KR20130069463A - Pectenotoxin-2 derivative, and anticancer agent containing the same - Google Patents

Abstract

PURPOSE: A pectenotoxin-2 derivative with various useful physical properties is provided to be used as an anticancer agent or a precursor thereof. CONSTITUTION: A pectenotoxin-2 derivative is denoted by chemical formula 1. An anticancer composition contains the derivative and removes cancer cells in human body. The cancer cells include cancer cells of lung, colon, central nervous system, skin, ovary, kidney, breast, or stomach.

Description

Pectenotoxin-2 derivatives, and anticancer composition comprising the same {PECTENOTOXIN-2 DERIVATIVE, AND ANTICANCER AGENT CONTAINING THE SAME}

The present application relates to a pectenotoxin-2 derivative and an anticancer composition comprising the pectenotoxin-2 derivative.

Natural Pectenotoxin-2 is a compound that is isolated from marine warts, causing diarrhea. The pectenotoxin-2 has strong cytotoxicity against cancer cells with an average IC ₅₀ (50% inhibitory concentration) of 10 ^-9 M to 10 ^-8 M for sensitive cancer cells, and lung cancer. It is known that it can have anticancer activity against various cancer cells such as colon cancer, central nervous system cancer, melanoma, ovarian cancer, kidney cancer, breast cancer, stomach cancer and colon cancer. Accordingly, there has been a study on the extraction of natural pectenotoxin-2 from marine marine flagella and use as an anticancer agent. For example, there have been related studies such as "extraction method of pectenotoxin II and anticancer agent using the same (Korea Patent No. 10-0135571)".

However, in order to use the compound as an anticancer agent, it should be proved that the result of clinical experiments is not harmful to the living body, and as a result of clinical experiments using the natural pectenotoxin-2 in mice, it has been shown to be hepatotoxic. There was a limit to using it as an anticancer agent.

Accordingly, the present application provides a pectenotoxin-2 derivative having various substituents, which is more easily and economically produced.

In addition, the present application provides an anticancer composition comprising the pectenotoxin-2 derivative, which has high cytotoxicity against cancer cells but does not have side effects such as liver toxicity.

However, the problems to be solved by the present invention are not limited to the above-mentioned problems, and other problems not mentioned can be clearly understood by those skilled in the art from the following description.

A first aspect of the present application provides a Pectenotoxin-2 (PTX-2) derivative represented by the following Chemical Formula 1:

[Formula 1]

;

;

In Formula 1,

R ¹ is a functional group represented by Formula 2 or Formula 3:

[Formula 2]

,

,

(3)

;

;

Among the above formulas,

R ² is an alkyl group which may include a substituent, -COR ³ , -CONHR ⁴ , -CONHSO ₂ NHR ⁵ , or -CONHSO ₂ R ⁶ , R ³ is an alkyl group which may include a substituent, and R ⁴ is H, A phenyl group which may include a substituent or an alkyl group which may include a substituent, R ⁵ is a phenyl group which may include a substituent, or an alkyl group which may include a substituent, and R ⁶ is an amine group which may include a substituent , A phenyl group which may include a substituent, or an N-saturated cyclic hydrocarbon group which may include a substituent.

The second aspect of the present application provides an anticancer composition comprising the pectenotoxin-2 derivative according to the first aspect of the present application.

By means of the present application, pectenotoxin-2 derivatives having various substituents can be produced more easily and economically. In addition, as the present invention enables the easy and economical preparation of the pectenotoxin-2 derivative, it is possible to increase the possibility that the pectenotoxin-2 derivative can be commercialized as an anticancer agent.

The pectenotoxin-2 derivatives prepared according to the present disclosure may possess various useful properties according to their specific chemical structures. In particular, the pectenotoxin-2 derivative prepared according to the present application may be usefully used as an anticancer agent or a precursor thereof. The pectenotoxin-2 derivatives may exhibit anticancer effects by inhibiting the polymerization of actin in the growth of cancer cells. As a result of performing cytotoxicity tests on various cancer cells, IC ₅₀ is nM (nano molarity; nano molarity). Or pM (pico molarity) was found to show a very strong anti-cancer effect. In addition, the pectenotoxin-2 derivatives prepared according to the present invention do not exhibit liver toxicity exhibited by natural pectenotoxin-2 isolated from marine coccyx, and the types of applicable cancers are lung cancer, colon cancer, central nervous system cancer, and black color. It is expected that it may be usefully used as an anticancer agent for various cancers in the future, because it is diverse as species, ovarian cancer, kidney cancer, breast cancer, gastric cancer, and colon cancer.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art can easily carry out the present invention. It should be understood, however, that the present invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. In the drawings, the same reference numbers are used throughout the specification to refer to the same or like parts.

Throughout this specification, when an element is referred to as "including " an element, it is understood that the element may include other elements as well, without departing from the other elements unless specifically stated otherwise.

The terms "about "," substantially ", etc. used to the extent that they are used herein are intended to be taken as a reference to either the numerical value or to the numerical value when the manufacturing and material tolerance inherent in the stated meaning is presented, Accurate or absolute numbers are used to prevent unauthorized exploitation by unauthorized intruders of the mentioned disclosure. Also, throughout the present specification, the phrase " step "or" step "does not mean" step for.

Throughout this specification, when a member is located "on" another member, this includes not only when one member is in contact with another member but also when another member exists between the two members.

Throughout this specification, the term "combination thereof" included in the expression of the machine form means one or more combinations or combinations selected from the group consisting of the constituents described in the expression of the machine form, And the like.

Throughout this specification, "halo" or "halo group" may be F, Cl, Br, or I, but is not limited thereto.

For the purposes of the present specification, "alkyl" or "alkyl group" may be a linear or branched, saturated or unsaturated alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, Pentyl, hexyl, heptyl, octyl, nonyl, decyl, or isomers thereof, but is not limited thereto.

Throughout this specification, the term “aryl” or “aryl group”, alone or as part of another group, refers to a monocyclic or bicyclic aromatic ring such as phenyl, substituted phenyl, as well as conjugated groups. Such as naphthyl, phenanthrenyl, indenyl, tetrahydronaphthyl and indanyl, and the like. For example, the "aryl" or "aryl group" includes one or more rings having 6 or more atoms, up to 5 rings containing up to 22 atoms may be present, Double bonds between suitable heteroatoms can alternately (resonate) exist. The "aryl" or "aryl group" is optionally halogen, such as F, Br, Cl or I, alkyl such as methyl, ethyl, propyl, alkoxy such as methoxy or ethoxy, hydroxy, carboxy, carbamoyl, alkyl Including but not limited to oxycarbonyl, nitro, alkenyloxy, trifluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano, alkyl S (O) m (m = O, 1, 2) or thiols It may be substituted with one or more groups which are not limited. For example, the "aryl" or "aryl group" may be phenyl, phenyl substituted as described above, phenyl, naphthyl, or naphthyl substituted as described above, but is not limited thereto.

Throughout this specification, "alkoxy" or "alkoxy group" may include, but is not limited to, an "alkyl group" as defined above and an alkoxy group bonded to an oxygen atom.

In the present specification, the "alkylene-dioxy group" may be an alkylene group located between two oxygen, the "alkylene group" may be an alkylene group having 1 to 10 carbon atoms, for example, methylene , Ethylene, propylene, butylene, pentylene, hexylene, hexylene, octylene, nonylene, decylene, or isomers thereof, but is not limited thereto.

Throughout this specification, the term "amine group", alone or as part of another group, refers to -NH ₂ , and the "amine group" also refers to one or two substituents, such as alkyl, which may be the same or different. , Aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, carbonyl Or optionally substituted with carboxyl.

