WO2012033266A1

WO2012033266A1 - Novel artemisinin or deoxoartemisinin-glycolipid hybrid derivatives and antiangiogenic use thereof

Info

Publication number: WO2012033266A1
Application number: PCT/KR2011/000043
Authority: WO
Inventors: Man Kii Jung; Ricci Jeremy; Kwang Kyun Park; Won Yoon Chung
Original assignee: Industry-Academic Cooperation Foundation, Yonsei University
Priority date: 2010-09-07
Filing date: 2011-01-05
Publication date: 2012-03-15
Also published as: KR101277710B1; KR20120025272A

Abstract

The present invention relates to a novel artemisinin or deoxoartemisinin-glycolipid hybrid derivatives and antiangiogenic use thereof. The artemisinin or deoxoartemisinin-glycolipid hybrid derivatives of the present invention exhibit two or more times stronger activity than the existing drugs and little or no cellular toxicity to address safety to human body.

Description

NOVEL ARTEMISININ OR DEOXOARTEMISININ-GLYCOLIPID HYBRID DERIVATIVES AND ANTIANGIOGENIC USE THEREOF

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION

The present invention relates to a novel artemisinin or deoxoartemisinin-glycolipid hybrid derivatives and antiangiogenic use thereof.

DESCRIPTION OF THE RELATED ART

Angiogenesis is a physical process in which new blood vessels are formed from preexisting vessels. The blockade of vascular endothelial growth factor results in regression of the disease and prolongation of survival when used for anti-cancer therapy.¹ Discovery of new antiangiogenic agents based on small molecules is an attractive approach for the treatment of cancer.

Artemisinin, a sesquiterpene endoperoxide isolated from Artemisia annua L², is represented by the following chemical formula:

Artemisinin and its derivatives have been reported as potential antitumor agents,³ and also been known to have antiangiogenic activity.⁴ In a previous report, we described the potent antiangiogenic effects of artemisinin derivatives.⁵ Non acetal-type derivates at C-12 of artemisinin and their dimers including a fullerene conjugate were synthesized and some of them showed potent in vivo antiangiogenic activity on the chorioallantoic membrane that was higher than or comparable to those of fumagillin and thalidomide.⁵ Furthermore, novel amide derivatives of a C-12 non acetal deoxoartemisinin trimer were synthesized and showed potent in vivo antiangiogenic activity according to the results of mouse matrigel plug assays.³'¹

Recently, some studies have reported the antiangiogenic activity of glycolipids.⁶ Daumone, originally isolated from Caenorhabditis elegans, was identified by our laboratory and its total synthesis was presented.⁷ Daumone is represented by the following chemical formula:

In a continuation of the investigation, we studied the anticancer activity of daumone against human cell lines.⁶ Daumone and tri-deoxyrhamnose derivatives containing amide side chains were the most potent anticancer compounds that we surveyed, with effective concentrations in the nanomolar range, which is comparable to that of doxorubicin.⁸

Although various antiangiogenic agents have been developed, adverse side effects and limitations associated with antitumor therapies have recently become apparent. Cancer is a complex disease. In order to improve the activity of anticancer agents, treatment using hybrid dnjgs, an approach that incorporates two drugs in a single molecule, has been developed.⁹ The use of hybrid drugs can impact multiple targets simultaneously. Throughout this application, several patents and publications are referenced and citations are provided in parentheses. The disclosure of these patents and publications is incorporated into this application in order to more fully describe this invention and the state of the art to which this invention pertains. SUMMARY OF THE INVENTION

The present inventors have made intensive research to develop a novel compound having excellent antiangiogenic and anticancer activity. As a result, the inventors have synthesized various artemisinin or deoxoartemisinin-glycolipid hybrid derivatives which exhibit two or more times stronger activity than that of the existing drugs, thus completed the present invention. Accordingly, it is an object of this invention to provide a novel artemisinin or deoxoartemisinin-glycolipid hybrid derivative.

It is another object of this invention to provide a pharmaceutical composition for preventing or treating an angiogenic disease.

It is still another object of this invention to provide a method for preventing or treating an angiogenic disease.

Other objects and advantages of the present invention will become apparent from the detailed description to follow taken in conjugation with the appended claims and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 represents the method of synthesizing compound 3i, one of the chemical compounds prepared in Example, by coupling reaction of deoxoartemisinin and glycolipid.

Fig. 2 represents the chemical structure of the deoxoartemisinin-glycolipid hybrid derivative of the present invention prepared in Example.

Rg. 3 is an image showing the antiangiogenic activity of artemisinin or deoxoartemisinin-glycolipid hybrid derivatives to the CAM (chick chorioallantoic membrane), (a) an image of control CAM, (b) an image of CAM treated with the artemisinin or deoxoartemisinin-glycolipid hybrid derivative of the present invention at a concentration of 2.5 nmol/egg.

DETAILED DESCRIPTION OF THIS INVETNION

In one aspect of the present invention, there is provided an artemisinin or deoxoartemisinin-glycolipid hybrid derivative represented by the Chemical Formula selected from the group consisting of the following Chemical Formulas 1-3:

wherein each Ri and R₂ is independently hydrogen, halogen, Ci-C₁₀alkyl, Ci-Ci₀alkenyl, Ci-Cioalkynyl, Q-Qo aryl, Q-Qo alkylaryl, Q-Qo arylalkyl, or Q-Qo heteroaryl;

each of R₃-R6 is independently hydrogen, hydroxyl, alkoxy, carboxyl, halogen, nitro, Ci- CioalkyI, Q-Cioalkenyl, d-Qoalkynyl, C5-C50 aryl, Q-Ceo alkylaryl, Q-Qo arylalkyl, or Q-Qo heteroaryl;

X and Yare each independently substituted or unsubstituted linear or branched Q-Qo alkylene, or substituted or unsubstituted linear or branched Q-Q₀alkenylene; and each of m, n and k is independently 0 or 1.

The present inventors have made intensive research to develop a novel compound having excellent antiangiogenic and anticancer activity. As a result, the inventors have synthesized various artemisinin or deoxoartemisinin-glycolipid hybrid derivatives which exhibit two or more times stronger activity than that of the existing drugs, thus completed the present invention.

The artemisinin or deoxoartemisinin-glycolipid hybrid derivatives of the present invention may be synthesized by reacting various artemisinin or deoxoartemisinin derivatives with various glycoprotein derivatives. Deoxoartemisinin means a form of artemisinin in which an oxygen connected to a carbon at position 12 by a double bond is missed. If the hybrid of the present invention is synthesized from a deoxoartemisinin, the hybrid gets to have a nonacetal form at the 12^th carbon position.

