WO2020226520A1 - A new terpenoid derivative and its use in chemoprevention and supporting cancer chemotherapy - Google Patents
A new terpenoid derivative and its use in chemoprevention and supporting cancer chemotherapy Download PDFInfo
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- WO2020226520A1 WO2020226520A1 PCT/PL2020/050035 PL2020050035W WO2020226520A1 WO 2020226520 A1 WO2020226520 A1 WO 2020226520A1 PL 2020050035 W PL2020050035 W PL 2020050035W WO 2020226520 A1 WO2020226520 A1 WO 2020226520A1
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- cancer chemotherapy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/608—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a ring other than a six-membered aromatic ring in the acid moiety
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Definitions
- the subject of the invention is a new terpenoid derivative and its use in chemoprevention and supporting cancer chemotherapy.
- Cancers are one of the most common diseases in the world. The frequency of their occurrence is constantly growing and is so high that they are included in the main civilization diseases. The variety of cancer cell lines and the patient's individual predispositions result in the need to search for new therapeutic solutions in the aspect of the treatment used. Terpenoids are one of the most numerous and most diverse groups of chemical substances of natural origin, which is a rich reservoir of compounds with biological activity, including anti-cancer activity.
- Monoterpenes for the treatment of dry eye syndrome are known in the art (WO2019040772).
- Patent application US2018153851 discloses monoterpenes used for the treatment of chronic respiratory diseases.
- US2018360792 provides monoterpenoids effective in the treatment of alopecia areata and compositions for use on the skin.
- JP2011074092 discloses a composition comprising a monocyclic monoterpenoid for ocular administration.
- CN 107411083 provides a composition containing monoterpenoids derived from jasmine gardenia for use in memory enhancement and sleep disorders.
- NE0218 (3 -bromo-2-oxo- propionic acid 4-isopropenyl-cyclohex-l-enylmethyl ester) disclosed in W02018102412 is a new compound formed by the covalent bonding of two compounds: 3-bromopyruvate (3-BF), an alkylating agent that inhibits metabolism of cancer cells, and perillyl alcohol (POH), a natural monoterpene with anti-cancer properties.
- JP2014224148 provides a pharmaceutical composition that induces the inhibition of angiogenesis, activates the process of cell apoptosis and also slows the growth of cancer cells.
- the composition contains monoterpenoids obtained from Siberian fir extract.
- the formulation is used to treat diseases associated with the process of angiogenesis, such as retinopathy, chronic and acute nephritis, psoriasis, chronic asthma, endometriosis and others.
- US2011294752 discloses new mixtures of saponins and compounds isolated from acacia (Acacia victoriae) containing a triterpene residue to which oligosaccharide and monoterpenoid residues are attached. Mixtures and compounds have properties that regulate apoptosis and cytotoxicity of cells and have anti-tumor potential against various types of cancer cells.
- terpenoids The main goal of modern cancer research with the use of terpenoids is to identify substances with desired properties and to determine the molecular mechanisms of their action at in vitro and in vivo levels. It is also extremely important to obtain new derivatives with strictly defined modifications in the structure of the molecule, which will allow to increase the effectiveness of the chemopreventive action of the compound or to use it as a factor modulating the pharmacokinetics of standard anticancer drugs.
- the object of the invention is to provide an effective agent with chemopreventive properties and supporting cancer chemotherapy.
- the subject of the invention is a new terpenoid derivative i.e. ethyl 3-(2,6,6- trimethylcyclohex-l-en-l-yl)prop-2-enoate (TMPE) of formula 1
- the subject of the invention is a new compound of formula 1 for use as a medicament.
- the subject of the invention is a new compound of formula 1 for use in chemoprevention and in supporting cancer chemotherapy, especially colorectal cancer.
- a further subject of the invention is a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula 1 and a pharmaceutically acceptable carrier or excipient.
- Fig. 1 Dependence of cell survival of LoVo/Dx and HT/29/Dx cells on TMPE concentration. Statistical significance was determined using Student's t-test (* P ⁇ 0.05).
- Fig. 2 Electrophoregram showing total DNA isolated from LoVo/Dx and HT29/Dx cells after incubation with TMPE. M - Fast Ruler Low Range marker.