Throughout this specification, the term "PTX-2" has been used to refer to "fectenotoxin-2", and the terms pectenotoxin-2 and the term PTX-2 are the same.

A first aspect of the present application provides a Pectenotoxin-2 (PTX-2) derivative represented by the following Chemical Formula 1:

[Formula 1]

;

;

In Formula 1,

R ¹ is a functional group represented by Formula 2 or Formula 3:

(2)

,*

,

(3)

;

;

Among the above formulas,

R ² is an alkyl group which may include a substituent, -COR ³ , -CONHR ⁴ , -CONHSO ₂ NHR ⁵ , or -CONHSO ₂ R ⁶ , R ³ is an alkyl group which may include a substituent, and R ⁴ is H, A phenyl group which may include a substituent or an alkyl group which may include a substituent, R ⁵ is a phenyl group which may include a substituent, or an alkyl group which may include a substituent, and R ⁶ is an amine group which may include a substituent , A phenyl group which may include a substituent, or an N-saturated cyclic hydrocarbon group which may include a substituent.

를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. 즉, 상기 R²가 치환기를 포함할 수 있는 알킬기인 경우, 상기 치환기는 페닐기를 포함할 수 있으나, 이에 제한되는 것은 아니다. 또한, 상기 R²가 치환기를 포함할 수 있는 알킬기인 경우, 상기 알킬기는 이중 결합 또는 삼중 결합 등 다중 결합을 포함하는 것일 수 있으며, 분지형 또는 고리형의 알킬기를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.According to an embodiment of the present disclosure, R ² is —CH ₂ CH═CH ₂ , or

It may be to include, but is not limited thereto. That is, when R ² is an alkyl group which may include a substituent, the substituent may include a phenyl group, but is not limited thereto. In addition, when the R ² is an alkyl group which may include a substituent, the alkyl group may include a multiple bond such as a double bond or a triple bond, and may include a branched or cyclic alkyl group, but is not limited thereto. It doesn't happen.

According to the exemplary embodiment of the present application, the -COR ³ may include -COCH ₃ or -COCH ₂ Br, but is not limited thereto. That is, when R ² is -COR ³ and R ³ is an alkyl group which may include a substituent, the substituent may include a halo group such as F, Cl, Br, I, but is not limited thereto.

, 또는

를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. 즉, 상기 R²가 -CONHR⁴이고 상기 R⁴가 치환기를 포함할 수 있는 페닐기인 경우, 상기 치환기는 F, Cl, Br, I 등의 할로기를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. 또한, 상기 R²가 -CONHR⁴이고 상기 R⁴가 치환기를 포함할 수 있는 알킬기인 경우, 상기 치환기는 티올기, 또는 에스테르기를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. 또한, 상기 알킬기는 이중 결합 또는 삼중 결합 등 다중 결합을 포함하는 것일 수 있으며, 분지형 또는 고리형의 알킬기를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. According to an embodiment of the present disclosure, the -CONHR ⁴ is -CONH ₂ , -CONHCH ₂ CH ₃ , -CONHCH ₂ CH ₂ CH ₃ , -CONHCH ₂ CH ₂ CH ₂ CH ₃ , -CONHCH ₂ CH = CH ₂ ,- CONHCH ₂ CH ₂ SH, -CONHCH ₂ CH ₂ COOCH ₂ CH ₃ , -CONHCH ₂ CH ₂ SSCH ₂ CH ₂ NHCOOCH ₃ ,

, or

It may be to include, but is not limited thereto. That is, when R ² is -CONHR ⁴ and R ⁴ is a phenyl group which may include a substituent, the substituent may include a halo group such as F, Cl, Br, I, but is not limited thereto. In addition, when R ² is -CONHR ⁴ and R ⁴ is an alkyl group which may include a substituent, the substituent may include a thiol group or an ester group, but is not limited thereto. In addition, the alkyl group may include multiple bonds such as double bonds or triple bonds, and may include branched or cyclic alkyl groups, but is not limited thereto.

, 또는

를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. 즉, 상기 R²가 -CONHSO₂NHR⁵이고 상기 R⁵가 치환기를 포함할 수 있는 알킬기인 경우, 상기 치환기는 하이드록시기, 에테르기, 에스테르기, 아민기, 또는 -SSCH₂CH₂NH₂를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. 또한, 상기 알킬기는 다중 결합을 포함하는 것일 수 있으며, 분지형 또는 고리형의 알킬기를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.According to an embodiment of the present disclosure, the -CONHSO ₂ NHR ⁵ is -CONHSO ₂ NHCH ₂ CH ₂ OH, -CONHSO ₂ NHCH ₂ CH ₂ OSi (CH ₃ ) ₂ C (CH ₃ ) ₃ , -CONHSO ₂ NHCH ₂ COOCH ₂ CH ₃ , -CONHSO ₂ NHCH ₂ CH ₂ SSCH ₂ CH ₂ NH ₂ ,

, or

It may be to include, but is not limited thereto. That is, when R ² is -CONHSO ₂ NHR ⁵ and R ⁵ is an alkyl group which may include a substituent, the substituent is a hydroxy group, an ether group, an ester group, an amine group, or -SSCH ₂ CH ₂ NH ₂ It may be to include, but is not limited thereto. In addition, the alkyl group may be to include a multiple bond, it may include a branched or cyclic alkyl group, but is not limited thereto.

,

,

(여기에서, Boc는 부톡시 카르보닐임), 또는

를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. 즉, 상기 R²가 -CONHSO₂R⁶이고 상기 R⁶가 아민기인 경우, 상기 아민기는 하나 또는 둘의 치환기를 포함하는 것일 수 있으며, 상기 치환기는 알킬기, 또는 에스테르기로 치환된 알킬기를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. 또한, 상기 R²가 -CONHSO₂R⁶이고 상기 R⁶가 치환기를 포함할 수 있는 페닐기인 경우, 상기 치환기는 알킬기를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다. 또한, 상기 R²가 -CONHSO₂R⁶이고 상기 R⁶가 치환기를 포함할 수 있는 N-포화시클릭탄화수소기인 경우, 상기 N-포화시클릭탄화수소기는 오각고리, 또는 육각고리를, 하나, 또는 둘 이상 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.
According to an embodiment of the present disclosure, the -CONHSO ₂ R ⁶ is -CONHSO ₂ N (CH ₃ ) CH ₂ COOCH ₂ CH ₃ ,

,

,

(Wherein Boc is butoxy carbonyl), or

It may be to include, but is not limited thereto. That is, when R ² is -CONHSO ₂ R ⁶ and R ⁶ is an amine group, the amine group may include one or two substituents, and the substituent includes an alkyl group substituted with an alkyl group or an ester group. May be, but is not limited thereto. In addition, when R ² is -CONHSO ₂ R ⁶ and R ⁶ is a phenyl group which may include a substituent, the substituent may include an alkyl group, but is not limited thereto. Also, when R ² is -CONHSO ₂ R ⁶ and R ⁶ is an N-saturated cyclic hydrocarbon group which may include a substituent, the N-saturated cyclic hydrocarbon group may be a pentagonal ring, a hexagonal ring, or It may include two or more, but is not limited thereto.

The second aspect of the present application provides an anticancer composition comprising the pectenotoxin-2 derivative according to the first aspect of the present application.

