WO2009122447A1 - Semi-synthetic sesquiterpene lactone parthenin compound useful for cytotoxicity against cancer cell lines and anticander agent - Google Patents

Semi-synthetic sesquiterpene lactone parthenin compound useful for cytotoxicity against cancer cell lines and anticander agent Download PDF

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Publication number
WO2009122447A1
WO2009122447A1 PCT/IN2009/000218 IN2009000218W WO2009122447A1 WO 2009122447 A1 WO2009122447 A1 WO 2009122447A1 IN 2009000218 W IN2009000218 W IN 2009000218W WO 2009122447 A1 WO2009122447 A1 WO 2009122447A1
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hydroxy
cancer
azuleno
furan
dione
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PCT/IN2009/000218
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English (en)
French (fr)
Inventor
Ghulam Nabi Qazi
Subhash Chandra Taneja
Jaswant Singh
Ajit Kumar Saxena
Vijay Kumar Sethi
Bhahwal Ali Shah
Ajay Kumar
Samar Singh Andotra
Fayaz Malik
Shanmugavel Muthiah
Satyam Kumar Agrawal
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Council Of Scientific & Industrial Research
Department Of Biotechnology
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Publication of WO2009122447A1 publication Critical patent/WO2009122447A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the pre ⁇ nt invention relates to semi-synthetic sesquiterpene lactone parthenin compound of generjl formula 1, useful for cytotoxicity against cancer cell lines and anticancer activity.
  • the present invention relates to semi-synthetic sesquiterpene lactone parthenin compound of general formula 1, useful for anticancer and anti-tumor activity and cytotoxicity against human cancer cell lines at a therapeutically effective dosage.
  • the present invention reUjtes to the field of chemotherapeutics particularly use of novel semiTsynthetic analogues of a sesquiterpene lactone, parthenin, a constituent of Parthenium horsferophprus as cytotoxic agent.
  • the invention particularly relates to structure modification of a natu/al product i.e. a sesquiterpene lactone commonly known as parthenin with a view to imppye ajrid modify the bioactivity, particularly its cytotoxicity and hence anticancer activity.
  • the semi-synthetic molecules of this invention are new as they have not been either prepared or reported for cytotoxic/anticancer activity.
  • the semi-synthetic molecules along with the cytotoxic/anticancer activity disclosed in the present invention are novel and not known in art of subject matter Of the present invention. These novel analogues when screened in vitro displayed projnounced cytotoxic activity at low concentrations in various human cancer cell lines.
  • Parthenium hysterophorus commonly known as congress weed is an aggressive weed of the America including Caribbean. It is somewhat unattractive member of the composite (Asteraceae) family. In the last 100 years, it has found its way to Africa, Australia and Asia.
  • Parthenium causes severe human and animal health problems. It is responsible for allergic contact dermatitis in human and toxic to catties. Allergic contact dermatitis may be caused by the major sesquiterpene lactone parthenin or other constituents which are found in the trichomes of leaf and stem [Herz,W. J. Am. Chem. Soc. 26, 5011 (1959)]. Probably it is also responsible for the toxic effect in livestock. It has also been found to cause respiratory allergies.
  • Parthenium is having some industrial uses as reported in the literatures [Sastry, Tenjarla, CS. and K.Y. Kavathekar, (1990) Publications and Informations Directorate, CSIR, New Delhi].
  • hysterophon ⁇ is described as a weed to be used as tonic, febrifuge, and emmenagogue.
  • Root decoction is useful in dysentery [Singh, U., Wadhwani, A.M. and John, B.M. (1996), Dictionary of economic plants in India ICAR, New Delhi].
  • Parthenium is also reported to display activity against hepatic ameobiasis [Sharma, G.L.
  • Parthenin the major sesquiterpene lactones from Parthenium hysterophorus also possesses q , ⁇ -unsaturated -Y- lactone moiety which is considered to be an essential requirement for lactones to possess such activity [S.M.Kupchan et al. J.Med. Chem. ⁇ 2, 1147 (1971)].
