′, and H-6′);

7.23 (m, 4H, −Ph); 7.18 (d, J = 2.2 Hz, 2H, −Ph); 7.02 (d, J = 2.2 Hz,

2H, H-3, and H-4′); 6.80 (d, J = 2.0 Hz, 1H, H-8); 6.77 (s, 1H, H-6);

5.10 (s, 4H, −OCH₂); 4.17 (m, 2H, −OCH₂); 3.40 (m, 1H, OCH);

2.93 (d, J = 4.2 Hz, 2H, N−CH₂); 2.41 (s, 6H, −CH₃); 1.41 (d, J = 3.3

Hz, 6H, −CH₃); ¹³C NMR (75 MHz, CDCl₃): δ 178.4, 163.4, 162.9,

160.3, 157.8, 136.7, 133.9, 130.3, 128.7, 126.8,125.9, 117.7, 114.8,

107.3, 105.4, 104.8, 101.0, 70.1, 68.9, 65.0, 50.8, 18.9, 18.7. ES-MS:

594 (M + 1); HRMS: calc. for C₃₇H₃₉NO₆= 594.2856; obtained =

594.2847.

MHz, CDCl₃): δ 8.12 (d, J = 8.6 Hz, 1H, H-5), 7.46−7.30 (m, 10H,

−Ph), 7.26−7.23 (m, 2H, −Ph), 7.11 (d, J = 1.9 Hz, 2H), 7.00 (d, J =

8.5 Hz, 1H, −Ph), 6.98 (s, 1H, H-8), 6.95−6.86 (m, 3H, −Ph), 6.76

(s, 1H, H-4′), 6.69 (s, 1H, H-3), 5.09 (s, 4H, −OCH₃), 4.21−4.14 (m,

3H, −OCH₂and −OCH), 3.23 (t, J = 4.7 Hz, 4.6 Hz, 4H, −CH₂),

2.91−2.81 (m, 2H, −NCH₂), 2.66 (dd, J = 5.2 Hz, 4.1 Hz, 4H,

−CH₂). Elemental analysis: calculated for C₄₂H₄₀N₂O₆: C = 75.43; H

= 6.03; N = 4.19; found: C = 75.37; H = 6.20; N = 4.13.

3′,5′-Dimethoxy-7-[3-tert-butylamino-2-hydroxypropoxy]ﬂavone

(73). Yield 66%; mp 145−146 °C; MS (FAB): 428 (M + 1); IR (KBr)

3431, 1631 cm⁻¹; ¹H NMR (200 MHz, DMSO-d₆): δ 7.93 (d, J = 8.8

Hz, 1H, H-5), 7.32 (d, J = 1.9 Hz, 1H, H-8), 7.15 (d, J = 2.0 Hz, 2H,

H-2′. and H-6′), 7.08 (dd, J = 8.9 Hz, 2.0 Hz, 1H, H-6), 6.92 (s, 1H, H-

4′), 6.68 (s, 1H, H-3), 4.17−4.01 (m, 3H, −OCH₂and −OCH), 3.82

(s, 6H, −OCH₃), 2.77−2.59 (m, 2H, −NCH₂), 1.08 (s, 9H, −CH₃).

Elemental analysis: calculated for C₂₄H₂₉NO₆: C = 67.43; H = 6.84; N

= 3.28; found: C = 67.59; H = 6.73; N = 3.39.

3′,5′-Dimethoxy-7-[3-isopropylamino-2-hydroxypropoxy]ﬂavone

(74). Yield 87%; mp 155−156 °C; MS (FAB): 414 (M + 1); IR (KBr):

3426, 1630 cm⁻¹; ¹H NMR (200 MHz, DMSO-d₆): δ 7.95 (d, J = 8.9

Hz, 1H, H-5), 7.34 (s, 1H, H-8), 7.18 (d, J = 1.8 Hz, 2H, H-2′, and H-

6′), 7.09 (dd, J = 8.9 Hz, 1.9 Hz, 1H, H-6), 6.96 (s, 1H, H-4′), 6.70 (s,

1H, H-3), 4.20−3.90 (m, 3H, −OCH₂and −OCH), 3.85 (s, 6H,

−OCH₃), 2.84−2.58 (m, 3H, −NCH₂and −NCH), 1.03 (d, J = 6.2

Hz, 6H, −CH₃). Elemental analysis: calculated for C₂₃H₂₇NO₆: C =

66.81; H = 6.58; N = 3.39; found: C = 66.69; H = 6.13; N = 3.62.