According to one embodiment of the present application, the anticancer composition may be to include those used to remove cancer cells in the human body, but is not limited thereto. The pectenotoxin-2 derivatives herein may possess a variety of useful physical properties, depending on their specific chemical structures. In particular, the pectenotoxin-2 derivative prepared according to the present application may be usefully used as an anticancer agent or a precursor thereof. The pectenotoxin-2 derivative may exhibit an anticancer effect by inhibiting the polymerization of actin in the growth of cancer cells, but is not limited thereto.

According to one embodiment of the present application, the cancer cells may include, but are not limited to, cancer cells of the lung, colon, central nervous system, skin, ovary, kidney, breast, stomach, or colon.

According to one embodiment of the invention, the anti-cancer composition IC ₅₀ 10 ^-10 M to about ^10, but may be having an anti-cancer effect of 8 M, but is not limited thereto. For example, the anticancer composition may have an anticancer effect of about 10 ⁻¹⁰ M to about 10 ⁻⁹ M, or about 10 ⁻⁹ M to about 10 ⁻⁸ M, of the half maximal inhibitory concentration (IC ₅₀ ). It may be, but is not limited thereto. That is, the pectenotoxin-2 derivative of the present application may have an excellent anticancer effect by exhibiting cytotoxicity comparable to or more than natural pectenotoxin-2, but is not limited thereto. On the other hand, the pectenotoxin-2 derivative prepared according to the present application does not show the hepatotoxicity represented by the natural pectenotoxin-2 isolated from marine coccyx, and thus may be more suitable for commercialization as an anticancer agent, but is not limited thereto. It doesn't happen.

Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited thereto.

[ Example ]

All of the reagents used in this example are those commercially available, and unless otherwise specified, are used without special purification.

The ¹ H spectra in this example was collected using a Bruker UI500 spectrometer at a resonance frequency of 500.1 MHz. The solvent used was acetone-d ₆ .LRMS (ESI) and the spectra were recorded using Agilent 1100 LC / MSD. HPLC (high performance liquid chromatography) analysis was performed using a Kromasil 100-5C 18 (150 × 4.6 mm) reversed phase column at a flow rate of 1 mL / min. Methanol-water solvent was used with 214 nm UV detector and 235 nm UV detector.

In this example, the "fectenotoxin-2 derivative" herein is abbreviated as "PTX-2 derivative", and the two substances are the same.

1. Preparation of PTX- 2 Derivatives of Examples 1 to 26 , and NMR ( Nuclear Magnetic Resonance) Data

[ Example  One]

First, a solution was prepared by dissolving PTX-2 (1 mg, 0.001 mmol) dissolved in dichloromethane (DCM) in pyridine diluted with DCM. Thereafter, acetic anhydride (1.167 mg, 0.011 mmol, 10 equivalents) and DMAP (dimethylaminopyridine, 0.698 mg, 0.005 mmol, 5 equivalents) were slowly added to the solution. Thereafter, the prepared solution was filled with nitrogen gas and stirred at room temperature for 3 hours. A small amount of the resultant obtained as a result of the stirring was performed, and HPLC was performed, thereby checking whether the reaction proceeded successfully. HPLC measurement increased the proportion of MeOH (methanol) solvent from 20% to 80% for 20 minutes and the product peak was found at 19.9 minutes.

On the other hand, for reference, the NMR and mass spectrometry data of the PTX-2 derivative of Example 1 were as follows:

¹ H NMR (500 MHz, ACETONE-d ₆ ): δ 6.45 (d, J = 15.1, 1H), 5.50-5.54 (m, 1H), 5.47 (dd, J = 16.4, 3.2, 1H), 5.37 (d , J = 3.6, 1H), 5.29-5.36 (m, 1H), 4.84-4.88 (m, 1H), 4.26-4.32 (m, 1H), 4.23-4.26 (m, 2H), 4.20 (dd, J = 12.1, 3.0, 1H), 4.06-4.16 (m, 3H), 3.98 (s, 1H), 3.78-3.84 (m, 2H), 3.75 (d, J = 7.4, 3H), 3.49-3.56 (m, 3H ), 3.28-3.34 (m, 5H), 2.43-2.54 (m, 6H), 1.76-1.82 (m, 2H), 1.71-1.75 (m, 4H), 1.61-1.70 (m, 7H), 1.48-1.61 (m, 8H), 1.38-1.45 (m, 1H), 1.31 (d, J = 3.9, 1H), 1.24-1.30 (m, 6H), 1.18 (br.s., 6H), 1.11 (d, J = 7.2, 9H), 0.97 (d, J = 6.3, 3H); LRMS (ESI): 923.8 [M + Na] ⁺ .

[ Example  2]

First, a solution was prepared by dissolving PTX-2 (1 mg, 0.001 mmol) dissolved in DCM in pyridine diluted with DCM. Then, bromoacetic acid (3.176 mg, 0.022 mmol, 20 equiv) and DMAP (0.022 mg, 0.020 mmol, 20 equiv) were slowly added to the solution. Thereafter, the prepared solution was filled with nitrogen gas and stirred at room temperature for 3 hours. A small amount of the resultant obtained as a result of the stirring was performed, and HPLC was performed, thereby checking whether the reaction proceeded successfully. The HPLC measurement increased the proportion of MeOH solvent from 60% to 90% for 20 minutes and the product peak was seen at 21 minutes.

On the other hand, for reference, the NMR and mass spectrometric data of the PTX-2 derivative of Example 2 were as follows:

¹ H NMR (500 MHz, ACETONE-d ₆ ): δ 7.23 (t, J = 7.4, 3H), 7.16 (d, J = 7.7, 3H), 7.11-7.15 (m, 1H), 6.36 (d, J = 16.5, 1H), 5.42-5.46 (m, 1H), 5.36 (dd, J = 15.5, 2.9, 2H), 5.30 (d, J = 9.6, 1H), 4.89 (s, 1H), 4.84 (s, 1H), 4.67 (br. S., 1H), 4.41 (br. S., 4H), 4.24-4.37 (m, 3H), 4.18-4.23 (m, 1H), 4.16 (d, J = 12.4, 1H ), 4.05 (d, J = 6.9, 1H), 3.95-4.00 (m, 2H), 3.88 (s, 2H), 3.77-3.83 (m, 1H), 3.74 (s, 2H), 3.65 (br.s , 2H), 2.30 (s, 5H), 1.96 (br. S., 3H), 1.92 (br. S., 7H), 1.89 (d, J = 8.5, 8H), 1.83 (s, 5H), 1.69 (s, 6H), 1.48-1.66 (m, 17H), 1.36-1.42 (m, 3H), 1.24-1.33 (m, 11H), 1.15-1.20 (m, 7H), 1.04-1.11 (m, 5H ), 0.96 (d, J = 6.6, 4H), 0.82-0.89 (m, 6H); LRMS (ESI): 1001.4 [M + Na] ⁺ .

[ Example  3]

First, PTX-2 (1 mg, 0.001 mmol) dissolved in DCM, DMAP (0.559 mg, 0.004 mmol, 4 equiv) diluted with DCM, and ethyl isocyanate (0.034 mmol, 30 equiv) were mixed. Thereafter, nitrogen gas was charged and stirred for about 3 hours at room temperature. A small amount of the resultant obtained as a result of the stirring was performed, and HPLC was performed, thereby checking whether the reaction proceeded successfully. The HPLC measurement increased the proportion of MeOH solvent from 60% to 90% for 20 minutes and the product peak was found at 17.9 minutes.