  • the anti-tumor effects of the major sesquiterpene lactones of Parthenium hysterophorus, parthenin have been studied both in vivo and in vitro by Mew et al in 1982. In vivo studies showed that molecule could either cure mice or increase their survival time after intraperitoneal or subcutaneous injection with tumour cells.
  • Sesquiterpene lactones isolated from some natural sources have been shown to possess activity against tumor growth and inflammatory conditions [I. Hall et al., "Anti-inflammatory activity of sesquiterpene lactones and related compounds, " J. Pharm. ScI, vol. 68, pp. 537-542 (1979); I. Hall et al., "Mode of action of sesquiterpene aactones as anti-Inflammatory agents," J. Pharm. Sci., vol. 69, pp. 537-543 (1980)].
  • Sesquiterpene lactone helenalin and related compounds have reportedly displayed antitumor activity (K. Lee, "Antitumor Agents. 32. Synthesis and Antitumor Activity of Cyplopentenone perivatives Related to Helenalin," J. Med. Chem., vol. 21, pp. 819-822 (1978); K. Lee et al., "Cytotoxicity of Sesquiterpene Lactones," Cancer Research, vol. 3 l,pp 164? «- 1654 (1971)]; Other related work includes [J. Cassady, "Potential antitumor agents. Synthesis, reactivity, and cytotoxicity of alpha. -methylene carbonyl compounds, " J. Med Chem., vol.
  • Another object of the present invention is to provide a method for the preparation of the said semi-synthetic sesquiterpene lactone parthenin compound of general formula 1.
  • Yet another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the said semi-synthetic sesquiterpene lactone parthenin compound of general formula 1, optionally along with pharmaceutically acceptable additives and carriers.
  • Stjll another object of the present invention is to provide the use of the compounds or pharmaceutical composition thereof for the anticancer activity and cytotoxicity against human cancer cell lines.
  • the present invention provides a sesquiterpene lactone parthenin compound of general formula 1, obtained semi-synthetically from plant weed Parthenium hysterophorus.
  • the semi-synthetic compounds show cytotoxicity on a panel of human cancer cell lines at low concentrations, thus can be effectively used in cancer therapy.
  • the present invention provides a semi-synthetic sesquiterpene lactone of compound of general formula 1
  • R 2 is H or an alkyl group having C2-C10 alkyl chain or hydroxyethoxyl radical
  • R 3 is selected from the group comprising hydrogen, halogen, hydroxyl radicals
  • R 4 is selected from the group comprising hydrogen, halogen, hydroxyl, hydroxyethoxyl and N- imidazolyl radicals wherein halogen is chloro or bromo radicals
  • R 5 is selected from the group comprising hydrogen, hydroxyl, acetoxyl and propyloxyl radicals
  • R 7 is an alkyl radical having C2-C8 alkyl chain
  • R is H or an alkyl radical having C2-C 10 alkyl chain or an aromatic group.
  • the aromatic radical is selected from furan, thiophene and substituted benzene.
  • substituted benzene is 4- substituted benzene or 3,4-disubstituted benzene or 3,4,5-trisubstituted benzene, wherein substituent pn the benzene ring is selected from the group comprising chloro, bromo, hydroxy, methpxy, methylenedioxy, nitro, amino, and amino acyl group.
  • alkyl radical is C1-C8 alkyl chain.
  • halogen is selected from chloro-, bromo- and iodo- radicals.
  • a pharmaceutical composition comprising an effective amount of semi-synthetic sesquiterpene lactone compound of general formula l(i) or l(ii) optionally along with pharmaceutically acceptable carriers or additives, useful for anticancer activity against cancer cell lines.
  • the pharmaceutically acceptable carriers or additives used are selected form Gum Acacia (1.0 to 2.0%), DMSO ⁇ 0.3 to 1.0% ⁇ and / or Normal Saline.
  • the said composition induces programmed cell death (apoptosis) as means of cancer cell killing, a desired molecular target of anti-cancer drugs.
  • the present invention provides a method for treating cancer in a subject, wherein the said method comprising the steps of administering the effective amount of semisynthetic sesquiterpene lactone compound of general formula 1 as claimed in claim 1 or pharmaceutical composition thereof.