One of the distinctive features of the deoxoartemisinin-glycolipid hybrid derivatives is to have a nonacetal form at the 12* carbon position. The C-12 nonacetal-type artemisinin- glycolipid hybrids show more excellent antiangiogenic activity than the C-12 acetal-type artemisinin-glycolipid hybrids.

In the Chemical Formulas 1-3, the substituent indicated as Ri or R₂ which is bound to the oxygen is each independently hydrogen, halogen, Q-Cioalkyl, CrQ₀ alkenyl, Q-Cioalkynyl, QrQo aryl, Q-Qo alkylaryl, Q-Qo arylalkyl, or Q-Qo heteroaryl; preferably hydrogen, substituted or unsubstituted linear or branched Ci-C₅alkyl, or benzyl.

The term "Q-Q₀ alkyl" as used herein in conjunction with R group of the Formulas, means linear or branched monovalent saturated hydrocarbon having 1-10 carbon atoms, which includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyi, or various isomers thereof, but not limited to.

The term "Q-Qo alkenyl" as used herein refers to branched or unbranched unsaturated hydrocarbon having 1-10 carbon atoms and one or more carbon-carbon double bonds. Alkenyl may comprise two or more carbon-carbon double bonds, and the double bonds may be conjugated or nonconjugated with each other. Alkenyl includes vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, petadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3- butene)-pentenyl, heptenyl, octenyl, nonenyi, decenyl, or isomers thereof, but not limited to.

The term "Q-Qo alkynyl" as used herein refers to randomly substituted {e.g., substituted one or more) hydrocarbon radical (monovalent hydrocarbon) comprising 1 to 10 carbon atoms and one or more carbon-carbon triple bond.

The term "Q-Qo aryl" as used herein refers to wholly or partially substituted or unsubstituted unsaturated monocyclic or polycyclic carbon ring having 6-60 carbon atoms, which satisfies the law of Hiickel. Aryl {e.g., phenyl) may be substituted at various positions by various substituent_* for example by halo, hydroxy!, nitro, cyano, substituted or unsubstituted linear or branched Q-Q alkyl, or linear or branched Q-Q alkoxy, but not limited to.

The term "arylalkyl {e.g. benzyl)" means alkyl group which is substituted by one or more aryl groups. The term "alkylaryl (alkaryl)" means aryl group which is substituted by one or more alkyl groups.

The term "heteroaryl" means heterocyclic aromatic group containing heteroatoms such as N, O and S. Heteroaryl may be substituted at various positions by various substituent, for example by halo, hydroxyl, nitro, cyano, substituted or unsubstituted linear or branched Q-Q alkyl, or linear or branched Q-Q alkoxy, but not limited to.

In the Chemical Formulas 1-3, the substituent indicated as the one of R₃-Re which is directly bound to the ring carbon is independently hydrogen, hydroxyl, alkoxy, carboxyl, halogen, nitro, Q-Q₀ alkyl, Q-Q₀ alkenyl, Q-Q₀ alkynyl, Q-Qo aryl, Q-Qo alkylaryl, Q-Qo arylalkyl, or Q-Qo heteroaryl; preferably hydrogen, hydroxyl, alkoxy, carboxyl, or substituted or unsubstituted linear or branched Q-Q alkyl.

In the Chemical Formulas 1-3, X and Y are each independently substituted or unsubstituted linear or branched Q-Q₀ alkylene, or substituted or unsubstituted linear or branched Q-Q₀alkenylene; preferably substituted or unsubstituted linear or branched Q-Q₀ alkylene.

The term "Q-Q₀ alkylene" as used herein refers to linear or branched divalent alkyl radical having 1-10 carbon atoms, which includes but not limited to methylene, ethylene, iso- propylene, butylene, sec-butylene, pentylene, 1-methyl pentylene, 5-methyl pentylene, hexylene, heptylene, octylene, nonylene, decylene, or isomers theroof.

The term "Q-Q₀ alkenylene" refers to linear or branched divalent unsaturated alkyl radical having 1-10 carbon atoms and one or more carbon-carbon double bonds. Alkenylene may comprise two or more carbon-carbon double bonds, and the double bonds may be conjugated or nonconjugated with each other.

In the Chemical Formulas 1-3, each of m, n and k is independently 0 or 1. The artemisinin or deoxoartemisinin-glycolipid hybrid derivatives of the present invention may be synthesized by coupling various artemisinin or deoxoartemisinin derivatives with diverse glycolipid derivatives. If the carboxyl acid or ester of the artemisinin or deoxoartemisinin derivative reacts with the hydroxyl or alkoxy of the glycolipid derivative to form the one of the hybrids of the present invention, n is 1. On the other hand, if the hydroxyl or alkoxy of the artemisinin or deoxoartemisinin derivative reacts with the carboxyl acid or ester of the glycolipid derivative to form the one of the hybrids of the present invention, n is 0.

If the m is 1 in the Chemical Formulas 1-3, the hybrid of the present invention is C-12 acetal-type artemisinin-glycolipid hybrid. If the m is 0 and the k is 1, the hybrid of the present invention is C-12 nonacetal-type artemisinin-glycolipid hybrid. Even though the m is 0, the hybrid of the present invention is C-12 acetal-type artemisinin-glycolipid hybrid if the k and the n are both 0.

The artemisinin or deoxoartemisinin-glycolipid hybrids of the present invention may comprise 12 or more chiral centers and the various stereoisomers of the hybrids are intended to be included within the scope of the invention.

In an preferred embodiment, the artemisinin or deoxoartemisinin-glycolipid hybrid derivative of the present invention may be represented by the one of the following Chemical Formulas 4-12:

The compounds represented by the chemical formulas 1-12 are novel chemical compounds and exhibit still more excellent antiangiogenic activity than existing drugs.

In another aspect of the present invention, there is provided a method of synthesizing the artemisinin or deoxoartemisinin-glycolipid hybrid derivative of claim 1 or 2, which comprises: coupling the compound of the following Chemical Formula 13 with the compound of the following Chemical Formula 14; or coupling the compound of the following Chemical Formula 15 with the compound of the following Chemical Formula 16:

5)

wherein each of Ri, R₂, R' and R" is independently hydrogen, halogen, Q-Qoalkyl, Q- C₁₀alkenyl, Ci-C₁₀alkynyl, Q-Qo aryl, Q-Qo alkylaryl, Q-Qo arylalkyi, or Q-Qo heteroaryl; each of R3-R5 is independently hydrogen, hydroxyl, alkoxy, carboxyl, halogen, nitro, Q-

Cioalkyl, Q-Qoalkenyl, Ci-Q₀alkynyl, Q-Qo aryl, Q-Qo alkylaryl, Q-Qo arylalkyi, or Q-Qo heteroaryl;

X and Yare each independently substituted or unsubstituted linear or branched Ci-Q₀ alkylene, or substituted or unsubstituted linear or branched Q-Ci₀alkenylene; and each m and k is independently 0 or 1.