3′,5′-bis(4-Methylbenzyloxy)-7-[3-tert-butylamino-2-

hydroxypropoxy]ﬂavone (80). Yield 71%; mp 135 °C; FT-IR (KBr):

1

1643, 1606, 1442 cm⁻¹; H NMR (300 MHz, CDCl₃): δ 8.04 (d, J =

8.7 Hz, 1H, H-5); 7.35 (d, J = 4.8 Hz, 4H, -Ph, H-2′, and H-6′); 7.22

(d, J = 4.8 Hz, 4H, −Ph); 7.10 (d, J = 2.1 Hz, 2H, H-3, and H-4′); 7.00

(d, J = 2.1 Hz, 2H, −Ph,); 6.74 (d, J = 1.8 Hz, 1H, H-8); 6.70 (s, 1H,

H-6); 5.04 (s, 4H, −OCH₂); 3.93 (m, 3H, −OCH₂); 2.90 (m, 1H,

−NCH₂); 2.84 (m, 1H, −NCH₂); 2.36 (s, 6H, −CH₃); 1.18 (s, 9H,

−CH₃); ¹³C NMR (75 MHz, CDCl₃): δ 178.3, 163.3, 163.1, 160.1,

157.7, 137.8, 133.0, 129.1, 127.5, 126.6, 117.3, 114.8, 107.0, 105.3,

104.9, 100.9, 81.0, 74.8, 71.1, 70.1, 69.5, 68.1, 52.5, 50.7, 28.1, 26.4,

20.8. ESMS: 608 (M + 1), HRMS: calc. for C₃₈H₄₁NO₆= 608.3010;

obtained = 608.3015.

3′,5′-bis(4-Methylbenzyloxy)-7-[3-isopropylamino-2-

hydroxypropoxy]ﬂavone (81). Yield 66%; mp 145 °C; ESMS: 594

(M + 1); FT-IR (KBr): 1646, 1603 cm⁻¹; ¹H NMR (300 MHz, CDCl₃):

δ 8.06 (d, J = 8.7 Hz, 1H, H-5); 7.34 (d, J = 4.8 Hz, 4H, −Ph, H-2′ and

M

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Journal of Medicinal Chemistry

Article

H-6′); 7.21 (d, J = 4.8 Hz, 4H, −Ph) 6.94 (d, J = 2.1 Hz, 2H, H-3, and

H-4′); 6.73 (d, J = 1.8 Hz, 1H, H-8); 6.68 (s, 1H, H-6); 5.03 (s, 4H,

−OCH₂); 4.09 (m, 3H, −OCH₂); 2.90 (m, 2H, −NCH₂); 2.84 (m,

1H, −NCH); 2.36 (s, 6H, −CH₃); 1.12 (d, J = 3.3 Hz, 6H, −CH₃);

¹³C NMR (75 MHz, CDCl₃): δ 177.8, 163.2, 162.7, 160.3, 157.7,

1H, H-5′), 6.68 (s, 1H, H-3), 4.28−4.19 (m, 3H, −OCH₂and

−OCH), 3.18−3.14 (m, 1H, −NCH₂), 2.97−2.94 (m, 1H, −NCH₂),

1.34 (s, 9H, −CH₃). Elemental analysis: calculated for C₂₂H₂₅NO₆:

C = 66.15; H = 6.31; N = 3.51; found: C = 66.26; H = 6.27; N = 3.27.

3′,4′-Dihydroxy-7-[3-isopropylamino-2-hydroxypropoxy]ﬂavone

(88). Yield 88%; mp 187 °C (decomposes); MS (FAB): 386 (M + 1);

137.9, 133.5, 133.3, 129.3, 127.7, 126.9, 117.9, 114.6, 107.7, 105.4,

104.9, 101.0, 71.1, 70.3, 67.9, 52.5, 49.0, 22.9, 22.8, 21.2. 594 (M + 1);

HRMS: calc. for C₃₇H₃₉NO₆= 594.2856; obtained = 594.2847.

3′,5′-bis(4-Methylbenzyloxy)-7-[3-(2-chlorobenzylamino)-2-

hydroxypropoxy]ﬂavone (82). Yield 61%; mp 178 °C; FT-IR (KBr):

1

IR (KBr): 3425, 1624 cm⁻¹; H NMR (200 MHz, DMSO-d₆): δ 7.96

(d, J = 7.1 Hz, 1H, H-5), 7.47 (s, 1H, H-8), 7.45 (d, J = 8.2 Hz, 1H, H-

2′), 7.30 (s, 1H, H-6), 7.10 (d, J = 8.1 Hz, 1H, H-6′), 6.95 (d, J = 7.6

Hz, 1H, H-5′), 6.68 (s, 1H, H-3), 4.23−4.18 (m, 3H, −OCH₂and

−OCH), 3.21−3.18 (m, 3H, −NCH₂and −NCH), 1.27 (d, J = 6.2

Hz, 6H, −CH₃). Elemental analysis: calculated for C₂₁H₂₃NO₆: C =

65.44; H = 6.02; N = 3.63; found: C = 65.37; H = 6.18; N = 3.47.