  • composition of the present invention is useful for the treatment of cancer selected from the group comprising alimentary or gastrointestinal tract cancer, breast cancer, brain cancer, bladder cancer, bone cancer, colon cancer, kidney cancer, leukemia, liver cancer, lymphoma, lung cancer, muscle cancer, ovarian cancer, prostate cancer and skin cancer.
  • the subject is mammal including human.
  • the route of administering the said composition is selected from oral, nasal, intra-peritoneal and intra-venous.
  • composition used is selected from the group comprising liquid, tablet, capsule, powder, gel, granules.
  • the additives used are selected from the group of its pharmaceutically acceptable salts, hydrates, solvates, crystals and the like.
  • the cancer is selected from the group comprising alimentary or gastrointestinal tract cancer, breast cancer, brain cancer, bladder cancer, bone cancer, colon cancer, kidney cancer, leukemia, liver cancer, lymphoma, lung cancer, muscle cancer, ovarian cancer, prostate cancer and skin cancer.
  • the therapeutically effective dose of the said composition is in the range of 10-lOOmg/ml.
  • the said composition induces programmed cell death (apoptosis) as means of cancer cell killing, a desired molecular target of anti-cancer drugs.
  • the cancer cells lines are from breast, bone, bladder, colon, liver, skin, lymphoma, leukemia, kidney, lung, muscle, ovarian and prostate cancer.
  • the said composition induces programmed cell death (apoptosis) by means of pro-oxidant effect inhibiting cell proliferation and caspase-3 induction.
  • the killing of cancer cell lines is up to 98% when the concentration of the said composition is ranging between IxIO "6 M - 5x10 "5 M.
  • a method for treating cancer in a subject comprises the steps of administering the effective amount of semi-synthetic sesquiterpene lactone compound of general formula 1 or pharmaceutical composition thereof.
  • the subject is mammal including human.
  • the route of administering the said composition is selected from oral, nasal, intra-peritoneal and intra-venous.
  • the form in which the said composition used is selected from the group comprising liquid, tablet, capsule, powder, gel, granules.
  • the present invention provides a process for preparation of semi-synthetic sesquiterpene lactone compound of general formula 1 comprising the steps: (i) reacting the parthenin with an aldehyde selected from a group consisting of formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, valeraldehyde, heptanaldehyde, benzaldehyde, 4-chlorobenzaldehyde, 4-methoxy benzaldehyde, piperonal and cinnamaldehyde in presence of l,8-diazabicyclo[5,4,0]undec-7-ene
  • an aldehyde selected from a group consisting of formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, valeraldehyde, heptanaldehyde, benzaldehyde, 4-chlorobenzaldehy
  • Scheme 12 represents synthesis of compound of formula l(i), where, OH, OCH 3 ,
  • Table 1 shows in vitro toxicity against some human cancer cell lines of compounds of formula 1
  • Table 2 shows in vitro toxicity against some other human cancer cell lines of compounds of formula 1
  • the present invention is aimed to develop a potent cytotoxic/anti-cancer drug which is active at low concentration and poses minimum side effects.
  • the semi-synthetic compounds of the present invention have neither been reported in the chemical literature nor have been used for the cytotoxic activity.
  • the synthesis of the novel compounds have been accomplished through the combination of various chemical steps known in the art of synthesis though not for the purpose of synthesizing of the compounds of formulae 1 as described above.
  • a structural formulae 1 comprising the chemical structures as shown in the drawings or a pharmaceutically acceptable composition
  • R is H or an alkyl radical having C2-C10 alkyl chain or a aromatic moiety wherein the aromatic group is selected from a substituted benzene and where substituted benzene is a 4-substituted benzene or a 3,4- disubstituted benzene or 3,4,5-trisubstituted benzene, where substituent on benzene ring are selected from chloro, bromo, hydroxy, methoxy, methylenedioxy, nitro, amino, and amino acyl groups;
  • Ri is H or a radical selected from hydoxymethyl, acetoxymethyl grpups ;
  • R 2 is H or an alkyl group having C2-C10 alkyl chain pr hydroxyethoxyl radical; where R 3 is selected from hydrogen, hal
  • the present invention comprises the compounds prepared via different reactions that may incl ⁇ de Baylis Hillman reaction, nucleophilic addition across ⁇ , ⁇ -unsaturated double bond, etc.