In an preferred embodiment, the coupling is earned out by a transesterification reaction. The carboxyl acid or ester of the artemisinin or deoxoartemisinin derivative may react with the hydroxyl or alkoxy of the glycolipid derivative to form the one of the hybrids of the present invention, or the hydroxyl or alkoxy of the artemisinin or deoxoartemisinin derivative may react with the carboxyl add or ester of the glycolipid derivative to form the one of the hybrids of the present invention. For example, one of the artemisinin or deoxoartemisinin-glycolipid hybrid derivatives of the present invention may be synthesized by the coupling reaction depicted in Figure 1.

In still another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating an angiogenic disease comprising (a) a pharmaceutically effective amount of the artemisinin or deoxoartemisinin-glycolipid hybrid derivative; and (b) a pharmaceutically acceptable carrier.

In a further aspect of the present invention, there is provided a method for preventing or treating an angiogenic disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising (a) a pharmaceutically effective amount of the artemisinin or deoxoartemisinin-glycolipid hybrid derivative; and (b) a pharmaceutically acceptable carrier.

The term "pharmaceutically effective amount" refers to an amount enough to show and accomplish efficades and activities of the compound of this invention for preventing or treating an angiogenic disease. The pharmaceutical composition of this invention comprises a pharmaceutically acceptable carrier besides the active ingredient compound.

The pharmaceutically acceptable earner contained in the pharmaceutical composition of the present invention, which is commonly used in pharmaceutical formulations, but is not limited to, includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, rubber arable, potassium phosphate, arginate, gelatin, potassium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, and mineral oils. The pharmaceutical composition according to the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, and a preservative. Details of suitable pharmaceutically acceptable earners and formulations can be found in Remingtons' Pharmaceutical Sciences (19th ed., 1995), which is incorporated herein by reference.

The pharmaceutical composition of this invention may be administered orally or parenterally. For non-oral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection or transdermal administration may be employed.

A suitable dose of the pharmaceutical composition of the present invention may vary depending on pharmaceutical formulation methods, administration methods, the patient's age, body weight, sex, severity of diseases, diet, administration time, administration route, an excretion rate and sensitivity for a used pharmaceutical composition. Physicians of ordinary skill in the art can determine an effective amount of the pharmaceutical composition for desired treatment Preferably, the pharmaceutical composition of the present invention is administered with a daily dose of 0.001-1000 mg/kg (body weight).

According to the conventional techniques known to those skilled in the art, the pharmaceutical composition according to the present invention may be formulated with pharmaceutically acceptable carrier and/or vehicle as described above, finally providing several forms including a unit dose form and a multi-dose form. Non-limiting examples of the formulations include, but not limited to, a solution, a suspension or an emulsion in oil or aqueous medium, an elixir, a powder, a granule, a tablet and a capsule, and may further comprise a dispersion agent or a stabilizer.

According to a preferred embodiment, the pharmaceutical composition is used to prevent or treat an angiogenic disease, for example cancer, hemangiomas, diabetic retinopathy, retinopathy of prematurity, rejection after corneal transplant, angiogenic glaucoma, erythromelanosis follicularis faciei et coli, proliferative retinopathy, psoriasis, hemophilic arthritis, plaque angiogenesis in atherosclerosis, keloid, granulation tissue in wound, blood vessel adhesion, rheumatoid arthritis, osteoarthritis, autoimmune disease, Crohn's disease, recurrent stenosis, atherosclerosis, enteroadhesion, cat scratch disease, ulcer, liver cirrhosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, rejection after organ transplant, glomerulonephritis, diabetes, or inflammation.

The artemisinin or deoxoartemisinin-glycolipid hybrid derivative which is an active ingredient in the pharmaceutical composition of the present invention is preferably represented by the one of trie above Chemical Formulas 7-10, most preferably by the Chemical Formula 10. The compound of the Chemical Formula 10 shows no cytotoxicity, even though it has especially strong inhibiting activity to angiogenesis.

The pharmaceutical composition of the present invention may be used to treat an angiogenic disease including cancer, preferably, breast cancer, lung cancer, or oral cancer, most preferably oral cancer. The chemical compound represented by the one of the above Chemical Formulas 7-10 has an excellent antiangiogenic activity so that it can effectively treat breast cancer, lung cancer, or oral cancer.

The present invention will now be described in further detail by examples. It would be obvious to those skilled in the art that these examples are intended to be more concretely illustrative and the scope of the present invention as set forth in the appended claims is not limited to or by the examples.

EXAMPLES

Example 1: Preparation of Artemisinin or Deoxoartemisinin-glycolipid Hybrid Derivatives

The various derivatives of Artemisinin (dihydroartemisinin (la), hydroxyethyl deoxoartemisinin (lb), hydroxypropyl deoxoartemisinin (lc), and carboxymethyl deoxoartemisinin (Id)) were prepared according to the previously-described procedures.¹⁰ Glycolipid (daumone) and its derivatives (dibenzoyl daumone (2a) and daumone alcohol (2b)) were synthesized according to the previously-reported procedures.^7,8 Then, a short series of artemisinin-glycolipid hybrids (3a-3k) covalently linked were prepared by efficient coupling reactions and their structures were confirmed by spectral analysis as follows: 1. Preparation of Compound 3a

A stirred solution of dihydroartemisinin (DHA) (20.6 mg, 0.072 mmol), EDC (139.0 mg, 0.72 mmol, Sigma Aldrich, Korea) and DMAP (88.0 mg, 0.72 mmol, Sigma Aldrich, Korea) in DMF (2 ml) was combined with daumone 2 (20.0 mg, 0.072 mmol) at room temperature during 12 hours. The reaction mixture was quenched with slow addition of satured citric acid (2 ml), extracted with ethyl acetate (3x5 ml) and washed with NaHC0₃ (5 ml) and brine (5 ml). The organic layer was dried over MgS0₄, filtered and concentrated in vacuo. The mixture was purified by flash column chromatography on silica gel with ethyl acetate as eluant to give compound 3a (28.8 mg, 0.053 mmol, 733 % yield).