3′,5′-Dihydroxy-7-[3-tert-butylamino-2-hydroxypropoxy]ﬂavone

(89). Yield 96%; mp 153 °C (decomposes); MS (FAB): 400 (M + 1);

1

1645, 1604, 1441 cm⁻¹; H NMR (300 MHz, CDCl₃): δ 8.05 (d, J =

8.7 Hz, 1H, H-5); 7.30 (m, −Ph, 10H); 7.14(m, −Ph, 4H); 6.97 (d,

J = 6.2 Hz, 2H, H-2′, and H-6′); 6.77 (s, 1H, H-3); 6.72 (s, 1H, H-8);

6.72 (s, 1H, H-6); 5.07 (s, 4H, −OCH₂); 4.14 (m, 3H, −OCH₂and

−NCH₂); 2.90 (m, 2H, OCH₂and OCH); 2.87 (m, 2H, −NCH₂);

2.40 (s, 6H, −CH₃); ¹³C NMR (75 MHz, CDCl₃): δ 177.8, 163.2,

162.7, 160.3, 157.7, 137.9, 136.4, 133.9, 133.5, 133.3, 130.3, 129.6,

128.8, 127.6, 126.9, 117.9, 114.7, 107.8, 105.4, 105.0, 101.1, 70.9, 70.3,

67.9, 50.9, 50.8, 21.2. ESMS: 676 (M + 1), HRMS: calc. for

C₄₁H₃₈ClNO₆= 676.2466; obtained = 676.2445.

3′,5′-bis(4-Methylbenzyloxy)-7-[3-di-isopropylamino-2-

hydroxypropoxy]ﬂavone (83). Yield 61%; mp 156 °C; ¹H NMR (300

MHz, CDCl₃): δ 8.05 (d, J = 8.7 Hz, 1H, H-5); 7.30 (m, 2H, H-2′, and

H-6′); 7.14 (m, 4H, −Ph); 6.97 (d, J = 6.2 Hz, 2H, −Ph); 6.77 (s, 1H,

H-3); 6.72 (s, 1H, H-8); 6.56 (s, 1H, H-6); 5.07 (s, 4H, −OCH₂);

4.57 (m, 1H, −OCH₂); 4.34 (m, 1H, −OCH₂); 3.98 (m, 1H, OCH);

3.65 (m, 2H, −NCH₂); 3.23 (m, 2H, −NCH); 2.37 (s, 6H, −CH₃);

1.53 (d, J = 6.2 Hz, 12H, −CH₃); ESMS: 636 (M + 1); Elemental

analysis: calc. for C₄₀H₄₅NO₆: C = 75.56; H = 7.13; N = 2.20;

obtained: C = 75.24; H = 7.01; N = 2.01.

3′,5′-bis(3,5-Dichlorobenzyloxy)-7-[3-tert-butylamino-2-

hydroxypropoxy]ﬂavone (84). Yield 54%; mp 143 °C; ES-MS: 718

(M + 1), ¹H NMR (300 MHz, CDCl₃): ¹H NMR (300 MHz, CDCl₃):

δ 7.95 (d, J = 8.6 Hz, 1H, H-5); 7.61 (m, 3H, −Ph, H-2′, and H-6′);

7.40 (m, 2H, −Ph); 7.14 (m, 4H, −Ph); 6.78 (d, J = 2.2 Hz, 2H, H-4′,

and −Ph); 6.50 (m, 1H, H-3); 6.60 (m, 1H, H-8); 6.50 (s, 1H, H-6);

5.09 (s, 4H, −OCH₂); 4.17 (m, 2H, −OCH₂and −OCH); 3.96 (m,

1H, −OCH₂); 2.56 (m, 1H, −NCH₂); 2.42 (m, 1H, −NCH₂); 1.22 (s,

9H, −CH₃); Elemental analysis calc. for C₃₆H₃₃Cl₄NO₆: C = 60.27; H

= 4.64; N = 1.95; obtained, C = 60.57; H = 4.44; N = 1.75.

1

IR (KBr): 3401, 1618 cm⁻¹; H NMR (200 MHz, DMSO-d₆): δ 7.98

(d, J = 8.8 Hz, 1H, H-5), 7.30 (s, 1H, H-8), 7.13 (d, J = 8.8 Hz, 1H,

H-6), 6.90 (d, J = 1.2 Hz, 2H, H-2′, and H-6′), 6.7 (s, 1H, H-3), 6.52

(s, 1H, H-4′), 4.27−4.23 (m, 3H, OCH₂and −OCH), 3.18−2.99

(m, 2H, −NCH₂), 1.32 (s, 9H, −CH₃). Elemental analysis: calculated

for C₂₂H₂₅NO₆: C = 66.15; H = 6.31; N = 3.51; found: C = 66.19; H =

6.47; N = 3.43.