  • the method comprises the reaction of Parthenin with trimethyl amine in presence of primary alcohols such as ethanol, methanol, ethlyleglycol and the like were used effect 1,4-addition on ⁇ , ⁇ -unsaturated pentanone or ⁇ -butyrolactone ring system to produce desired compounds of formula 1.
  • primary alcohols such as ethanol, methanol, ethlyleglycol and the like were used effect 1,4-addition on ⁇ , ⁇ -unsaturated pentanone or ⁇ -butyrolactone ring system to produce desired compounds of formula 1.
  • the cells at sub- confluent stage were harvested from flask by treatment with trypsin (0.05% trypsin in PBS containing 0.02% EDTA) and suspended in complete growth medium. Cells with cell viability of more than 97% by trypan blue exclusion technique were used for determination of cytotoxicity.
  • N ⁇ hrpmosuccinimide (NBS, lOOmg, 0.56mmol) was added to a solution of natural Parthenin
  • the human cancer cell lines were obtained either from National Center for Cell Science, Pune or National Cancer Institute, Fredrick, Md., USA. Cells were grown in tissue culture flasks in complete growth medium (RPMI- 1640 medium with 2mM glutamine, lOO ⁇ g/ml streptomycin, pH 7.4, sterilized by filtration and supplemented with 10% sterilized fetal calf serum and 100 units/ml penicillin before use) at 37 0 C in an atmosphere of 5% CO 2 and 90% relative humidity in a carbon dioxide incubator. The cells at sub-confluent stage were harvested from flask by treatment with trypsin (0.05% trypsin in PBS containing 0.02% EDTA) and suspended in complete growth medium. Cells with cell viability of more than 97% by trypan blue exclusion technique were used for determination of cytotoxicity.
  • complete growth medium RPMI- 1640 medium with 2mM glutamine, lOO ⁇ g/ml streptomycin, pH 7.4, sterilized by filtration and supplemented with 10%
  • Test material was dissolved in DMSO (dimethyl sulphoxide) to obtain a stock solution of 2x10 "2 M.
  • the stock solution was serially diluted with complete growth medium containing 5P ⁇ g/ml of gentamycin to obtain working test solutions of required concentrations.
  • the suspension of human cancer cell lines of required cell density in complete growth medium was prepared and cell suspension (100 ⁇ l/well) of each cell line was added to wells of 96- well tissue culture plate. Suitable blanks and controls were also included. The plates were incubated for 24hrs in a carbon dioxide incubator.
  • the working test solutions of different concentrations were added after incubation. The plates were further incubated for 48-hrs after addition of test material.
  • the cell growth was stopped by gently layering of 50 ⁇ l of TCA (50% trichloroacetic acid) on top of the medium in all the wells.
  • TCA 50% trichloroacetic acid
  • the plates were incubated at 4°C for one hour to fix the cells attached to bottom of the wells. Liquids of all the wells were gently pipetted out and discarded. The plates were washed five times with distilled water to remove TCA, growth medium, low molecular weight metabolites, serum proteins etc. The plates were air dried.
  • Cell growth was measured by staining with sulforhodamine B dye (SRB). The SRB solution (100 ⁇ l, 0.4% in 1% acetic acid) was added to each well and the plates were incubated at room temperature for 30 minutes.
  • SRB sulforhodamine B dye
  • the unbound SRB was quickly removed by washing the wells five times with 1% acetic acid solution and plates were air dried. Tris buffer (100 ⁇ l, 0.01 M, pH 10.4) was added to all the wells and plates were gently stirred for 5 minutes on a mechanical stirrer. The optical density was recorded on ELISA reader at 540 nra. The cell growth in presence of test material was calculated in term of percentage of growth inhibition.
  • the Parthenin compounds produced DNA fragmentation in HL- 60 cells indicating that some of the compounds kill cells by programmed cell death exemplified by agarose-gel DNA fragmentation pattern of about 180 base pairs ladder.