To confirm the chemical structure of the artemisinin-glycolipid hybrid synthesized, NMR spectra were obtained on Bruker AC250 spectrometer using Me4Si as an internal standard and ¹³C NMR spectra (100 MHz) were measured on the same instrument. The GC-MS and direct mass were operated on an HP 5980Π GC-HP 5988 and JMS-700 Mstation spectrometer in FAB mode. Infrared spectra were taken on a Nicolet Impact 400 spectrometer. Anhydrous solvents were either obtained from commercial sources or dried and distilled immediately prior to use under a constant flow of dry nitrogen. All other reagents were used as received from Sigma Adrich, TO, or Hsher.

The spectra data obtained were as follows:

*H NMR (250 MHz, CDCI3) δ ppm 0.84 (d, J=6.95 Hz, 3H), 0.96 (d, 5.69 Hz, 3H), 1.12 (d, J=6.00 Hz, 3H), 1.28 (d, J=6.00 Hz, 3H), 1.43 (s, 3H), 1.48-1.95 (m, 17H), 1.98-2.14 (m, 1H), 2.30-2.38 (m, 1H), 2.42 (dd, J=7.58 Hz, 2H), 2.50-2.64 (m, 1H), 3.53-3.86 (m, 4H), 4.70 (s, 1H), 5.44 (s, 1H), 5.76 (s, 0.5H), 5.80 (s, 0.5H). ¹³C NMR (63 MHz, CDCI₃) δ ppm 12.10, 17.70, 18.85, 20.19, 21.03, 21.96, 24.57, 25.06, 25.92, 31.77, 34.07, 34.16, 35.21, 36.20, 36.69, 37.22, 45.22, 51.55, 68.07, 69.28, 69.86, 70.92, 80.12, 91.47, 91.78, 95.80, 104.44, 172.54. IR (KBr, cm ¹) v max 3431, 2928, 2878, 2361, 2337, 1747, 1455, 1376, 1234, 1203, 1131, 1098, 1031; HRMS (FAB) calcd for [M + Na]⁺ m/z 565.2989, found 565.2970. 2. Preparation of Compound 3b

A stirred solution of hydroxyethyldeoxoartemisinin (22.6 mg, 0.072 mmol), EDC (139.0 mg, 0.72 mmol) and DMAP (88.0 mg, 0.72 mmol) in DMF (2 ml) was combined with daumone (20.0 mg, 0.072 mmol) at room temperature during 12 hours. The reaction mixture was quenched with slow addition of satured citric acid (2 ml), extracted with ethyl acetate (3x5 ml) and washed with NaHC(¾ (5 ml) and brine (5 ml). The organic layer was dried over gS0₄, filtered and concentrated in vacuo. The mixture was purified by flash column chromatography on silica gel with ethyl acetate as eluant to give compound 3b (24.4 mg, 0.043 mmol, 59.1 % yield).

To confirm the chemical structure of the artemisinin-glycolipid hybrid synthesized, the spectra data were obtained in the same manner as described above, and the resulting data were as follows:

*H NMR (250 MHz, CDCI₃) . ppm 0.87 (d, J=7.27 Hz, 3H), 0.96 (d, J=4.74 Hz, 3H),

1.12 (d, 6.00 Hz, 3H), 1.28 (d, J=5.69 Hz, 3H), 1.41 (s, 3H), 1.53-2.15 (m, 19H), 2.24-2.42 (m, 3H), 2.58-2.79 (m, 1H), 3.49-3.92 (m, 4H), 4.06-4.38 (m, 3H), 4.70 (s, 1H), 5.30 (s, 1H). ¹³C NMR (63 MHz, CDCI₃) . ppm 12.91, 17.70, 18.90, 20.16, 24.70, 24.77, 24.89, 25.19, 26.05, 29.69, 34.00, 34.26, 34.43, 35.21, 36.53, 36.76, 37.47, 44.26, 52.30, 62.46, 68.11, 69.34, 69.88, 70.97, 71.76, 81.06, 88.96, 95.82, 103.23, 173.78. IR (KBr, cm^"1) v max 3450, 2928, 2878, 2361, 2337, 1734, 1455, 1376, 1130, 1100, 1044.: HRMS (FAB) calcd for CaoHsAo [M]⁺ /77/Z593.3302, found 593.3382.

3. Preparation of Compound 3c

A stirred solution of hydroxypropyldeoxoartemisinin (23.6 mg, 0.072 mmol), EDC (139.0 mg, 0.72 mmol) and DMAP (88.0 mg, 0.72 mmol) in DMF (2 ml) was combined with daumone (20.0 mg, 0.072 mmol) at room temperature during 12 hours. Trie reaction mixture was quenched with slow addition of satured citric acid (2 ml), extracted with ethyl acetate (3x5 ml) and washed with NaHC0₃ (5 ml) and brine (5 ml). The organic layer was dried over MgS0₄, filtered and concentrated in vacuo. The mixture was purified by flash column chromatography on silica gel with ethyl acetate as eluant to give compound 3c (10.0 mg, 0.017 mmol, 23.6 % yield).

*H NMR (250 MHz, CDCI₃) 5 ppm 0.86 (d, 7.27 Hz, 3H), 0.96 (d, J=5.37 Hz, 3H), 1.13 (d, J=6.00 Hz, 3H), 1.28 (d, J=6.00 Hz, 3H), 1.42 (s, 3H), 1.55-2.17 (m, 25H), 2.24-2.41 (m, 3H), 2.60-2.74 (m, 1H) 3.48-3.88 (m, 4H), 4.11 (t, 6.32 Hz, 2H), 4.16 29 (m, 1H), 4.71 (s, 1H), 5.30 (s, 1H). ¾ NMR (63 MHz, CDCI₃) 5 ppm 12.87, 17.72, 18.90, 20.16, 24.73, 24.91, 24.97, 25.20, 25.98, 26.68, 30.28, 31.21, 34.27, 34.43, 35.21, 36.57, 36.78, 37.48, 44.25, 52.26, 62.76, 68.07, 69.32, 69.85, 70.89, 74.74, 81.12, 89.15, 95.78, 103.14, 173.88.: IR (KBr, cm ¹) v max 3440, 2928, 2873, 2364, 2342, 1732, 1455, 1376, 1175, 1138, 1102, 1043. : HRMS (FAB) calcd for

[M + Na]⁺ m/z 607.3458, found 607.3436.

4. Preparation of Compound 3d

A stirred solution of D dihydroartemisinin (DHA) (11.2 mg, 0.039 mmol), EDC (75.0 mg, 0.39 mmol) and DMAP (47.9 mg, 0.39 mmol) in DMF (2 ml) was combined with dibenzoyl daumone (19.0 mg, 0.039 mmol) at room temperature during 12 hours. The reaction mixture was quenched with slow addition of satured dtric acid (2 ml), extracted with ethyl acetate (3x5 ml) and washed with NaHC0₃ (5 ml) and brine (5 ml). The organic layer was dried over MgS0₄, filtered and concentrated in vacuo. The mixture was purified by flash column chromatography on silica gel with ethyl acetate as eluant to give compound 3d (18.4 mg, 0.025 mmol, 62.5 % yield).