On the other hand, for reference, the NMR and mass spectrometric data of the PTX-2 derivative of Example 3 were as follows:

¹ H NMR (500 MHz, ACETONE-d ₆ ): δ 8.12 (d, J = 5.5, 1H), 6.53-6.59 (m, 1H), 6.37 (d, J = 16.0, 1H), 5.43 (d, J = 3.3, 1H), 5.33-5.41 (m, 1H), 5.29 (d, J = 9.9, 1H), 4.66 (dd, J = 16.2, 2.2, 2H), 4.23-4.31 (m, 2H), 4.20 ( dd, J = 12.2, 2.1, 1H), 3.93-4.01 (m, 2H), 3.81 (dd, J = 9.9, 5.5, 1H), 3.72-3.77 (m, 1H), 3.60 (dd, J = 11.3, 4.4, 1H), 3.37-3.44 (m, 1H), 3.28-3.33 (m, 1H), 3.11-3.27 (m, 1H), 2.99 (s, 2H), 2.90 (s, 1H), 2.87 (s, 1H), 2.55-2.65 (m, 1H), 2.48 (dd, J = 12.4, 6.9, 1H), 2.19-2.29 (m, 2H), 2.17 (dt, J = 4.4, 2.2, 1H), 1.91-1.94 (m, 3H), 1.90 (s, 1H), 1.89 (s, 1H), 1.83 (d, J = 16.0, 2H), 1.70 (s, 3H), 1.46-1.69 (m, 14H), 1.36-1.43 (m, 2H), 1.28-1.32 (m, 5H), 1.27 (s, 4H), 1.16-1.19 (m, 7H), 1.13-1.16 (m, 2H), 1.11 (d, J = 6.9, 3H) , 1.06-1.09 (m, 3H), 0.97 (d, J = 6.9, 3H), 0.85 (d, J = 6.9, 3H); LRMS (ESI): 952.4 [M + Na] ⁺ .

[ Example  4]

Example 4 was synthesized in the same manner as in Example 3 except for using propyl isocyanate instead of ethyl isocyanate, and the ratio of MeOH solvent was 60% to 90% in HPLC measurement to confirm whether the reaction proceeded successfully. % Was increased for 20 minutes, and the product peak was found at 18.7 minutes.

On the other hand, for reference, the NMR and mass spectrometric data of the PTX-2 derivative of Example 4 were as follows:

¹ H NMR (500 MHz, ACETONE-d ₆ ): δ 6.32-6.44 (m, 1H), 5.43 (br. S., 1H), 5.34-5.41 (m, 1H), 5.28 (d, J = 8.0, 1H), 4.65 (d, J = 10.7, 2H), 4.55 (s, 1H), 4.24-4.32 (m, 2H), 4.17-4.24 (m, 3H), 4.11 (d, J = 5.0, 1H), 3.97 (br. S., 2H), 3.79 (d, J = 6.1, 1H), 3.74 (s, 1H), 3.56-3.66 (m, 2H), 3.31 (d, J = 3.9, 1H), 2.59 ( br.s., 6H), 2.48 (s, 5H), 2.51 (s, 5H), 2.20-2.29 (m, 5H), 2.17 (br.s., 3H), 1.88 (s, 6H), 1.92 ( s, 7H), 1.71 (s, 3H), 1.69 (br. s., 8H), 1.65 (br. s., 12H), 1.59 (br. s., 6H), 1.53 (br. s., 14H ), 1.40 (br. S., 5H), 1.28 (br. S., 24H), 1.26 (br. S., 10H), 1.17 (d, J = 3.9, 13H), 1.10 (d, J = 6.9 , 3H), 1.07 (d, J = 6.6, 8H), 0.96 (br. S., 7H), 0.93 (d, J = 7.7, 7H), 0.87 (br. S., 5H), 0.85 (br. s., 9H), 0.84 (br. s., 5H); LRMS (ESI): 966.7 [M + Na] ⁺ .

[ Example  5]

Example 5 was synthesized in the same manner as in Example 3 except for using butyl isocyanate instead of ethyl isocyanate, and the ratio of MeOH solvent was 60% to 90% in HPLC measurement to confirm whether the reaction proceeded successfully. % Was increased for 20 minutes, and the product peak was found at 20.4 minutes.

On the other hand, for reference, the NMR and mass spectrometric data of the PTX-2 derivative of Example 5 were as follows:

¹ H NMR (500 MHz, ACETONE-d ₆ ): δ 6.37 (dd, J = 15.0, 1.0, 1H), 5.42-5.46 (m, 2H), 5.38 (dd, J = 16.0, 3.0, 2H), 5.29 (d, J = 9.9, 2H), 4.66 (d, J = 14.0, 3H), 4.52 (s, 1H), 4.30 (t, J = 8.5, 3H), 4.25 (d, J = 4.7, 1H), 4.20 (d, J = 9.9, 2H), 3.99 (s, 2H), 3.96 (d, J = 3.9, 1H), 3.81 (dd, J = 9.8, 5.4, 2H), 3.75 (s, 2H), 3.58 -3.62 (m, 2H), 3.41 (td, J = 10.8, 1.0, 1H), 3.29-3.33 (m, 4H), 3.22-3.29 (m, 1H), 3.02-3.11 (m, 1H), 2.90 ( s, 1H), 2.86 (s, 1H), 2.62 (d, J = 2.5, 3H), 2.46-2.53 (m, 2H), 2.24 (d, J = 6.9, 4H), 2.17 (dt, J = 4.4 , 2.2, 9H), 1.96 (s, 7H), 1.90-1.94 (m, 14H), 1.89 (s, 3H), 1.70 (s, 7H), 1.65 (br.s., 5H), 1.47-1.59 ( m, 16H), 1.35-1.43 (m, 6H), 1.29 (br. s., 5H), 1.27 (s, 7H), 1.18 (d, J = 3.6, 12H), 1.08 (d, J = 7.2, 7H), 0.97 (d, J = 6.6, 6H), 0.85 (d, J = 7.2, 6H); LRMS (ESI): 980.8 [M + Na] ⁺ .

[ Example  6]

Example 6 was synthesized in a similar manner to Example 3 except that allyl isocyanate was used instead of ethyl isocyanate, and the ratio of MeOH solvent was 60% to 90% in HPLC measurement to confirm whether the reaction proceeded successfully. % Was increased for 20 minutes, and the product peak was found at 19.1 minutes.

On the other hand, for reference, the NMR and mass spectrometry data of the PTX-2 derivative of Example 6 were as follows:

¹ H NMR (500 MHz, ACETONE-d ₆ ): δ 5.29 (d, J = 11.6, 1H), 4.68 (br. S., 1H), 4.55 (s, 1H), 4.28 (d, J = 3.6, 1H), 4.23 (br. S., 1H), 4.19 (br. S., 1H), 3.98 (br. S., 1H), 3.95 (br. S., 1H), 3.82 (br. S., 1H), 3.75 (br. S., 1H), 3.59 (br. S., 1H), 3.29-3.33 (m, 1H), 2.49 (br. S., 1H), 2.22-2.28 (m, 1H) , 1.70 (d, J = 6.1, 2H), 1.62-1.68 (m, 3H), 1.50-1.61 (m, 3H), 1.41 (d, J = 11.8, 1H), 1.27 (s, 3H), 1.29 ( s, 3H), 1.18 (s, 3H), 1.06-1.12 (m, 3H), 0.97 (br. s., 1H), 0.96 (br. s., 1H), 0.84-0.89 (m, 2H); LRMS (ESI): 964.9 [M + Na] ⁺ .

[ Example  7]

Example 7 was synthesized in the same manner as in Example 3 except for using ethyl 3-isocyanatopropanoate instead of ethyl isocyanate, MeOH solvent in HPLC measurement to confirm whether the reaction was successful The ratio of was increased from 75% to 95% for 20 minutes and the product peak was found at 9.1 minutes.