3′,5′-Dihydroxy-7-[3-isopropylamino-2-hydroxypropoxy]ﬂavone

(90). Yield 95%; mp 185 °C (decomposes); MS (FAB): 386 (M + 1);

1

IR (KBr): 3244, 1623 cm⁻¹; H NMR (200 MHz, DMSO-d₆): δ 9.85

(s, 2H, −OH), 7.72 (d, J = 8.8 Hz, 1H, H-5), 7.06 (d, J = 1.7 Hz, 1H,

H-8), 6.87 (dd, J = 8.8 Hz, 1.9 Hz, 1H, H-6), 6.66 (d, J = 1.7 Hz, 2H,

H-2′, and H-6′), 6.45 (s, 1H, H-3), 6.29 (s, 1H, H-4′), 4.00−3.97 (m,

3H, −OCH₂and −OCH), 3.13−3.03 (m, 1H, −NCH₂), 2.94−2.75

(m, 2H, −NCH₂and −NCH), 1.24 (d, J = 5.7 Hz, 6H, CH₃); ¹³C

NMR: δ 176.7, 163.3, 163.1, 159.3, 157.7, 133.2, 126.6, 117.6, 115.4,

106.9, 106.3, 104.6, 101.9, 70.9, 65.3, 50.3, 46.9, 19.0, 18.6. Elemental

analysis: calculated for C₂₁H₂₃NO₆: C = 65.44; H = 6.02; N = 3.63;

found: C = 66.26; H = 6.18; N = 3.44.

(R)-(−)-3′,5′-Dibenzyloxy-7-[3-tert-butylamino-2-

hydroxypropoxy]ﬂavone (70b). A mixture of 3′,5′-dibenzyloxy-7-

hydroxyﬂavone (46, 1.0 g, 2.2 mmol) and (S)-(+)-epichlorohydrin

(1.0 mL, 12.0 m mol) was heated at 120 °C for ∼2 h. The cooled

reaction mixture was taken in toluene, and a solution of aq. NaOH (10

mg, 0.0.25 mmol) and benzyltriethyl ammonium chloride (10 mg, 0.04

mmol) were added followed by stirring at room temperature for 2 h.

On completion, the organic layer was separated and dried and the

solvent was evaporated at reduced pressure to give crude 3′,5′-

dibenzyloxy-7-(2,3-epoxypropoxy)ﬂavone (56b) of R-conﬁguration

(yield 0.9 g, 80%). The thus-obtained (R)-3′,5′-dibenzyloxy-7-(2,3-

epoxypropoxy)ﬂavone (56b, 600 mg, 4.9 mmol) and tert-butyl amine

(0.26 mL, 9.8 mmol) in dry methanol (50 mL) were reﬂuxed for ∼6 h.

The solvent was evaporated at reduced pressure, and the crude

product was puriﬁed by column chromatography to aﬀord (R)-

(−)-3′,5′-dibenzyloxy-7-(3-tert-butylamino-2-hydroxypropoxy)ﬂavone

(70b). Yield = 0.65 g, 93%; mp = 158 °C; [α]_D= −8.6° (c = 1.5%,

CHCl₃).

(S)-(+)-3′,5′-Dibenzyloxy-7-[3-tert-butylamino-2-

hydroxypropoxy]ﬂavone (70a). A mixture of 3′,5′-dibenzyloxy-7-

hydroxyﬂavone (46, 1.2 g, 2.6 mmol) and (R)-(−)-epichlorohydrin

(1.12 mL, 15.0 mmol) was heated at 120 °C for ∼2 h. The cooled

reaction mixture was taken in toluene, and a solution of aq. NaOH (15

mg, 0.37 mmol) and benzyltriethylammonium chloride (15 mg, 0.06

mmol) were added and stirred at room temperature for 2 h. The

organic layer was separated and dried, and the solvent was removed at

reduced pressure to give crude (S)-(+)-7-(2,3-epoxypropoxy)-3′,5′-

dibenzyloxyﬂavone (56a) (yield 1.12 g, 83%). The solution of the (S)-

3′,5′-dibenzyloxy-7-(2,3-epoxypropoxy)ﬂavone (56a, 500 mg, 4.9

mmol) in dry methanol (50 mL) and tert-butyl amine (0.2 mL, 9.8

mmol) was reﬂuxed for ∼6 h. The solvent was removed at reduced

pressure, and the crude product was puriﬁed by column chromatog-

raphy to aﬀord (S)-(+)-3′,5′-dibenzyloxy-7-(3-tert-butylamino-2-

hydroxypropoxy)ﬂavone (70a). Yield = 0.52 g, 93%; mp = 165 °C;

[α]_D= +9.0° (c = 20 mg/7.5 mL of CHCl₃).