*H NMR (250 MHz, CDCI₃) 5 ppm 0.84 (d, J=7.27 Hz, 3H), 0.96 (d, J=6.00 Hz, 3H), 1.19 (d, J=6.00 Hz, 3H), 1.29 (d, 6.00 Hz, 3H), 1.43 (s, 3H), 1.48-2.70 (m, 17H), 3.82-3.91 (m, 1H), 3.92 (m, 1H), 4.13^.07 (m, 2H), 4.95 (s, 1H), 5.40 (s, 1H), 5.78 (s, 0.5H), 5,82 (s, 0.5H), 7.40-7.55 (m, 4H), 7.59 (t, 7.27 Hz, 2H), 8.01-8.16 (m, 4H). ¹³C NMR (63 MHz, CDCI₃) 8 ppm 12.12, 17.88, 19.06, 20.16, 21.93, 24.55, 24.65, 25.19, 25.93, 29.69, 31.78, 34.04, 34.26, 36.20, 36.77, 37.18, 45.20, 51.53, 66.97, 70.66, 71.20, 72.28, 80.08, 91.45, 91.70, 93.69, 104.39, 128.40, 128.44, 129.53, 129.64, 129.83, 129.99, 133.14, 133.18, 165.65, 165.74, 172.28. IR (KBr, cm^"1) v max 2930, 2873, 2364, 2337, 1721, 1451, 1368, 1310, 1266, 1107, 1025. : HRMS (FAB) calcd for

[M + Na]⁺ m/z 773.3513, found 773.3510 .

5. Preparation of Compound 3e

A stirred solution of hydroxyemyldeoxoartemisinin (11.0 mg, 0.035 mmol), EDC (67.3 mg, 0.35 mmol) and D AP (42.9 mg, 0.35 mmol) in DMF (2 ml) was combined with dibenzoyl daumone (17.0 mg, 0.035 mmol) at room temperature during 12 hours. The reaction mixture was quenched with slow addition of satured citric acid (2 ml), extracted with ethyl acetate (3x5 ml) and washed with NaHC0₃ (5 ml) and brine (5 ml). The organic layer was dried over MgS0₄, filtered and concentrated in vacuo. The mixture was purified by flash column chromatography on silica gel with ethyl acetate as eluant to give compound 3e (14.0 mg, 0.018 mmol, 51.2 % yield).

*H NMR (250 MHz, CDCI₃) 5 ppm 0.86 (d, J=721 Hz, 3H), 0.95 (d, J=5.37 Hz, 3H), 1.19 (d, =6.00 Hz, 3H), 1.28 (d, J=6.32 Hz, 3H), 1.40 (s, 3H), 1.52-2.30 (m, 20H), 2.24-2.58 (m, 3H), 2.58-2.82 (m, 1H), 3.78-3.95 (m, 1H), 4.04-4.17 (m, 1H), 4.17-4.46 (m, 3H), 4.95 (s, 1H), 5.08-5.25 (m, 2H), 5.30 (s, 1H), 7.47 (t, J=7.42 Hz, 4H), 7.59 (t, J=7.27 Hz, 2H), 8.09 (dd, 14.06, 7.42 Hz, 4H).: IR (KBr, cm^"1) v max 2934, 2873, 2360, 2342, 1722, 1452, 1381, 1310, 1267, 1175, 1104, 1068, 1025. : HRMS (FAB) calcd for CwHsjNaC [M + Na]⁺ m/z 801.3826, found 801.3862.

6. Preparation of Compound 3f

A stirred solution of hydroxyprapyldeoxoartemisinin (11.5 mg, 0.035 mmol), EDC (67.3 mg, 0.35 mmol) and DMAP (42.9 mg, 0.35 mmol) in DMF (2 ml) was combined with dibenzoyi daumone (17.0 mg, 0.035 mmol) at room temperature during 12 hours. The reaction mixture was quenched with slow addition of satured citric acid (2 ml), extracted with ethyl acetate (3x5 ml) and washed with NaHC⁽¾ (5 ml) and brine (5 ml). The organic layer was dried over gS0₄, filtered and concentrated in vacuo. The mixture was purified by flash column chromatography on silica gel with ethyl acetate as eluant to give compound 3f (13.4 mg, 0.017 mmol, 48.2 % yield).

*H NMR (250 MHz, CDCI₃) . ppm 0.85 (d, 7.58 Hz, 3H), 0.94 (d, J=5.05 Hz, 3H), 1.20 (d, J=6.32 Hz, 3H), 1.26 (d, J=4.42 Hz, 3H), 1.41 (s, 3H), 1.44-2.34 (m, 22H), 2.34-2.56 (m, 3H), 2.65 (dd, J= 13.58, 6.63 Hz, 1H), 3.79-3.93 (m, 1H), 4.04-4.26 (m, 4H), 4.95 (s, 1H), 5.10-5.26 (m, 2H), 5.29 (s, 1H), 7.47 (t, J=7.27 Hz, 4H), 7.59 (t, J=7.11 Hz, 2H), 8.09 (dd, _ = 14.22, 7.27 Hz, 4H).: IR (KBr, cm^"1) v max 2929, 2864, 2355, 2337, 1722, 1451, 1377, 1310, 1266, 1176, 1151, 1106, 1068, 1025. : HRMS (FAB) calcd for QjHeoNaOjz [M + Na]⁺ mjz 815.3982, found 815.3953.

7. Preparation of Compounds 3g and 3h

(3g) (3h)

A stirred solution of cartxjxymethyldeoxoarternisinin (15.0 mg, 0.046 mmol), EDC (88.0 mg, 0.46 mmol) and DMAP (56.1 mg, 0.46 mmol) in DMF (2 ml) was combined with olefinic daumone (15.0 mg, 0.046 mmol) at room temperature during 12 hours. The reaction mixture was quenched with slow addition of satured citric acid (2 ml), extracted with ethyl acetate (3x5 ml) and washed with NaHC(¾ (5 ml) and brine (5 ml). The organic layer was dried over MgS0₄, filtered and concentrated in vacuo. The mixture was purified by flash column chromatography on silica gel with petroleum ether/ethyl acetate (1:1 v/v) as eluant to give compound 3g (2.0 mg, 0.004 mmol, 7.7 % yield) and Compound 3h (4.1 mg, 0.007 mmol, 15.7 % yield).