On the other hand, for reference, the NMR and mass spectrometric data of the PTX-2 derivative of Example 7 were as follows:

¹ H NMR (500 MHz, ACETONE-d ₆ ): δ 5.43 (d, J = 3.6, 1H), 5.36 (dd, J = 15.7, 3.3, 1H), 5.28 (d, J = 9.6, 1H), 4.91 (s, 1H), 4.86 (s, 1H), 4.68 (br. s., 1H), 4.28-4.34 (m, 3H), 4.27 (s, 2H), 4.20 (d, J = 10.2, 2H), 4.06-4.15 (m, 10H), 4.02 (t, J = 10.7, 2H), 3.97 (s, 2H), 3.82 (t, J = 4.8, 1H), 3.78 (d, J = 9.9, 1H), 3.74 (d, J = 1.4, 2H), 3.69 (dd, J = 11.4, 4.5, 1H), 3.59-3.64 (m, 2H), 3.45-3.54 (m, 2H), 3.41 (t, J = 9.6, 2H ), 3.28-3.32 (m, 3H), 3.12-3.16 (m, 2H), 3.06-3.09 (m, 2H), 2.67-2.71 (m, 1H), 2.61-2.65 (m, 2H), 2.58 (t , J = 6.1, 6H), 2.37-2.49 (m, 5H), 2.27-2.34 (m, 2H), 2.21-2.25 (m, 3H), 2.21 (s, 3H), 1.96 (d, J = 1.9, 3H), 1.92 (dt, J = 4.5,2.3, 6H), 1.88 (s, 3H), 1.86 (d, J = 6.1, 2H), 1.79 (d, J = 14.6, 2H), 1.66-1.69 (m , 8H), 1.64 (dd, J = 11.3,2.5, 8H), 1.59 (d, J = 5.5, 3H), 1.59 (d, J = 15.4, 3H), .39-1.46 (m, 6H), 1.31 (d, J = 3.9, 3H), 1.27 (s, 6H), 1.24 (td, J = 7.1,3.7, 11H), 1.18 (d, J = 9.1,12H), 1.07 (d, J = 6.9, 6H ), 0.98 (d, J = 6.6, 6H), 0.90 (d, J = 6.9, 6H); LRMS (ESI): 1024.8 [M + Na] ⁺ .

[ Example  8]

Example 8 was synthesized in a similar manner to Example 3 except that phenylethyl isocyanate was used instead of ethyl isocyanate, and the proportion of MeOH solvent was determined at 60% by HPLC to determine whether the reaction was successful. Increased to 90% for 20 minutes, The product peak was confirmed at 21.4 minutes.

On the other hand, for reference, the NMR and mass spectrometry data of the PTX-2 derivative of Example 8 were as follows:

¹ H NMR (500 MHz, ACETONE-d ₆ ): δ 7.96 (br. S., 5H), 7.23-7.36 (m, 35H), 7.15-7.23 (m, 14H), 6.37 (d, J = 17.1, 1H), 5.44 (br. S., 1H), 5.38 (d, J = 14.9, 1H), 5.29 (d, J = 8.5, 1H), 4.69 (br. S., 1H), 4.16-4.32 (m , 4H), 3.88-3.96 (m, 8H), 3.79-3.83 (m, 1H), 3.72-3.76 (m, 2H), 3.56-3.62 (m, 2H), 3.34-3.40 (m, 2H), 3.29 (d, J = 14.0, 2H), 1.96 (s, 2H), 1.92 (br.s., 3H), 1.85-1.90 (m, 3H), 1.69 (s, 4H), 1.47-1.65 (m, 11H ), 1.25-1.32 (m, 8H), 1.16 (d, J = 8.3, 8H), 1.06 (d, J = 6.6, 4H), 0.96 (d, J = 6.1, 4H), 0.81-0.86 (m, 3H); LRMS (ESI): 1028.8 [M + Na] ⁺ .

[ Example  9]

Example 9 was synthesized in a similar manner to Example 3 except that 4-bromophenyl isocyanate was used instead of ethyl isocyanate, and the proportion of MeOH solvent was measured in HPLC to determine whether the reaction proceeded successfully. Increased from 75% to 95% for 20 minutes, The product peak was confirmed at 11.3 minutes.

On the other hand, for reference, the NMR and mass spectrometric data of the PTX-2 derivative of Example 9 were as follows:

¹ H NMR (500 MHz, ACETONE-d ₆ ): δ 7.20-7.26 (m, 2H), 7.11-7.18 (m, 2H), 6.36 (d, J = 16.5, 1H), 5.42-5.46 (m, 1H ), 5.36 (dd, J = 15.5, 2.9, 1H), 5.30 (d, J = 9.6, 1H), 4.89 (br. S., 1H), 4.84 (s, 1H), 4.67 (br.s., 1H), 4.41 (br. S., 2H), 4.32-4.37 (m, 1H), 4.26-4.31 (m, 1H), 4.18-4.23 (m, 1H), 4.05 (d, J = 6.9, 1H) , 3.95-4.00 (m, 1H), 3.88 (s, 1H), 3.80 (dd, J = 10.7, 5.5, 1H), 3.74 (s, 1H), 2.30 (s, 2H), 1.92 (br.s. , 3H), 1.83 (s, 2H), 1.69 (s, 3H), 1.64 (d, J = 6.3, 3H), 1.49-1.61 (m, 4H), 1.48 (br.s., 1H), 1.36- 1.42 (m, 1H), 1.24-1.33 (m, 5H), 1.19-1.21 (m, 1H), 1.17 (s, 3H), 1.09 (br.s., 1H), 1.06 (d, J = 6.9, 1H), 0.96 (d, J = 6.6, 3H), 0.80-0.92 (m, 3H); LRMS (ESI): 1079.1 [M + Na] ⁺ .

[ Example  10]

First, PTX-2 (1 mg, 0.001 mmol), DMAP (1.41 mg, 0.0116 mmol, 10 equiv) dissolved in DCM, and TMS isocyanate (44.7 μL, 0.0348 mmol, 30 equiv) were mixed. Then, after filling with nitrogen gas and stirred for about 3 hours at room temperature. After the reaction was terminated, a small amount of methanol solution (MeOH: H ₂ O = 1: 1) was added and stirred for 1 hour. The resultant was then taken in traces to perform HPLC, at which time the proportion of MeOH solvent was increased from 65% to 90% for 20 minutes and the product peak was identified at 13.1 minutes.

On the other hand, for reference, the NMR and mass spectrometric data of the PTX-2 derivative of Example 10 were as follows:

¹ H NMR (500 MHz, ACETONE-d ₆ ): δ 7.46 (br. S., 1H), 6.42 (d, J = 17.3, 1H), 5.46-5.50 (m, 1H), 5.41 (dd, J = 15.7, 3.3, 1H), 5.29 (d, J = 10.5, 1H), 4.78 (br.s., 1H), 4.42 (d, J = 8.8, 1H), 4.38 (dd, J = 8.8, 7.2, 1H ), 4.29 (t, J = 7.4, 1H), 4.20 (d, J = 10.2, 1H), 3.98 (s, 1H), 3.79-3.85 (m, 1H), 3.74 (s, 1H), 3.62-3.73 (m, 2H), 3.47-3.55 (m, 2H), 3.30-3.35 (m, 1H), 2.99 (s, 1H), 2.87-2.93 (m, 1H), 2.57-2.66 (m, 1H), 2.46 -2.57 (m, 2H), 2.17-2.29 (m, 4H), 2.09 (s, 2H), 1.85-1.96 (m, 4H), 1.76-1.84 (m, 1H), 1.70 (s, 4H), 1.49 -1.68 (m, 12H), 1.35-1.43 (m, 2H), 1.30 (dd, J = 9.5, 2.9, 2H), 1.25-1.28 (m, 3H), 1.18 (s, 6H), 1.10 (dd, J = 6.7, 4.5, 6H), 0.93-0.98 (m, 3H); LRMS (ESI): 924.8 [M + Na] ⁺ .