3′,5′-bis(3,5-Dichlorobenzyloxy)-7-[3-isopropylamino-2-

hydroxypropoxy]ﬂavone (85). Yield 52%; mp 127 °C; ES-MS: 702

1

(M + 1); H NMR (300 MHz, CDCl₃): δ 8.13 (d, J = 8.8 Hz, 1H,

H-5); 7.22 (m, 8H, −Ph, H-2′, and H-6′); 6.98 (m, 4H, −Ph); 6.74

(d, J = 2.2 Hz, 1H, H-8); 6.70 (d, J = 1.2 Hz, 1H, H-6); 5.04 (s, 4H,

−OCH₂); 4.10 (m, 3H, −CH₂and −OCH); 2.75 (m, 1H, −NCH₂);

2.58 (m, 1H, −NCH₂); 2.36 (m, 1H, −NCH); 1.02 (d, J = 4.6 Hz,

6H, −CH₃); HRMS: calc. for C₃₅H₃₁Cl₄O₆= 702.0985, obtained =

702.0990.

General Procedure of Debenzylation. The suitable ﬂavones

62−64 or 70−71 (2.2 mmol) were taken in dry methanol (40 mL),

and Pd−C (30 mg) was added followed by shaking in Parr

hydrogenation assembly at 40 psi of hydrogen atmosphere. On

completion of the reaction, the catalyst was ﬁltered and the solvent

was removed to get crude ﬂavones 86−90, which were puriﬁed by

column chromatography.

3′,4′-Dihydroxy-6-[3-tert-butylamino-2-hydroxypropoxy]ﬂavone

(86). Yield 93%; mp 193 °C (decomposes); MS (FAB): 400 (M + 1);

1

IR (KBr): 3399, 1616 cm⁻¹; H NMR (200 MHz, DMSO-d₆): δ 7.93

(s, 1H, H-8), 7.55 (d, J = 9.5 Hz, 1H, H-2′), 7.53 (s, 1H, H-7), 7.39 (d,

J = 9.8 Hz, 1H, H-6′), 7.34 (d, J = 8.5 Hz, 1H, H-6), 6.93 (d, J = 8.0

Hz, 1H, H-5′), 6.62 (s, 1H, H-3), 4.41−4.12 (m, 3H, −OCH₂and

−OCH), 3.07−2.93 (m, 2H, −NCH₂), 1.33 (s, 9H, −CH₃). Elemental

analysis: calculated for C₂₂H₂₅NO₆: C = 66.15; H = 6.31; N = 3.51;

found: C = 66.26; H = 6.47; N = 3.61.

3′,4′-Dihydroxy-7-[3-tert-butylamino-2-hydroxypropoxy]ﬂavone

(87). Yield 97%; mp 165 °C (decomposes); MS (FAB): 400 (M + 1);

1

IR (KBr): 3274, 1623 cm⁻¹; H NMR (200 MHz, DMSO-d₆): δ 7.95

(d, J = 8.8 Hz, 1H, H-5), 7.47 (s, 1H, H-8), 7.44 (d, J = 9.4 Hz, 1H, H-2′),

7.29 (s, 1H, H-6), 7.10 (d, J = 8.8 Hz, 1H, H-6′), 6.95 (d, J = 8.1 Hz,

N

dx.doi.org/10.1021/jm201107g | J. Med. Chem. XXXX, XXX, XXX−XXX

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Article

(R)-(−)-3′,5′-Dihydroxy-7-[3-isopropylamino-2-hydroxypropoxy]-

ﬂavone (90b). A mixture of 3′,5′-dibenzyloxy-7-hydroxyﬂavone (46,

1.0 g, 2.2 mmol) and S-(+)-epichlorohydrin (1.0 mL, 12.0 mmol) was

heated at 120 °C for ∼2 h. The cooled mixture was taken in toluene,

and a solution of aq. NaOH (10 mg, 0.25 mmol) and

benzyltriethylammonium chloride (10 mg, 0.04 mmol) were added

and stirred at room temperature for 2 h. The organic layer was

separated, dried, and evaporated at reduced pressure to give crude (R)-

3′,5′-dibenzyloxy-7-(2,3-epoxypropoxy)ﬂavone (56b) (yield 0.9 g,

80%). A solution of (R)-3′,5′-dibenzyloxy-7-(2,3-epoxypropoxy)ﬂavone

(56b, 0.6 g, 4.9 mmol) and isopropylamine (0.5 mL,14.7 mmol) in dry

methanol (50 mL) was reﬂuxed for ∼6 h. The solvent was removed at

reduced pressure, and the crude product obtained was puriﬁed by column

chromatography to give (R)-3′,5′-dibenzyloxy-7-(3-isopropylamino-2-

hydroxypropoxy)ﬂavone (71b) (yield 0.55 g, 79%). (R)-3′,5′-Dibenzy-

loxy-7-(3-isopropylamino-2-hydroxypropoxy)ﬂavone (71b, 300 mg, 2.12

mmol) was shaken in dry methanol (40 mL) with 10% Pd/C (quantity

suﬃcient) under hydrogen atmosphere (40 psi). The catalyst was ﬁltered,

and the solvent was removed at reduced pressure to give the product (R)-

(+)-3′,5′-dihydroxy-7-(3-isopropylamino-2-hydroxypropoxy)ﬂavone

(90b). Yield = 0.2 g, 98%; mp = 124 °C; [α]_D= −9.0° (c = 20 mg/7.5

mL of 2% CHCl₃/MeOH).