To confirm the chemical structures of the artemisinin-glycolipid hybrids synthesized, the spectra data were obtained in the same manner as described above, and the resulting data were as follows:

Compound 3g. ^JH NMR (250 MHz, CDCI₃) . ppm 0.87 (d, J=7.58 Hz, 3H,) 0.97 (d,

J=5.69 Hz, 3H), 1.11 (d, J=6.00 Hz, 3H), 1.16-1.27 (m, 4H), 1.28 (d, 5.69 Hz, 3H), 1.41 (s, 3H), 1.49-2.23 (m, 17H), 2.25-2.49 (m, 2H), 2.61-2.83 (m, 1H), 3.58-3.85 (m, 3H), 3.63-3.71 (m, 1H), 4.70-4.82 (m, 1H), 4.73 (s, 1H), 4.91 (br. s., 1H), 4.94 (d, J= 10.19 Hz, 1H), 5.00 (d, J= 16.98 Hz, 1H), 5.34 (s, 1H), 5.70-5.93 (tdd, J= 16.98, 10.19, 6.63, 6.63 Hz, 1H). IR (KBr, cm^"1) v max 2924, 2851, 2369, 2337, 1734, 1456, 1368.: HRMS (FAB) calcd for C30H5A0 [M + H]⁺ 77/Z567.9899, found 567.9833

Compound 3h: ^JH NMR (250 MHz, CDd₃) . ppm 0.87 (d, J=7.58 Hz, 3H), 0,96 (d, J=5.37, 3H), 1.07-1.24 (m, 4H), 1.12 (d, J=6.32 Hz, 3H), 1.21 (d, J=6.00 Hz, 3H), 1.40 (s, 3H), 1.48-2.23 (m, 17H), 2.24-2.56 (m, 2H), 2.60-2.84 (m, 2H), 3.72-3.85 (m, 2H), 3.89 (m, 1H), 4.67-4.82 (m, 1H), 4.71 (s, 1H), 4.83-4.92 (m, 1H), 4.95 (d, J= 10.23 Hz, 1H), 5.00 (d, J= 16.94 Hz, IH), 5.32 (s, IH), 5.82 (tdd, J= 16.94, 10.23, 6.79, 6.79 Hz, IH).: IR (KBr, cm^"1) v max 3473, 2927, 2873, 2360, 2342, 1736, 1463, 1373, 1202, 1130, 1103, 1039.: HRMS (FAB) calcd for C₃iH₅oNa0₉ [M + Na]⁺ m/z 589.3353., found 589.3377. 8. Preparation of Compounds 3i and 3j

(3i) (3j)

A stirred solution of carboxymethyldeoxoartemisinin (24.8 mg, 0.076 mmol), EDC (146.0 mg, 0.76 mmol) and DMAP (93.0 mg, 0.76 mmol) in DMF (2 ml) was combined with daumone alcohol (24.8 mg, 0.076 mmol) at room temperature during 12 hours. The reaction mixture was quenched with slow addition of satured citric acid (2 ml), extracted with ethyl acetate (3x5 ml) and washed with NaHC(¾ (5 ml) and brine (5 ml). The organic layer was dried over MgS0₄, filtered and concentrated in vacuo. The mixture was purified by flash column chromatography on silica gel with ethyl acetate as eluant to give compound 3i (13.0 mg, 0.023 mmol, 29.9 % yield) and compound 3j (2.9 mg, 0.005 mmol, 6.7 % yield).

Compound 3i: *H NMR (250 MHz, CDCL3) . ppm 0.87 (d, J=7.58 Hz, 3H), 0.96 (d, J=5.37 Hz, 3H), 1.11 (d, 4.42 Hz, 3H), 1.27 (d, J=6.46 Hz, 3H), 1.42 (s, 3H), 1.55-2.57 (m, 21H), 2.57-2.83 (m, 2H), 3.59-3.95 (m, 4H), 4.06^.20 (m, J=5.37 Hz, 3H), 4.67^.84 (m, IH), 4.84-4.98 (m, IH), 5.32 (s, IH). IR (KBr, cm ¹) v max 3497, 2927, 2873, 1736, 1452, 1376, 1315, 1234, 1268, 1176, 1105, 1054, 1014.: HRMS (FAB) calcd for QoHs o [M + Na]⁺ m/z570.3404, found 570.3430

Compound 3j: *H NMR (400 MHz, CDCI₃) . ppm 0.87 (d, J=7.52 Hz, 3H), 0.97 (d,

J=5.78, 3H), 1.04-1.55 (m, 8H), 1.12 (d, 5.91 Hz, 3H), 1.27 (d, 6.42 Hz, 3H), 1.40 (s, 3H), 1.73-2.39 (m, 13H), 2.39-2.58 (m, IH), 2.58-2.83 (m, 2H), 3.61-3.72 (m, 3H), 3.73-3.95 (m, 2H), 4.66-4.81 (m, 2H), 4.89 (s, IH), 5.32 (s, IH). IR (KBr, cm^"1) v max 3423, 2929, 2859, 2360, 2341, 1720, 1453, 1376, 1316, 1267, 1178, 1105, 1047, 1017.: HRMS (FAB) calcd for C30H50O10 [M + Na]⁺ 77/Z570.3404, found 570.3423.

9. Preparation of Compound 3k

(3k)

A stirred solution of carboxymethyldeoxoartemisinin (13.9 mg, 0.043 mmol), EDC (81.0 mg, 0.43 mmol) and DMAP (51.9 mg, 0.43 mmol) in DMF (2 ml) was combined with dibenzoyldaumone aldehyde (20.0 mg, 0.043 mmol) at room temperature during 12 hours. The reaction mixture was quenched with slow addition of satured citric acid (2 ml), extracted with ethyl acetate (3x5 ml) and washed with NaHC(¾ (5 ml) and brine (5 ml). The organic layer was dried over MgS0₄, filtered and concentrated in vacuo. The mixture was purified by flash column chromatography on silica gel with ethyl acetate as eluant to give compound 3k (9.8 mg, 0.013 mmol, 29.6 % yield).