[ Example  11]

First, PTX-2 (0.5 mg, 0.0005 mmol), benzyl bromide (5.1 μL, 0.015 mmol, 30 equiv) dissolved in DCM and TBAI (1.84 mg, 0.005 mmol, 10 equiv) were mixed. After adding CsCO ₃ (1.6 mg, 0.005 mmol, 10 equivalents) and a molecular sieve (molecular sieve), filled with nitrogen gas, the reaction was performed for 50 hours after heating to 80 ° C. The resultant was then taken in traces to perform HPLC, at which time the proportion of MeOH solvent was increased from 60% to 90% for 20 minutes and the product peak was identified at 21.3 minutes.

On the other hand, for reference, the mass spectrometry data of the PTX-2 derivative of Example 11 was as follows:

LRMS (ESI): 949.3 [M + Na] ⁺ .

[ Example  12]

Example 12 was synthesized in the same manner as in Example 11, except that allyl bromide was used instead of benzyl bromide, and the ratio of MeOH solvent was 60% to 90% in the HPLC measurement to confirm whether the reaction was successful. It increased for 20 minutes and the product peak was found at 20.8 minutes.

On the other hand, for reference, the mass spectrometry data of the PTX-2 derivative of Example 12 was as follows:

LRMS (ESI): 899.1 [M + Na] ⁺ .

[ Example  13]

First, PTX-2 (0.5 mg, 0.0005 mmol) and chloroacetyl isocyanate (0.24 μL, 0.0029 mmol, 5 equivalents) dissolved in DCM were mixed and charged with nitrogen gas, followed by stirring at room temperature for 10 minutes. The resultant was then taken in traces to perform HPLC, and the proportion of MeOH solvent was increased from 65% to 90% for 20 minutes in HPLC measurements to determine whether the reaction proceeded successfully. At this time, the primary product chloroacetyl carbamate was decomposed to confirm the product peak at 20.0 minutes, and a small amount of PTX-2 carbamate of Example 10 was also produced.

On the other hand, for reference, the NMR and mass spectrometric data of the PTX-2 derivative of Example 13 were as follows:

¹ H NMR (500 MHz, ACETONE-d ₆ ): δ 6.40 (dd, J = 15.7, 1.9, 1H), 5.53-5.56 (m, 1H), 5.41 (dd, J = 15.7, 3.0, 1H), 5.28 (d, J = 9.6, 1H), 4.88-4.91 (m, 1H), 4.72 (d, J = 2.5, 1H), 4.45 (dd, J = 9.2, 6.7, 1H), 4.26-4.32 (m, 1H ), 4.17-4.23 (m, 1H), 3.95-4.00 (m, 2H), 3.86-3.94 (m, 1H), 3.81 (dd, J = 10.2, 5.5, 1H), 3.73-3.77 (m, 1H) , 3.52 (t, J = 9.6, 1H), 3.29-3.33 (m, 1H), 2.89 (d, J = 16.5, 1H), 2.57-2.65 (m, 1H), 2.50 (dd, J = 12.4, 6.9 , 1H), 2.37-2.45 (m, 1H), 2.21-2.30 (m, 1H), 2.14-2.20 (m, 2H), 1.96 (s, 1H), 1.90-1.94 (m, 4H), 1.88-1.90 (m, 2H), 1.77-1.83 (m, 1H), 1.70 (s, 4H), 1.58-1.69 (m, 7H), 1.48-1.58 (m, 6H), 1.38-1.43 (m, 1H), 1.18 (s, 6H), 1.14 (d, J = 6.9, 3H), 1.10 (d, J = 6.9, 3H), 0.96 (d, J = 6.9, 3H); LRMS (ESI): 907.6 [M + Na] ⁺ .

[ Example  14]

Diisocyanates of cystiamine were synthesized by the method reported in the references (J. Org. Chem., 1996, 61, 3883-3884) and used for the following reactions.

First, 1 mg of PTX-2 dissolved in DCM, 1.22 mg of DMAP (0.01 mmol, 10 equiv), and 6.1 mg of disulfide isocyanate (0.03 mmol, 30 equiv) were mixed, followed by stirring at room temperature with nitrogen gas. After the reaction, 1.3 μL of MeOH (0.03 mmol, 30 equiv) was added. The resultant was then taken in traces to perform HPLC, and in order to check whether the reaction was successful, the proportion of MeOH solvent was increased for 20 minutes from 65% to 90% during HPLC measurement, and the product peak was confirmed at 19.3 minutes. .

On the other hand, for reference, the NMR and mass spectrometric data of the PTX-2 derivative of Example 14 were as follows:

¹ H NMR (500 MHz, ACETONE-d ₆ ): δ 8.80 (br. S., 1H), 6.45 (br. S., 1H), 6.37 (d, J = 14.5, 1H), 5.44 (d, J = 2.8, 1H), 5.38 (dd, J = 15.4, 3.2, 1H), 5.29 (d, J = 10.4, 1H), 4.67 (d, J = 10.7, 3H), 4.57 (s, 1H), 4.23- 4.33 (m, 3H), 4.17-4.23 (m, 2H), 4.03-4.10 (m, 3H), 3.94-4.00 (m, 3H), 3.80-3.85 (m, 6H), 3.75 (d, J = 8.2 , 2H), 3.62 (d, J = 6.3, 5H), 3.59 (s, 11H), 3.40-3.50 (m, 14H), 3.29-3.33 (m, 4H), 2.49-2.64 (m, 3H), 2.20 -2.29 (m, 5H), 2.17 (dt, J = 4.4, 2.2, 3H), 1.94 (s, 2H), 1.89-1.93 (m, 6H), 1.89 (s, 2H), 1.82-1.88 (m, 2H), 1.69-1.71 (m, 7H), 1.63-1.69 (m, 8H), 1.49-1.60 (m, 12H), 1.40 (dd, J = 12.1, 7.1, 2H), 1.31 (d, J = 3.8 , 2H), 1.29 (d, J = 4.1, 3H), 1.27 (s, 7H), 1.18 (d, J = 3.2, 12H), 1.11 (d, J = 6.3, 2H), 1.08 (d, J = 6.6, 6H), 0.97 (d, J = 6.9, 6H), 0.86 (d, J = 6.6, 6H); LRMS (ESI): 1117.7 [M + Na] ⁺ .

[ Example  15]

To synthesize the PTX-2 derivative of Example 15, after mixing the PTX-2 derivative of Example 14, DCM, and DDT (50 equiv) and charging with nitrogen gas Stir at room temperature. The resultant was then taken in traces to perform HPLC, at which time the proportion of MeOH solvent was increased from 65% to 90% for 20 minutes and the product peak was found at 18.2 minutes.

On the other hand, for reference, the mass spectrometry data of the PTX-2 derivative of Example 15 was as follows:

LRMS (ESI): 984.6 [M + Na] ⁺ .