(S)-(+)-3′,5′-Dihydroxy-7-[3-isopropylamino-2-hydroxypropoxy]-

ﬂavone (90a). A mixture of 3′,5′-dibenzyloxy-7-hydroxyﬂavone (46,

1.2 g, 2.6 mmol) and R-epichlorohydrin (1.2 mL, 15.0 mmol) was

reﬂuxed at 120 °C for ∼2 h. The cooled reaction mixture was taken in

toluene, and a solution of aq. NaOH (15 mg, 0.37 mol) and

benzyltriethylammonium chloride (15 mg, 0.06 mmol) were added to

water and allowed to stir at room temperature for 2 h. The organic

layer was separated, dried, and concentrated at reduced pressure to

give crude (S)-3′,5′-dibenzyloxy-7-(2,3-epoxypropoxy)ﬂavone (56a)

(yield 1.12 g, 83%). A solution of (S)-7-(2,3-epoxypropoxy)-3′,5′-

dibenzyloxyﬂavone (56a, 500 mg, 4.9 mmol) and isopropylamine (0.3

mL,14.7 mmol) in dry methanol (50 mL) was reﬂuxed at 120 °C for

∼6 h. The solvent was removed at reduced pressure to get crude

product and was subjected to column chromatography to aﬀord (S)-

3′,5′-dibenzyloxy-7-(3-isopropylamino-2-hydroxypropoxy)ﬂavone

(71a) (yield 0.44 g, 79%). (S)-3′,5′-Dibenzyloxy-7-(3-isopropylamino-

2-hydroxypropoxy)ﬂavone (71a, 250 mg, 2.12 mmol) in dry methanol

(40 mL) and 10% Pd/C (quantity suﬃcient) was shaken in hydrogen

atmosphere at ∼40 psi. The catalyst was ﬁltered, and the solvent was

removed to give the product (S)-(+)-3′,5′-dihydroxy-7-[3-(isopropy-

lamino)-2-hydroxypropoxy]ﬂavone (90a). Yield = 0.16 g, 98%; mp =

130 °C; [α]_D= +15.4° (c = 20 mg/7.5 mL of 2% CHCl₃/MeOH).

In Vivo Antihyperglycemic and Antidyslipidemic Activity

Evaluation. Sucrose-Loaded Rat Model (SLM). Male albino rats

of Charles Foster/Wistar strain of average body weight (160

20 g) were selected for this study. The blood glucose level of

each animal was checked by glucometer using glucostrips

(Boehringer Mannheim) after 16 h of starvation. Animals showing

blood glucose levels between 60 and 80 mg/dL were divided into

groups of 5−6 animals in each. Animals of the experimental group

were administered on suspension of the desired synthetic com-

pound orally (made in 1.0% gum acacia) at a dose of 100 mg/kg

of body weight. Animals of the control group were given an equal

amount of 1.0% gum acacia. A sucrose load (10.0 g/kg) was given

to each animal orally exactly after 30 min post-administration of

the test sample/vehicle. Blood glucose proﬁle of each rat was again

determined at 30, 60, 90, and 120 min after administration of

sucrose by glucometer. Food but not water was withheld from the

cages during the course of experimentation.¹⁵Quantitative glucose

tolerance of each animal was calculated by the area under curve

(AUC) method (Prism Software). Comparing the AUC of experi-

mental and control groups determined the percentage of

antihyperglycemic activity.

citrate buﬀer, pH 4.5, and the calculated amount of the fresh solution

was injected intraperitoneally to the over-fasted rats at the dose 60 mg/kg.

Blood glucose was checked 48 h later by glucostrips (Boehringer

Mannheim), and animals showing blood glucose value between 160 and

300 mg/dl were selected and grouped, with each group consisting of 5−6

animals. Oral sucrose load (2.5 g/kg) was given simultaneously with

compounds 70, 70a, or 90 or with metformin. The experimental groups

were dosed at 100 mg/kg, and the control group was given n equal

volume of 1% gum acacia. The blood glucose proﬁle was measured at 0,

30, 60, 90, 120, 180, 240, and 300 min, respectively, after the sucrose

challenge.¹⁶Food was withdrawn during the period 0−5 h only. Animals

received water ad lib.