- Fig. 3 A Dependence of cell survival of LoVo/Dx cells on doxorubicin concentration in the presence of TMPE. Statistical significance was determined using Student's t-test (* P ⁇ 0.05).
- Fig. 3B Dependence of cell survival of HT29/Dx cells on doxorubicin concentration in the presence of TMPE. Statistical significance was determined using Student's t-test (* P ⁇ 0.05).
- Fig. 4. Accumulation of doxorubicin in LoVo and LoVo/Dx cells in the presence of a newly synthesized TMPE derivative. Statistical significance was determined using Student's t-test (* P ⁇ 0.05). Control - accumulation of doxorubicin in cells without TMPE.
- Fig. 5 Accumulation of doxorubicin in HT and HT29/Dx cells in the presence of the newly synthesized TMPE derivative. Statistical significance was determined using Student's t-test (* P ⁇ 0.05). Control - accumulation of doxorubicin in cells without TMPE.
- Ethyl 3-(2,6,6-trimethylcyclohex-l-en-l-yl)prop-2-enoate was obtained by reacting b-cyclocitral with triethyl phosphonoacetate in presence of sodium hydride and tetrahydrofuran as the reaction medium.
- the mechanism of the reaction is that the carbonyl group of the ketone reacts with the a-metallophosphonate, in this case triethyl phosphonoacetate, to give the alkene in the form of olefins and esters easily soluble in organic solvents or phosphoric acids.
- the Horner - Wadsworth-Emmons reaction begins with deprotonation of the phosphonate to form a phosphonate carbanion.
- the nucleophilic reagent attaches to the aldehyde (or ketone), whereas this step determines the reaction rate. Final elimination leads to the (E)-alkene and (Z)-alkene compounds.
- reaction was monitored by TLC and carried out until the substrate had reacted completely (72 h). After completion of the reaction, 45 mL of distilled water was added to the reaction mixture, and the whole mixture was extracted three times with 30 mL portions of hexane. The organic phase was dried over anhydrous magnesium sulfate and filtered. Then the excess solvent was evaporated. 0.12 g of crude product was obtained, which was then purified using a flash column chromatography, eluting with hexane and ethyl acetate 5:3. 0.10 g of pure product was obtained, which represents 51% yield.
- Sulforodamine B is a dye that binds to the amino acids of cellular proteins, which allows determining the total amount of cellular protein, and thus the number of cells after the end of the experiment.
- SRB method was also used to study changes in the cytotoxicity of doxorubicin in the presence of a synthesized derivative. The experiments performed showed the concentration-dependent ability of TMPE to inhibit the growth of both LoVo/Dx and HT29/Dx cells (Fig. 1).
- apoptotic DNA ladder obtained by conventional electrophoresis of DNA derived from cells incubated with the compound at a concentration of 100 mM (Fig. 2). This result suggests the induction of apoptosis in HT/29 and FoVo/Dx cells by the compound according to the invention.
- FoVo and HT29 cell lines were used in spectrofluorimetric studies consisting of measuring intracellular fluorescence of doxorubicin. They show sensitivity to doxorubicin and thus were a couple of control lines in the experiment. Their use confirmed that TMPE has the characteristics of a resistance modulator sensitizing cells to the drug. Studies have shown that the increased cytotoxicity of the TMPE/drug combination towards resistant cells is due to the greater concentration of the drug in the tumor cell nuclei in the presence of a synthesized derivative (Fig. 4 and Fig. 5).
- TMPE modulates the multi-drug resistance phenotype in a human colon cancer cell line. This indicates that the obtained derivative will be an effective chemopreventive and an supporting agent in cancer chemotherapy.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a new terpenoid derivative which is ethyl (3-(2,6,6-trimethylcyclohex- 1 -en- 1 -yl)prop-2-enoate of formula 1. The method for preparation of this compound is that β- cyclocitral is subjected to an HWE reaction. The reaction is carried out in an ice bath in the presence of triethyl phosphonoacetate in tetrahydrofuran. The subject of the invention is also the use of a new derivative in chemoprevention and in supporting cancer chemotherapy.