[ Example  16]

First, PTX-2 (0.5 mg, 0.0005 mmol) dissolved in DCM, and tosyl isocyanate (0.14 μL, 0.001 mmol, 2 equivalents) were mixed, and charged with nitrogen gas, followed by stirring at 0 ° C. for 4 hours. The resultant was then taken in traces to perform HPLC, at which time the proportion of MeOH solvent was increased from 65% to 90% for 20 minutes and the product peak was identified at 14.9 minutes.

On the other hand, for reference, the NMR and mass spectrometric data of the PTX-2 derivative of Example 16 were as follows:

¹ H NMR (500 MHz, ACETONE-d ₆ ): δ 7.73-7.84 (m, 3H), 7.13-7.19 (m, 4H), 6.81-6.87 (m, 1H), 6.66 (br. S., 3H) , 6.35-6.40 (m, 1H), 6.00 (br. S., 5H), 5.30-5.41 (m, 12H), 4.60 (d, J = 2.8, 1H), 4.55 (s, 1H), 4.45 (t , J = 8.4, 1H), 4.23-4.30 (m, 3H), 4.17-4.21 (m, 2H), 3.96 (s, 1H), 3.80-3.91 (m, 2H), 3.77 (s, 1H), 3.70 -3.75 (m, 1H), 3.59-3.66 (m, 1H), 3.54 (dd, J = 11.0, 5.0, 1H), 3.38 (s, 1H), 3.33-3.36 (m, 1H), 3.31 (d, J = 5.2, 1H), 2.32-2.36 (m, 5H), 2.16-2.19 (m, 7H), 2.14-2.16 (m, 5H), 2.13-2.14 (m, 3H), 2.08-2.10 (m, 7H ), 1.92 (dt, J = 4.4, 2.2, 5H), 1.89 (d, J = 7.7, 3H), 1.67-1.71 (m, 6H), 1.54-1.65 (m, 24H), 1.17 (d, J = 9.1, 10H), 1.08 (d, J = 6.9, 6H), 0.97 (d, J = 6.9, 3H), 0.69 (d, J = 6.9, 3H); LRMS (ESI): 1078.6 [M + Na] ⁺ .

[ Example  17]

First, PTX-2 (1 mg, 0.001 mmol), pyridine (0.56 μL, 0.007 mmol, 7 equiv) dissolved in DCM and chlorosulfonyl isocyanate (0.34 μL, 0.004 mmol, 4 equiv) were mixed. Then, after filling with nitrogen gas, the mixture was stirred at 0 ° C. for 5 hours. Triethylamine (0.41 μL, 0.003 mmol, 3 equiv), and 4-aminophenol (0.15 mg, 0.003 mmol, 3 equiv) were then added and reacted at room temperature for 1 hour. The resultant was then taken in traces to perform HPLC, at which time the proportion of MeOH solvent was increased from 75% to 90% for 20 minutes and the product peak was identified at 6.0 minutes.

On the other hand, for reference, the mass spectrometry data of the PTX-2 derivative of Example 17 was as follows:

LRMS (ESI): 1095.6 [M + Na] ⁺ .

[ Example  18]

Example 18 was synthesized in a similar manner to Example 17, except that 2-hydroxyethyl amine was used instead of 4-aminophenol. The proportion of MeOH solvent was increased for 20 minutes from 65% to 90% in HPLC to check whether the reaction proceeded successfully and the product peak was found at 11.3 minutes.

On the other hand, for reference, the mass spectrometry data of the PTX-2 derivative of Example 18 was as follows:

LRMS (ESI): 1047.5 [M + Na] ⁺ .

[ Example  19]

Example 19 was synthesized in a similar manner to Example 17 except that 2-hydroxyethyl amine, in which the alcohol was protected with tert butyl dimethyl silane (TBDMS) groups, was used instead of 4-aminophenol. The proportion of MeOH solvent was developed for 20 minutes from 65% to 90% in HPLC to see if the reaction was successful and then increased to 100%, The product peak was confirmed at 26.8 minutes.

On the other hand, for reference, the mass spectrometry data of the PTX-2 derivative of Example 19 was as follows:

LRMS (ESI): 1161.8 [M + Na] ⁺ .

[ Example  20]

Example 20 was synthesized in a similar manner to Example 17 except that glycine ethyl ester was used instead of 4-aminophenol. The proportion of MeOH solvent was increased for 20 minutes from 65% to 90% in HPLC to check whether the reaction proceeded successfully and the product peak was found at 18.2 minutes.

On the other hand, for reference, the mass spectrometry data of the PTX-2 derivative of Example 20 was as follows:

LRMS (ESI): 1089.7 [M + Na] ⁺ .

[ Example  21]

Example 21 was synthesized in a similar manner to Example 17, except that the aminoethyl amide of Cbz-glycine was used instead of 4-aminophenol. The proportion of MeOH solvent was increased for 20 minutes from 65% to 90% in HPLC to check whether the reaction proceeded successfully and the product peak was found at 19.3 minutes.

On the other hand, for reference, the mass spectrometry data of the PTX-2 derivative of Example 21 was as follows:

LRMS (ESI): 1237.7 [M + Na] ⁺ .

[ Example  22]

Example 22 was synthesized in a similar manner to Example 17 except that cystiamine was used instead of 4-aminophenol. The proportion of MeOH solvent was increased for 20 minutes from 65% to 90% in HPLC to check whether the reaction proceeded successfully and the product peak was confirmed at 13.8 minutes.

On the other hand, for reference, the mass spectrometry data of the PTX-2 derivative of Example 22 was as follows:

LRMS (ESI): 1138.7 [M + Na] ⁺ .

[ Example  23]

Example 23 was synthesized in a similar manner to Example 17, except that sarcosine ethyl ester was used instead of 4-aminophenol. The proportion of MeOH solvent was maintained at 75% for 20 minutes in HPLC to check whether the reaction proceeded successfully and the product peak was confirmed at 12.2 minutes.

On the other hand, for reference, the mass spectrometry data of the PTX-2 derivative of Example 23 was as follows:

LRMS (ESI): 1089.7 [M + Na] ⁺ .

[ Example  24]

Example 24 was synthesized in a similar manner to Example 17, except that proline methylester was used instead of 4-aminophenol. The proportion of MeOH solvent was increased in 20 minutes from 65% to 90% in HPLC to check whether the reaction proceeded successfully, The product peak was confirmed at 18.9 minutes.

On the other hand, for reference, the mass spectrometry data of the PTX-2 derivative of Example 24 was as follows:

LRMS (ESI): 1115.9 [M + Na] ⁺ .

[ Example  25]

Example 25 was synthesized in a similar manner to Example 17 except that piperidine was used instead of 4-aminophenol. The proportion of MeOH solvent was increased for 20 minutes from 65% to 90% in HPLC to check whether the reaction proceeded successfully and the product peak was found at 21.8 minutes.

On the other hand, for reference, the mass spectrometry data of the PTX-2 derivative of Example 25 was as follows:

LRMS (ESI): 1071.7 [M + Na] ⁺ .

[ Example  26]

Example 26 was synthesized in the same manner as in Example 17, except that bispiperidine protected with boc (butoxy carbonyl) was used instead of 4-aminophenol. The proportion of MeOH solvent was developed for 20 minutes from 65% to 90% in HPLC to see if the reaction was successful and then increased to 100%, The product peak was confirmed at 26.1 minutes.