Antihyperglycemic and Antidyslipidemic Activity in Diabetic db/

db Mice. C57BL/KsJ db/db mice 12−18 weeks, 40−50 g, bred in the

animal house of CDRI, Lucknow, were used for the evaluation of

antihyperglycemic activity. Mice showing blood glucose level 200−350

mg/dL, triglyceride level 170−250 mg/dL, cholesterol level 170−250

mg/dL, and HDL-C level 32−40 mg/dL were selected for the study.

The mice were housed in groups of 5 (same sex) in a room controlled

for temperature (23 2.0 °C) and 12-h/12-h light/dark cycle (lights

on at 6.00 ^A.M.). Body weight was measured daily from day 1 to day 10.

All animals had free access to fresh water and to a normal diet except

on the day of the postprandial protocol (day 6) and during the

overnight fast before the OGTT on day 10.¹⁷The animals always had

access to water during experimental periods. Blood glucose was

checked every morning up until day 9. On day 10 an oral glucose

tolerance test (OGTT) was performed after an overnight fasting.

Blood glucose was measured at −30.0 min, and test compounds were

administered. The blood glucose was again measured at 0 min just

after treatment, and at this juncture glucose solution was given at a

dose of 3 g/kg to all the groups including the vehicle-treated group.

The blood glucose levels were checked at 30, 60, 90, and 120 min after

glucose administration.¹⁸The data was analyzed for its area under

curve (AUC) and signiﬁcance on Prism software. The ED₅₀is the

eﬀective dose that produces on average response in 50% of animal

population. On the 11th day blood was withdrawn from retro-orbital

plexus of the mice for the estimation of plasma triglyceride, cholesterol,

HDL cholesterol, and insulin levels. Statistical analysis between groups

was made by Student t test.

Antihyperlipidemic Activity Evaluation in Triton-Induced Dyslipi-

demic Rat Model. A total of 8−10 weeks old male Wistar strain of rats

of average body weight 160 g were taken from the animal colony of the

Institute and divided into groups consisting of 10 animals in each.

Each group was housed in plastic cages and was fed ad lib the normal

pellet diet and water. Hyperlipidemia in rats was induced by

intraperitoneal administration of Triton X-100 (Sigma Chemical Co.,

U.S.A.) at the dose of 400 mg/kg. Flavone-derived compounds were

fed orally to the said rats at the dose of 100 mg/kg, respectively,

prepared in 1% gum acacia. Control animals received the same amount

of 1% gum acacia. Exactly 18 h after administration of Triton-X-100,

the blood of each animal was withdrawn from the retro-orbital plexus.

Serum was separated after centrifugation at 1500g for 10 min. Total

triglycerides and total cholesterol content in serum samples were

determined using the assay kits as supplied by Randox/Roche. The

results are expressed as the mean SEM. The statistical signiﬁcance

between groups is determined by analysis of variance and subsequent

Dunnet test.

Antidyslipidemic Activity. Antidyslipidemic activity evaluation of

compounds in Syrian golden hamsters (body weight 100−120 g, age

6−8 weeks old) was fed with high-fructose, high-fat diet (55% fructose,

13% fats) for 1 month for the development of dyslipidaemia in these

hamsters.¹⁹Dyslipidemic hamsters were selected and grouped for the

evaluation of antidyslipidemic activity of the compounds. The group

ﬁrst was treated as sham-treated control group and was given 1% gum

acacia. Other groups were treated as treatment groups and were dosed

at 10, 30, and 100 mg/kg of body weight of compounds. The standard

drug-treated group was given fenoﬁbrate at the 30 mg/kg dose. Dose-

dependent antidyslipidemic activities were also studied in these

hamsters, and the desired compound was dosed at 10, 30, and 100 mg/kg

to their respective groups. Treatments were done for 7 days. Body weight

Sucrose-Challenged Streptozotocin-Induced Diabetic Rat Model

(STZ-S). Male albino rats of Sprague−Dawley (SD) strain of body

weight 160

20 g were selected for the antihyperglycemic activity

evaluation in sucrose-challenged low-dose streptozotocin-induced rat

model. Streptozotocin (Sigma, U.S.A.) was dissolved in 100 mM

O

dx.doi.org/10.1021/jm201107g | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry

Article

was measured daily to study the body-weight-reducing activity of

compounds. At the end of the experiment, blood was withdrawn from

the retro-orbital plexus of the eye for the estimations of serum

triglyceride, total cholesterol, low-density lipoprotein cholesterol, high-

density lipoprotein cholesterol, lipoprotein lipase, and fasting serum

glucose by using Roche diagnostic kits. Glycerol and nonesteriﬁed free

fatty acid were estimated using Randox kits

AUTHOR INFORMATION

Corresponding Author

*E-mail: r_pratap@cdri.res.in. Tel.: +91-522-2212411 ext.