Description
A new terpenoid derivative and its use in chemoprevention and supporting cancer chemotherapy
The subject of the invention is a new terpenoid derivative and its use in chemoprevention and supporting cancer chemotherapy.
Cancers are one of the most common diseases in the world. The frequency of their occurrence is constantly growing and is so high that they are included in the main civilization diseases. The variety of cancer cell lines and the patient's individual predispositions result in the need to search for new therapeutic solutions in the aspect of the treatment used. Terpenoids are one of the most numerous and most diverse groups of chemical substances of natural origin, which is a rich reservoir of compounds with biological activity, including anti-cancer activity.
Monoterpenes for the treatment of dry eye syndrome are known in the art (WO2019040772). Patent application US2018153851 discloses monoterpenes used for the treatment of chronic respiratory diseases. US2018360792 provides monoterpenoids effective in the treatment of alopecia areata and compositions for use on the skin. JP2011074092 discloses a composition comprising a monocyclic monoterpenoid for ocular administration. CN 107411083 provides a composition containing monoterpenoids derived from jasmine gardenia for use in memory enhancement and sleep disorders. NE0218 (3 -bromo-2-oxo- propionic acid 4-isopropenyl-cyclohex-l-enylmethyl ester) disclosed in W02018102412 is a new compound formed by the covalent bonding of two compounds: 3-bromopyruvate (3-BF), an alkylating agent that inhibits metabolism of cancer cells, and perillyl alcohol (POH), a natural monoterpene with anti-cancer properties. JP2014224148 provides a pharmaceutical composition that induces the inhibition of angiogenesis, activates the process of cell apoptosis and also slows the growth of cancer cells. The composition contains monoterpenoids obtained from Siberian fir extract. In addition, the formulation is used to treat diseases associated with the process of angiogenesis, such as retinopathy, chronic and acute nephritis, psoriasis, chronic asthma, endometriosis and others. US2011294752 discloses new mixtures of saponins and compounds isolated from acacia (Acacia victoriae) containing a triterpene residue to which oligosaccharide and monoterpenoid residues are attached. Mixtures and compounds have
properties that regulate apoptosis and cytotoxicity of cells and have anti-tumor potential against various types of cancer cells.
The main goal of modern cancer research with the use of terpenoids is to identify substances with desired properties and to determine the molecular mechanisms of their action at in vitro and in vivo levels. It is also extremely important to obtain new derivatives with strictly defined modifications in the structure of the molecule, which will allow to increase the effectiveness of the chemopreventive action of the compound or to use it as a factor modulating the pharmacokinetics of standard anticancer drugs.
The object of the invention is to provide an effective agent with chemopreventive properties and supporting cancer chemotherapy.
The subject of the invention is a new terpenoid derivative i.e. ethyl 3-(2,6,6- trimethylcyclohex-l-en-l-yl)prop-2-enoate (TMPE) of formula 1
FORMULA 1
The subject of the invention is a new compound of formula 1 for use as a medicament. The subject of the invention is a new compound of formula 1 for use in chemoprevention and in supporting cancer chemotherapy, especially colorectal cancer.
A further subject of the invention is a pharmaceutical composition comprising a compound of formula 1 and a pharmaceutically acceptable carrier or excipient.
Description of the drawings
Fig. 1. Dependence of cell survival of LoVo/Dx and HT/29/Dx cells on TMPE concentration. Statistical significance was determined using Student's t-test (* P <0.05).
Fig. 2. Electrophoregram showing total DNA isolated from LoVo/Dx and HT29/Dx cells after incubation with TMPE. M - Fast Ruler Low Range marker.
Fig. 3 A. Dependence of cell survival of LoVo/Dx cells on doxorubicin concentration in the presence of TMPE. Statistical significance was determined using Student's t-test (* P <0.05). Fig. 3B. Dependence of cell survival of HT29/Dx cells on doxorubicin concentration in the presence of TMPE. Statistical significance was determined using Student's t-test (* P <0.05).
Fig. 4. Accumulation of doxorubicin in LoVo and LoVo/Dx cells in the presence of a newly synthesized TMPE derivative. Statistical significance was determined using Student's t-test (* P <0.05). Control - accumulation of doxorubicin in cells without TMPE.