On the other hand, for reference, the NMR and mass spectrometric data of the PTX-2 derivative of Example 26 were as follows:

¹ H NMR (500 MHz, ACETONE-d ₆ ): δ 6.38 (dd, J = 15.6, 1.7, 1H), 5.42-5.45 (m, 1H), 5.38 (dd, J = 15.8, 3.2, 1H), 5.31 (d, J = 10.7, 1H), 4.65-4.74 (m, 2H), 4.31-4.38 (m, 1H), 4.26-4.31 (m, 1H), 4.15-4.22 (m, 2H), 4.05-4.15 ( m, 2H), 3.94-4.00 (m, 2H), 3.79-3.86 (m, 2H), 3.73 (s, 1H), 3.28-3.36 (m, 1H), 2.93 (d, J = 16.1, 1H), 2.24 (d, J = 9.5, 2H), 2.17 (dt, J = 4.4, 2.2, 3H), 1.92 (dt, J = 4.4, 2.2, 5H), 1.89 (d, J = 7.9, 3H), 1.72- 1.82 (m, 5H), 1.70 (s, 5H), 1.68 (br.s., 3H), 1.55-1.65 (m, 10H), 1.45-1.51 (m, 2H), 1.43 (s, 11H), 1.40 (d, J = 7.3, 1H), 1.30 (d, J = 3.2, 4H), 1.25-1.28 (m, 5H), 1.17 (d, J = 2.2, 6H), 1.11-1.15 (m, 2H), 1.08 (d, J = 6.9, 3H), 0.97 (d, J = 6.6, 3H), 0.91 (d, J = 6.6, 3H); LRMS (ESI): 1254.8 [M + Na] ⁺ .

2. Example  1 to 26 PTX Synthesis of -2 Derivatives Scheme

[ Example  1 and 2]

[ Example  3 to 9]

[ Example  10]

[ Example  11 and 12]

[ Example  13]

[ Example  14 and 15]

[ Example  16]

[ Example  17 to 22]

[ Example  23 to 26]

3. Example  1 to 26 PTX Chemical structural formula of -2 derivatives (Table 1)

number constitutional formula Example  One

Example  2

Example  3

Example  4

Example  5

Example  6

Example  7

Example  8

Example  9

Example  10

Example  11

Example  12

Example  13

Example  14

Example  15

Example  16

Example  17

Example  18

Example  19

Example  20

Example  21

Example  22

Example  23

Example  24

Example  25

Example  26

4. Example  1 to 26 PTX Anticancer Effects of -2 Derivatives

In order to confirm the anticancer effect of the PTX-2 derivatives according to the present application, in this Example, some of the PTX-2 derivatives of Examples 1 to 26, and as a comparative example for various cell lines of PTX-2 Cytotoxicity experiments were also performed and the results are described using IC ₅₀ values in Table 2. The IC ₅₀ values listed in Table 2 are in ng / mL, the number of cells per well in the cytotoxicity experiment was 2,000, the time the compounds were treated was 72 hours, and a microculture tetrazolium (MTT) assay was used. To via the data shown in Table 2, in the embodiment of the PTX-2 derivative In vitro anticancer effects can be identified:

Sample
(Cancer cell) IC ₅₀   ( ng Of mL ) MDAH -2774
(Ovarian cancer) A549
(Lung cancer) HCT116
(Colon Cancer) HT29
(Colon Cancer) MB231
(Breast cancer) MCF7
(Breast cancer) SKOV3
(Ovarian cancer) PTX -2
( Comparative example ) 0.089 0.845 0.812 0.735 1.52 0.44 1.07 Example  One 38.2 19.2 17.6 33.9 23.1 2.90 24.2 Example  2 20.7 370 70.7 To 90 > 100 > 100 50.2 Example  4 4.90 2.48 3.48 3.12 4.79 0.42 0.38 Example  5 44.4 > 100 > 100 > 100 > 100 > 100 > 100 Example  6 ~ 100 66.5 53.3 53.8 75.9 54.1 > 100 Example  8 44.2 > 100 > 100 > 100 No activity No activity > 100 Example  10 54 - - - - - - Example  13 4.5 - - - - - - Example  16 39.6 16.51 38.4 39.6 - - - Example  19 32 24.9 ~ 100 ~ 100 - - - Example  22 70 - - - - - - Example  23 19.6 - - - - - - Example  25 48.8 27.4 27.2 93.4 - - - Example  26 15.7 - - - - - -

It will be understood by those of ordinary skill in the art that the foregoing description of the embodiments is for illustrative purposes and that those skilled in the art can easily modify the invention without departing from the spirit or essential characteristics thereof. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive. For example, each component described as a single entity may be distributed and implemented, and components described as being distributed may also be implemented in a combined form.

The scope of the present invention is defined by the appended claims rather than the detailed description, and all changes or modifications derived from the meaning and scope of the claims and their equivalents should be interpreted as being included in the scope of the present invention .

Claims (10)

Represented by the following formula (1),
Pectenotoxin-2 (PTX-2) derivatives:
[Formula 1]

;
In Chemical Formula 1,
R ¹ is a functional group represented by Formula 2 or Formula 3:
(2)

,
(3)

;
Among the above formulas,
R ² is an alkyl group which may include a substituent, -COR ³ , -CONHR ⁴ , -CONHSO ₂ NHR ⁵ , or -CONHSO ₂ R ⁶ ,
R ³ is an alkyl group which may include a substituent,
R ⁴ is H, a phenyl group which may include a substituent, or an alkyl group which may include a substituent,
R ⁵ is a phenyl group which may include a substituent, or an alkyl group which may include a substituent,
R ⁶ is an amine group which may include a substituent, a phenyl group which may include a substituent, or an N-saturated cyclic hydrocarbon group which may include a substituent.
The method of claim 1,
R ² is —CH ₂ CH═CH ₂ , or

It containing, pectenotoxin-2 derivatives.
The method of claim 1,
The -COR ³ is -COCH ₃ , or -COCH ₂ Br, pectenotoxin- ₂ derivative.
The method of claim 1,
The -CONHR ⁴ is -CONH ₂ , -CONHCH ₂ CH ₃ , -CONHCH ₂ CH ₂ CH ₃ , -CONHCH ₂ CH ₂ CH ₂ CH ₃ , -CONHCH ₂ CH = CH ₂ , -CONHCH ₂ CH ₂ SH, -CONHCH ₂ CH ₂ COOCH ₂ CH ₃ , -CONHCH ₂ CH ₂ SSCH ₂ CH ₂ NHCOOCH ₃ ,

, or

It containing, pectenotoxin-2 derivatives.
The method of claim 1,
The -CONHSO ₂ NHR ⁵ is -CONHSO ₂ NHCH ₂ CH ₂ OH, -CONHSO ₂ NHCH ₂ CH ₂ OSi (CH ₃ ) ₂ C (CH ₃ ) ₃ , -CONHSO ₂ NHCH ₂ COOCH ₂ CH ₃ , -CONHSO ₂ NHCH ₂ CH ₂ SSCH ₂ CH ₂ NH ₂ ,

, or

It containing, pectenotoxin-2 derivatives.
The method of claim 1,
The -CONHSO ₂ R ⁶ is -CONHSO ₂ N (CH ₃ ) CH ₂ COOCH ₂ CH ₃ ,

,

,

, or

It containing, pectenotoxin-2 derivatives.
An anticancer composition comprising the pectenotoxin-2 derivative according to any one of claims 1 to 6.
The method of claim 7, wherein
The anticancer composition is that comprising the one used to remove cancer cells in the human, anticancer composition.
The method of claim 8,
The cancer cells are cancer cells of the lung, colon, central nervous system, skin, ovaries, kidneys, breast, stomach, or colon, which is an anticancer composition.
The method of claim 7, wherein
The anticancer composition is an anticancer composition having an anticancer effect of IC ₅₀ 10 ^-10 M to 10 ^-8 M.