4347. Fax: +91-522-2623405.

■

Notes

The authors declare no competing ﬁnancial interest.

Pharmacokinetic Study in Sprague−Dawley Rats. The pharma-

cokinetic behavior was studied to estimate the relative bioavailability of

the compounds following the literature or in-house protocols. Young

and healthy male Sprague−Dawley rats weighing 225 25 g (obtained

from Laboratory Animal Division of Institute) were housed in well-

ventilated cages and kept at room temperature on a regular 12-h light−

dark cycle. The intravenous dosing formulation of compounds 70 was

prepared in DMF/PG/water (5:4:1, v/v) and ﬁnally ﬁltered through

0.2 μ ﬁlter before administration of 10 mg/kg dose, which was

administered through tail vein in rat. Blood samples were collected at

diﬀerent times ranging from 0.08 to 48 h post i.v. dose in heparinized

glass tube. For the oral pharmacokinetic study, the aqueous suspension

of compound 70 with 0.5% methyl cellulose was administered by oral

feeding needle in rats at dose 40 mg/kg. The animals were fasted for

10−12 h prior to dose. Blood samples were collected at diﬀerent times

ranging from 0.25 to 120 h after oral dose. The plasma was separated

by centrifuging at 2000g for 10 min at 4 °C and stored at −60 °C.

Sample analysis was done by LC-MS/MS method, and the linearity

range was taken to be 0.78−400 ng/mL. Pharmacokinetic parameters

were determined by using WinNonlin version 5.1 (Pharsight Corp,

U.S.A.).

The single-dose pharmacokinetic study of compound 70a at dose

25 mg/kg was done after oral administration in rats. The intravenous

dosing formulation of compound 70a was administered at 2.5 mg/kg

dose. The intravenous dosing formulation of compound 90a was

prepared in DMF/PG/water (2:4:4 v/v) and ﬁnally ﬁltered through

0.2 μ ﬁlter before administration of 2.5 mg/kg dose. For the oral

pharmacokinetic study, the aqueous suspension of compound 90a with

0.5% methyl cellulose was administered by oral feeding needle in rats

at dose 25 mg/kg. Blood samples were collected at diﬀerent times

ranging from 0.08 to 48 h after oral and intravenous dose. Sample

analysis was done by LC-MS/MS method, and the linearity range was

taken to be 0.78−400 ng/mL. Pharmacokinetic parameters were

determined by using WinNonlin version 5.1 (Pharsight Corp, U.S.A.).

Male albino rats of Sprague−Dawley (SD) strain of body weight

160 20 g were selected for the antihyperglycemic activity evaluation

in sucrose-challenged low-dose streptozotocin-induced rat model.

Streptozotocin (Sigma, U.S.A.) was dissolved in 100 mM citrate buﬀer,

pH 4.5, and the calculated amount of the fresh solution was injected

intraperitoneally to the overfasted rats at the dose 60 mg/kg. Blood

glucose was checked 48 h later by glucostrips (Boehringer

Mannheim), and animals showing blood glucose value between 160

and 300 mg/dL were selected and grouped, with each group consisting

of 5−6 animals. Oral sucrose load (2.5 g/kg) was given simultaneously

with compounds 70, 70a, or 90a or with metformin. The experimental

groups were dosed at 100 mg/kg, and the control group was given an

equal volume of 1% gum acacia. Blood glucose proﬁle was measured at

0, 30, 60, 90, 120, 180, 240, and 300 min, respectively, after sucrose

challenge. Food was withdrawn during the period 0−5 h only. Animals

received water ad lib.

ACKNOWLEDGMENTS

■

We acknowledge the division of Sophisticated and Analytical

Instrumentation Facilities (SAIF) of the Institute for providing

characterization and analysis data. Authors are also thankful to

CSIR, New Delhi, for awarding fellowships to A. K. Verma, M.

Satyanarayana, P. Tiwari, S. P. Srivastava, and A. B. Singh.

CDRI manuscript No. 188-2010.

ABBREVIATIONS USED

■

HDL-C,high-density lipoprotein cholesterol; LDL-C,low-den-

sity lipoprotein cholesterol; DMF,N,N-dimethylformamide;

HPLC,high-performance liquid chromatography; STZ,strepto-

zotocin; TG,triglycerides; CHOL,cholesterol; PL,phospholi-

pids; AUC,area under curve; ED₅₀,eﬀective dose for desired

response in 50% population; NEFA,nonesteriﬁed fatty acids;

LPL,lipoprotein lipase; MRT,maximum retention time; ESM-

S,electron spray mass spectroscopy; HRMS,high-resolution

mass spectroscopy; NMR,nuclear magnetic resonance; DMSO,-

dimethylsulfoxide; FAB-MS,fast atomic bombardment mass

spectroscopy

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ASSOCIATED CONTENT

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