Fig. 5. Accumulation of doxorubicin in HT and HT29/Dx cells in the presence of the newly synthesized TMPE derivative. Statistical significance was determined using Student's t-test (* P <0.05). Control - accumulation of doxorubicin in cells without TMPE.
Example 1
Characterization and preparation of ethyl 3-(2,6,6-trimethylcyclohex-l-en-l-yl)prop-2- enoate
Molecular formula: C14H22O2; Molar mass: 222.32
HRMS: (TOFMS ES+) calculated for: [C14H22O2] 223.1698, found [M+] 223.1699
IH NMR (600 MHz, CDCb, d, ppm) 1.03-1.06 (m, 3H, at C-13 and C-14), 1.39-1.42 (m, 3H, at C-11), 1.60-1.63 (m, 2H, at C-5), 1.68-1.72 (m, 3H, at C-12), 1.95 (t, / = 6.4 Hz, 2H, at C- 4), 2.05 (m, 2H, at C-3), 4.10-4.18 (m, 2H, at C-10), 5.94 (s, 1H, at C-8), 7.29 (s, 1H, at C-7). 13C NMR (150 MHz, CDCb, d, ppm) 15.96 (C-15), 20.72 (C-4), 21.44 (C-12), 28.48 (C-13), 28.56 (C-14), 33.72 (C-3), 34.61 (C-6), 35.64 (C-5), 61.54 (C-10), 107.77 (C-8), 124.06 (C-l), 134.70 (C-l l), 148.51 (C-7), 174.02 (C-9).
The method of preparation of ethyl 3-(2,6,6-trimethylcyclohex-l-en-l-yl)prop-2-enoate is based on the Horner- Wadsworth-Emmons reaction. Ethyl 3-(2,6,6-trimethylcyclohex-l-en- l-yl)prop-2-enoate was obtained by reacting b-cyclocitral with triethyl phosphonoacetate in presence of sodium hydride and tetrahydrofuran as the reaction medium.
Two-necked round-bottom flask placed in an ice bath, equipped with a magnetic stirrer, reflux condenser and protected from moisture, was charged with 0.45 g (19 mmol) of sodium hydride, and 10 ml of tetrahydrofuran was added dropwise with stirring. Then, 1.5 g (2.0 mmol) of triethyl phosphonoacetate in 10 ml of tetrahydrofuran was added and stirred for 15 minutes. After this time, a solution of 0.5 g of aldehyde, b-cyclocitral, in 20 ml of tetrahydrofuran was added dropwise with stirring. 30 minutes after the addition, the ice bath was removed. The reaction proceeded according to the scheme.
The mechanism of the reaction is that the carbonyl group of the ketone reacts with the a-metallophosphonate, in this case triethyl phosphonoacetate, to give the alkene in the form of olefins and esters easily soluble in organic solvents or phosphoric acids. The Horner - Wadsworth-Emmons reaction begins with deprotonation of the phosphonate to form a phosphonate carbanion. The nucleophilic reagent attaches to the aldehyde (or ketone), whereas this step determines the reaction rate. Final elimination leads to the (E)-alkene and (Z)-alkene compounds.
The reaction was monitored by TLC and carried out until the substrate had reacted completely (72 h). After completion of the reaction, 45 mL of distilled water was added to the reaction mixture, and the whole mixture was extracted three times with 30 mL portions of hexane. The organic phase was dried over anhydrous magnesium sulfate and filtered. Then the excess solvent was evaporated. 0.12 g of crude product was obtained, which was then purified using a flash column chromatography, eluting with hexane and ethyl acetate 5:3. 0.10 g of pure product was obtained, which represents 51% yield.
Example 2
Testing of the biological activity of a new terpenoid derivative
In vitro studies using a newly synthesized derivative were carried out on LoVo/Dx and HT29/Dx colorectal cancer cell lines which show resistance to the cytostatic drug doxorubicin. The tested lines are characterized by the over expression of the ABCB1 multi drug transporter responsible for the drug active efflux into the extracellular space, which directly contributes to the lack of sensitivity of cells to the chemotherapeutic agent used.