  • l(ii) where,
  • the cells were grown in culture and incubated with indicated concentrations of the compounds for 4 hr.
  • ROS reactive oxygen species
  • the level of intracellular ROS (peroxides) was determined by using 2 ⁇ T- dichlorofluoresceindiacetate.
  • the non-fluorescent compound DCFH-DA has the ability to permeate cells freely where it is deesterified to DCFH, which is further oxidized to DCF that remains entrapped inside the cells.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
PCT/IN2009/000218 2008-03-31 2009-03-31 Semi-synthetic sesquiterpene lactone parthenin compound useful for cytotoxicity against cancer cell lines and anticander agent WO2009122447A1 (en)

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* Cited by examiner, † Cited by third party
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KR101421140B1 (ko) 2010-04-23 2014-07-18 난카이 유니버시티 메킬리아 락톤 유도체, 그 약제학적 조성물 및 그 제조방법과 용도
CN104016952A (zh) * 2013-02-28 2014-09-03 东北林业大学 一种新的倍半萜活性成分及其制备方法与应用
WO2015188169A1 (en) * 2014-06-07 2015-12-10 Academia Sinica Novel sesquiterpene derivatives and their use in inflammation and cancer treatment
JP2018526457A (ja) * 2015-09-11 2018-09-13 ファフル エル−ディン エル−サーウィ，モハメド 薬用のアンブローシア属植物抽出物
CN113387915A (zh) * 2021-06-29 2021-09-14 海南师范大学 一种桉烷型倍半萜内酯类tbb衍生物及其制备方法、用途
CN114805382A (zh) * 2022-05-18 2022-07-29 中国科学院兰州化学物理研究所 一种倍半萜色酮类化合物及其分离和在制备抗胰腺癌药物中的应用
CN115819409A (zh) * 2022-12-06 2023-03-21 江西省科学院应用化学研究所 一种吉马烷型倍半萜内酯衍生物及其制备方法和应用

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101421140B1 (ko) 2010-04-23 2014-07-18 난카이 유니버시티 메킬리아 락톤 유도체, 그 약제학적 조성물 및 그 제조방법과 용도
RU2537319C2 (ru) * 2010-04-23 2015-01-10 Эксендатек Способы изготовления и назначение деривата sphaelactone и его композитные лекарства
CN104016952A (zh) * 2013-02-28 2014-09-03 东北林业大学 一种新的倍半萜活性成分及其制备方法与应用
CN104016952B (zh) * 2013-02-28 2016-05-18 东北林业大学 一种倍半萜活性成分及其制备方法与应用
WO2015188169A1 (en) * 2014-06-07 2015-12-10 Academia Sinica Novel sesquiterpene derivatives and their use in inflammation and cancer treatment
JP2018526457A (ja) * 2015-09-11 2018-09-13 ファフル エル−ディン エル−サーウィ，モハメド 薬用のアンブローシア属植物抽出物
JP7022064B2 (ja) 2015-09-11 2022-02-17 ファフル エル－ディン エル－サーウィ，モハメド 薬用のアンブローシア属植物抽出物
CN113387915A (zh) * 2021-06-29 2021-09-14 海南师范大学 一种桉烷型倍半萜内酯类tbb衍生物及其制备方法、用途
CN113387915B (zh) * 2021-06-29 2022-05-27 海南师范大学 一种桉烷型倍半萜内酯类tbb衍生物及其制备方法、用途
CN114805382A (zh) * 2022-05-18 2022-07-29 中国科学院兰州化学物理研究所 一种倍半萜色酮类化合物及其分离和在制备抗胰腺癌药物中的应用
CN114805382B (zh) * 2022-05-18 2023-06-27 中国科学院兰州化学物理研究所 一种倍半萜色酮类化合物及其分离和在制备抗胰腺癌药物中的应用
CN115819409A (zh) * 2022-12-06 2023-03-21 江西省科学院应用化学研究所 一种吉马烷型倍半萜内酯衍生物及其制备方法和应用

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