H NMR (250 MHz, CDCI₃) . ppm 0.86 (d, J=7.58 Hz, 3Η), 0.96 (d, 3.48 Hz, 3Η), 1.20 (d, J=6.00 Hz, 3H), 1.29 (d, 6.32 Hz, 3H), 1.41 (s, 3H), 1.48-2.35 (m, 20H), 2.36-2.57 (m, 2H), 2.57-2.86 (m, 2H), 3.78-3.96 (m, IH), 4.02-4.24 (m, 3H), 4.74-4.89 (m, IH), 4.95 (s, IH), 5.10-5.27 (m, 2H), 5.32 (s, IH), 7.47 (t, J=7.27 Hz, 4H), 7.59 (t, J=6.79 Hz, 2H), 8.08 (dd, J=16.27, 7.11 Hz, 4H). ¹³C NMR (63 MHz, CDCI₃) . ppm 13.02, 17.89, 19.17, 20.13, 24.65, 24.70, 25.43, 25.95, 25.98, 28.66, 29.73, 34.42, 36.04, 36.51, 37.01, 37.45, 44.23, 52.26, 67.02, 70.66, 71.27, 71.43, 71.62, 72.63, 80.84, 89.05, 89.14, 93.82, 103.21, 128.43, 129.62, 129.85, 129.88, 130.01, 133.15, 133.21, 165.67, 165.78, 171.66.: . IR (KBr, cm ¹) v max 3062, 2936, 2859, 1601, 1452, 1376, 1315, 1267, 1177, 1151, 1106, 1068, 1025.: HRMS (FAB) calcd for C_MHssNaOt_f [M + Na]⁺ /77/z801.3826, found 801.3801

Example 2: Evaluation of Antiangiogenic Activity

The in vivo antiangiogenic activity of the various hybrid compounds was evaluated using the CAM (chick chorioallantoic membrane) vessel development assay as previously described.^5,11

Briefly, fertilized eggs (Pulmuone Co., Kyungki-do, Korea) were incubated at 37 °C with 80-90% relative humidity. At day 3, a window was opened after the removal of 2 ml albumin in the eggs (Rgure 3).

At day 5 of incubation, test samples loaded on a quarter size Thermanox coverslip (Nunc, Roskilde, Denmark) was applied to the CAM of each individual embryo at a concentration of 2.5 nmol/egg. After 2 incubation days, a 20% fat emulsion was injected into the CAM for observation of the inhibition avascular zone. If an avascular zone of about 3-6 mm diameter, as indicated with an arrow in Rgure 4, was observed, then it was considered to represent effective inhibition on neovascularization. The results of these experiments are listed in Table 1. The standard drugs used for comparison were (-)-fumagillin and (-)-thalidomide. Table 1

ion Inhibition

Compounds Positive eggs Inhibit

/ eggs tested effect' (%)

Artemisinin 3 /10 - 30

Daumone 7/10 ++ 70

3a 5 /10 (l)^b + 50

3b 6/10 (2) + 60

3c 6/10 (2) + 60

3d 1 /10 (2) - 10

3e 6 /10 (2) + 60

3f 8 /10 +++ 80

3g 7 /10 (2) ++ 70

3h 5 /10 (5) Low toxic 50

3i 10 /10 +++ 100

3j 5 /10 + 50

3k 5 /10 (2) + 50

(-)- Fumagillin 4 /10 (1) - 40

(-)- Thalidomide 4/10 (4) Low toxic 40

Control⁰ 0 /10 - 0 inhibition effect; Antiangiogenic effect of plus (+) is similar to thalidomide or fumagillin, double plus (++) is stronger and triple plus (+++) is the strongest. ^bNumber in parentheses describes eggs in which the embryo died. ^ccontrol; solvent only (chloroform) to embryo. As shown in Table 1, it is interesting to note that most hybrids exhibited twice the antiangiogenic activity at a concentration of 2.5 nmol/egg than that of fumagilin or thalidomide as the standard drug.

Artemisinin showed a weak inhibitory effect at the given concentration, while glycolipid (daumone) remained stronger than standard drugs. Generally hybrids showed higher antiangiogenic activity than artemisinin and comparable to that of glycolipid (daumone).

However, C-12 acetal-type artemisinin-glycolipid hybrids (3a and 3d) exhibited weaker activity than non-acetal type hybrids. A benzoyl protected hybrid (3d) with acetal function at C- 12 of artemsinin displayed the weakest inhibitory activity, while a hybrid (3i) with free hydroxy! groups of glycolipid with non-acetal function of artemisinin showed complete (100%) inhibition of angiogenesis.

Interestingly, terminal olefin of the aliphatic side chain of a compound (3h) that has a good antitumor activity displayed dramatically increased toxicity, and 50 % of tested chicken embryos died at the given concentration.

The regioisomers (3h, 3j) showed only comparable antiangiogenic activity, thus suggesting the coupling position of the C-12 side function of artemisinin should link with the terminal carboxylic acids of glycolipids.

It is noteworthy that the hybrid compound (3i) that does not exhibit cytotoxicity has the most potent antiangiogenic activity in this assay. The requirement for the presence of the peroxide bond for antiangiogenesis needs to be determined by preparation and in vivo screening of desoxy derivatives of artemisinin .

In summary, hybrids of nonacetal and acetal types of artemisinin and glycolipid were synthesized in one-step reactions and most showed one to two times more potent in vivo antiangiogenic activity than standard drugs. Among the 11 synthetic compounds tested, hybrids 3f, 3g and 3i showed the most potent antiangiogenic activity, twice as much potency as fumagilin and thalidomide, known as antiangiogenic agents. In particular, hybrid 3i showed complete inhibition at 2.5 nm/egg with no toxicity. Compounds 3a and 3h showed similar activity to that of fumagillin. Evidence that acetal-type analogs at C-12 of artemisinin are more neurotoxic in animal studies than non acetal-type analogs is also emerging,¹² and may thus lead to the future abandonment of the currently clinically used acetal-type potential anticancer drug candidates. Therefore, nonacetal 12β (C-C)-type derivatives of artemisinin- glycolipid hybrids deserve further evaluation as possible anticancer drug candidates because of their high acid stability,³ low toxicity and high in wVoantiangiogenesis.

Example 3: Evaluation of Anticancer Activity

The anticancer activity of the artemisinin or deoxoartemisinin-glycolipid hybrids synthesized in Example 1 was evaluated using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay according to the previously described procedure (Carmichel, J. et al., Evaluation of a Tetrazolium-based Semiautomated Colorimetric Assay: Assessment of Chemosensitivity testing, Cancer Res., 47:936-42(1987)).

The in vitro cytotoxicity (I o) of the artemisinin or deoxoartemisinin-glycolipid hybrid derivatives to cancer cell was measured and the results are represented in Table 2.

Table 2

MDA-MB-231 (Korean Cell Line Bank, Seoul, Korea): metastatic breast cancer cells (estrogen receptor-negative)

MCF7 (Korean Cell Line Bank, Seoul, Korea): estrogen receptor-positive breast cancer cells

A549 (Korean Cell Line Bank, Seoul, Korea): lung cancer cells

HSC-2 (Japanese Collection of Research Bioresources (JCRB), Japan): oral squamous carcinoma cells (gingiva origin)

Ca.9.22 (Japanese Collection of Research Bioresources (JCRB), Japan): oral squamous carcinoma cell (mouth origin)

As shown in Table 2, the artemisinin or deoxoartemisinin-glycolipid hybrids of the present invention were found to have an anticancer activity to the various cancer cells, and showed especially excellent efficacy to oral cancer cell. In the actual experiment, compound 3b also exhibited more excellent anticancer activity to all the cancer cell lines than artemisinin or daumone alone.