The influence of the compound according to the invention on the growth of the above- mentioned tumor cells was evaluated using the sulforodamine B (SRB) test. Sulforhodamine B is a dye that binds to the amino acids of cellular proteins, which allows determining the total amount of cellular protein, and thus the number of cells after the end of the experiment. The SRB method was also used to study changes in the cytotoxicity of doxorubicin in the presence
of a synthesized derivative. The experiments performed showed the concentration-dependent ability of TMPE to inhibit the growth of both LoVo/Dx and HT29/Dx cells (Fig. 1).
In addition, so-called apoptotic DNA ladder obtained by conventional electrophoresis of DNA derived from cells incubated with the compound at a concentration of 100 mM (Fig. 2). This result suggests the induction of apoptosis in HT/29 and FoVo/Dx cells by the compound according to the invention.
Studies have shown that the use of low (5mM) non-toxic TMPE concentrations in combination with doxorubicin increased the cytotoxicity of cells characterized by P-gp overexpression (HT29/Dx (Fig. 3B) and FoVo/Dx (Fig. 3A)) in comparison to drug itself.
In addition to the drug-resistant cell lines, FoVo and HT29 cell lines were used in spectrofluorimetric studies consisting of measuring intracellular fluorescence of doxorubicin. They show sensitivity to doxorubicin and thus were a couple of control lines in the experiment. Their use confirmed that TMPE has the characteristics of a resistance modulator sensitizing cells to the drug. Studies have shown that the increased cytotoxicity of the TMPE/drug combination towards resistant cells is due to the greater concentration of the drug in the tumor cell nuclei in the presence of a synthesized derivative (Fig. 4 and Fig. 5).
The above results are evidence of the ability of the compound according to the invention to inhibit P-gp activity and thus to limit drug efflux. Based on the performed research, it can be concluded that TMPE modulates the multi-drug resistance phenotype in a human colon cancer cell line. This indicates that the obtained derivative will be an effective chemopreventive and an supporting agent in cancer chemotherapy.
Claims
1. A new terpenoid derivative of formula 1
FORMULA 1
2. The compound of formula 1 for use as a medicament.
3. The compound of formula 1 for use in chemoprevention and supporting chemotherapy of cancers, especially colorectal cancer.
4. A pharmaceutical composition comprising a compound of formula 1 and a pharmaceutically acceptable carrier or excipient.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL429790A PL240449B1 (en) | 2019-05-06 | 2019-05-06 | New terpenoid derivative and its application in chemoprevention and cancer chemotherapy support |
| PLP.429790 | 2019-05-06 |
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| WO2020226520A1 true WO2020226520A1 (en) | 2020-11-12 |
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| PCT/PL2020/050035 WO2020226520A1 (en) | 2019-05-06 | 2020-05-06 | A new terpenoid derivative and its use in chemoprevention and supporting cancer chemotherapy |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080200478A1 (en) * | 2006-02-16 | 2008-08-21 | Robinson Byron C | Antineoplastic and curcumin derivatives and methods of preparation and use |
| US20100284944A1 (en) * | 2007-03-30 | 2010-11-11 | Ioana Maria Ungureanu | Off-note blocking sensory organic compounds |
-
2019
- 2019-05-06 PL PL429790A patent/PL240449B1/en unknown
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2020
- 2020-05-06 WO PCT/PL2020/050035 patent/WO2020226520A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080200478A1 (en) * | 2006-02-16 | 2008-08-21 | Robinson Byron C | Antineoplastic and curcumin derivatives and methods of preparation and use |
| US20100284944A1 (en) * | 2007-03-30 | 2010-11-11 | Ioana Maria Ungureanu | Off-note blocking sensory organic compounds |
Non-Patent Citations (1)
| Title |
|---|
| KOZIOT A. ET AL.: "Synthesis of terpenoid oxo derivatives with antiureolytic activity", MOL BIOL REP., vol. 46, no. 1, 2019, pages 51 - 58, XP036735657, [retrieved on 20181022], DOI: 10.1007/sll033-018-4442-y * |
Also Published As
| Publication number | Publication date |
|---|---|
| PL240449B1 (en) | 2022-04-04 |
| PL429790A1 (en) | 2020-11-16 |
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