Having described a preferred embodiment of the present invention, it is to be understood that variants and modifications thereof falling within the spirit of the invention may become apparent to those skilled in this art, and the scope of this invention is to be determined by appended claims and their equivalents.

References

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Claims

What is claimed is:

1. An artemisinin or deoxoartemisinin-glycolipid hybrid derivative represented by the Chemical Formula selected from the group consisting of the following Chemical Formulas 1-3:

wherein each f¾ and R₂ is independently hydrogen, halogen, Ci-C₁₀alkyl, Ci-Q₀alkenyl, Ci-C₁₀alkynyl, Q-Qo aryl, Q-Qo alkylaryl, Q-Ceo arylalkyi, or QrQo heteroaryl;

each of R₃-Re is independently hydrogen, hydroxyl, alkoxy, carboxyl, halogen, nitro, Q- Cioalkyl, Ci-Ci₀alkenyl, CrCi₀alkynyl, QrQo aryl, Q-Q, alkylaryl, Q-Qo arylalkyi, or Q-Qo heteroaryl;

X and Yare each independently substituted or unsubstituted linear or branched Ci-Qo alkylene, or substituted or unsubstituted linear or branched Ci-Ci₀alkenylene; and

each of m, n and k is independently 0 or 1.

2. The artemisinin or deoxoartemisinin-glycolipid hybrid derivative according to claim 1,

wherein each Rj and R₂ is independently hydrogen, substituted or unsubstituted linear or branched Cr alkyl, or benzyl;

each of R₃-R5 is independently hydrogen, hydroxyl, alkoxy, carboxyl, or substituted or unsubstituted linear or branched Q- alkyl;

X and the Yare each independently substituted or unsubstituted linear or branched Q- Cio alkylene; and

each of m, n and k is independently 0 or 1.

3. The artemisinin or deoxoartemisinin-glycolipid hybrid derivative according to daim 1, wherein the artemisinin or deoxoartemisinin-glycolipid hybrid derivative is represented by the Chemical Formula selected from the group consisting of the following Chemical Formulas 4- · 12:

(5)

5

10

4. A method of synthesizing the artemisinin or deoxoartemisinin-glycolipid hybrid derivative of daim 1 or 2, which comprises:

coupling the compound of the following Chemical Formula 13 with the compound of the following Chemical Formula 14; or

coupling the compound of the following Chemical Formula 15 with the compound of the following Chemical Formula 16:

wherein each of Ri, R_2l R' and R" is independently hydrogen, halogen, Ci-Q₀alkyl, Q- C₁₀alkenyl, Ci-Ci₀alkynyl, Q-Qo aryl, Q-Qo alkytaryl, Q-Qo arylalkyl, or Q-Qo heteroaryl; each of R₃-R₆ is independently hydrogen, hydroxyl, alkoxy, carboxyf, halogen, nitro, Q- C₁₀alkyl, Ci-C₁₀alkenyl, Ci-Ci₀alkynyl, Q-Qo aryl, Q-Qo alkylaryl, Q-Qo arylalkyl, or Q-Qo heteroaryl;

X and Yare each independently substituted or unsubstituted linear or branched Ci-Q₀ alkylene, or substituted or unsubstituted linear or branched Q-Qoalkenylene; and

each m and k is independently 0 or 1.

5. The method according to claim 4, wherein the coupling is carried out by a transesterification reaction.

6. A pharmaceutical composition for preventing or treating an angiogenic disease comprising (a) a pharmaceutically effective amount of the artemisinin or deoxoartemisinin-glycolipid hybrid derivative as defined in any one of claims 1-3; and (b) a pharmaceutically acceptable carrier.

7. The composition according to claim 6, wherein the angiogenic disease is selected from the group consisting of cancer, hemangiomas, diabetic retinopathy, retinopathy of prematurity, rejection after comeal transplant, angiogenic glaucoma, erythromelanosis follicularis faciei et coli, proliferative retinopathy, psoriasis, hemophilic arthritis, plaque angiogenesis in atherosclerosis, keloid, granulation tissue in wound, blood vessel adhesion, rheumatoid arthritis, osteoarthritis, autoimmune disease, Crohn's disease, recurrent stenosis, atherosclerosis, enteroadhesion, cat scratch disease, ulcer, liver cirrhosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, rejection after organ transplant, glomerulonephritis, diabetes, and inflammation.

8. The composition according to claim 6, wherein the artemisinin or deoxoartemisinin- glycolipid hybrid derivative is represented by the Chemical Formula selected from the group consisting of the following Chemical Formulas 7-10:

9. The composition according to claim 7, wherein the angiogenic disease is breast cancer, lung cancer, or oral cancer.

10. The composition according to claim 9, wherein the artemisinin or deoxoartemisinin- glycolipid hybrid derivative is represented by the Chemical Formula selected from the group consisting of the following Chemical Formulas 7-10:

11. A method for preventing or treating an angiogenic disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising (a) a pharmaceutically effective amount of the artemisinin or deoxoartemisinin-glycolipid hybrid derivative as defined in any one of daims 1-3; and (b) a pharmaceutically acceptable carrier.

12. The method according to claim 11, wherein the angiogenic disease is selected from the group consisting of cancer, hemangiomas, diabetic retinopathy, retinopathy of prematurity, rejection after corneal transplant, angiogenic glaucoma, erythromelanosis follicularis faciei et coli, proliferative retinopathy, psoriasis, hemophilic arthritis, plaque angiogenesis in atherosclerosis, keloid, granulation tissue in wound, blood vessel adhesion, rheumatoid arthritis, osteoarthritis, autoimmune disease, Crohn's disease, recurrent stenosis, atherosclerosis, enteroadhesion, cat scratch disease, ulcer, liver cirrhosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, rejection after organ transplant, glomerulonephritis, diabetes, and inflammation.

13. The method according to claim 11, wherein the artemisinin or deoxoartemisinin- glycolipid hybrid derivative is represented by the Chemical Formula selected from the group consisting of the following Chemical Formulas 7-10:

14. The method according to claim 12, wherein the angiogenic disease is breast cancer, lung cancer, or oral cancer.

15. The method according to claim 13, wherein the artemisinin or deoxoartemisinin- glycolipid hybrid derivative is represented by the Chemical Formula selected from the group consisting of the following Chemical Formulas 7-10: