WO2018218841A1 - Lactames de miliusane anticancéreux - Google Patents

Lactames de miliusane anticancéreux Download PDF

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Publication number
WO2018218841A1
WO2018218841A1 PCT/CN2017/104966 CN2017104966W WO2018218841A1 WO 2018218841 A1 WO2018218841 A1 WO 2018218841A1 CN 2017104966 W CN2017104966 W CN 2017104966W WO 2018218841 A1 WO2018218841 A1 WO 2018218841A1
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Prior art keywords
compound
cancer
miliusate
formula
miliusane
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PCT/CN2017/104966
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English (en)
Inventor
Hongjie Zhang
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Hong Kong Baptist University
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Priority claimed from US15/610,926 external-priority patent/US9822071B2/en
Application filed by Hong Kong Baptist University filed Critical Hong Kong Baptist University
Priority to CN201780089677.9A priority Critical patent/CN110730775A/zh
Publication of WO2018218841A1 publication Critical patent/WO2018218841A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/54—Spiro-condensed

Definitions

  • the present invention is in the field of pharmaceuticals and chemical industries.
  • the present invention relates to anticancer agents based on miliusane compounds.
  • the present invention also includes its preparation and application method for treating cancer.
  • Cancer in one form or another, is a leading cause of death, and claimed the lives of more than 8.8 million people worldwide in 2015, according to the compiled statistics by WHO (WHO: http: //www. who. int/mediacentre/factsheets/fs297/en/; retrieved on April 15, 2017) . It is estimated that annual cancer cases will reach 22 million by 2036. Although numerous cancer chemotherapeutics are available today, they often have very narrow therapeutic indices and severe side effects. In addition, cancers can and often do develop resistance to many of these drugs. The fact that there currently are no drugs available that are capable of curing cancer diseases, makes the discovery and development of new anticancer drugs very much needed and the undertaking of such studies is imperative.
  • Miliusanes are a group of compounds containing an oxo-spirodecane substructure.
  • a few patents have been published related to the compounds containing an oxospirodecane or azaspirodecane or thiaspirocecane substructure (US 2009/0318548A1; US2011/021624A1 and WO2011098433A1) .
  • the present invention relates to anticancer compounds, which are synthesized based on miliusane. More particularly, the compounds of the present invention are derivatives of the core structures of miliusanes. It is a goal of the present invention to provide miliusane derivatives having biological activity against cancer, particularly colon cancer, breast cancer, prostate cancer, lung cancer, melanoma, leukemia, brain cancer, renal cancer, ovarian cancer, and oral epidermoid cancer.
  • the present invention provides a series of novel anticancer compounds belonging to a cluster of molecules, referred herein to as “miliusanes” , which were isolated from the leaves, twigs and flowers of Miliusa sinensis Finet and Gagnep. (Annonaceae) (Zhang HJ, Ma CY, Hung NV, Cuong NM, Tan GT, Santarsiero BD, Mesecar AD, Soejarto DD, Pezzuto JM, Fong HHS. Miliusanes, a class of cytotoxic agents from Miliusa sinensis. Journal of Medicinal Chemistry 2006; 49: 693-708) . Representative anticancer miliusane compounds are shown below:
  • the three miliusanes (miliusol, miliusate as well as miliusane I) are evaluated in the NCI 60 cell line panel.
  • NCI automated COMPARE analysis it is observed that the three compounds displayed different GI 50 response patterns as compared with other compounds in the NCI database, indicating a unique anticancer mechanism of the miliusanes, which warranted the use of these miliusane compounds for cancer treatment.
  • U.S. patent applications US13/931,997 and US14/927,485 disclose dozens of miliusane derivatives including N-methyl-2-pyrrolecarboxyl-miliusol, p-dimethylamino-benzoyl-miliusol, 4 ⁇ - (N-phenyl) miliusate, 4 ⁇ - (N-phenyl) miliusate, 4 ⁇ - (N-benzoyl-N-phenyl) miliusate, 4 ⁇ - (N-benzoyl-N-phenyl) miliusate, hexahydro-miliusate, 3, 4-dihydro-miliusate, 2′, 3′, 6′, 7′-tetrahydro-miliusate, 2-hydroxy-3, 4-dihydro-miliusate, 2-acetoxy-3, 4-dihydro-miliusate, 8′-oxo-miliusate, 8′-hydroxy-miliusate, 10′-hydroxy-8′-oxo-miliusate, 8
  • a first aspect of the present invention is a compound based on the core structures of miliusane for use in the treatment, prevention or delay of progression of a cancer in a patient.
  • a second aspect of the present invention is a pharmaceutically acceptable salt or prodrug based on the core structures of miliusane, for use in the treatment, prevention or delay of progression of a cancer in a patient.
  • a third aspect of the present invention is a pharmaceutical formulation comprising a compound based on the core structures of miliusane, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment, prevention or delay of progression of a cancer in a patient.
  • a fourth aspect of the present invention is a compound represented by the formula (IX) or formula (X) :
  • R 1 is alkyl
  • R 2 is aryl
  • a fifth aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (IX) or formula (X) and at least one pharmaceutically acceptable carrier.
  • a sixth aspect of the present invention is a method of treating, preventing or delaying the progression of cancer in a subject comprising administering a therapeutically effective amount of a compound of the formula (IX) or formula (X) to a subject in need thereof.
  • a first embodiment of the sixth aspect of the present invention there is provided a method of treating, preventing or delaying the progression of cancer in a subject wherein said cancer comprising colon cancer, breast cancer, prostate cancer, lung cancer, oral epidermoid cancer or melanoma cancer.
  • a second embodiment of the sixth aspect of the present invention there is provided a method of treating, preventing or delaying the progression of cancer in a subject wherein said subject is a human.
  • a third embodiment of the sixth aspect of the present invention there is provided a method of treating, preventing or delaying the progression of cancer in a subject further comprising the step of administering a therapeutically effective amount of a second anti-cancer agent, wherein said compound of claim 1 and said second anti-cancer agent are administered sequentially or administered simultaneously.
  • Compounds of the present invention may exist in different forms, such as free acids, free bases, enantiomers, racemates, diastereomers, esters and other prodrugs, salts and tautomers, and the disclosure includes all variant forms of these compounds.
  • the extent of protection includes counterfeit or fraudulent products, which contain or purport to contain a compound of the present invention irrespective of whether they do in fact contain such a compound and irrespective of whether any such compound is contained in a therapeutically effective amount.
  • packages that include a description or instructions which indicate that the package contains a species or pharmaceutical formulation of the present invention and a product, which is or comprises, or purports to be or comprise, such a formulation or species.
  • Such packages may be, but are not necessarily, counterfeit or fraudulent.
  • the present invention includes all such variation and modifications.
  • the present invention also includes all of the steps and features referred to or indicated in the specification, individually or collectively and any and all combinations or any two or more of the steps or features.
  • Patent law e.g., they can mean “includes” , “included” , “including” , and the like; and that terms such as “consisting essentially of” and “consists essentially of” have the meaning ascribed to them in U.S. Patent law, e.g., they allow for elements not explicitly recited, but exclude elements that are found in the prior art or that affect a basic or novel characteristic of the present invention.
  • miliusane as used herein includes reference to a compound comprising the basic structure shown as below:
  • the carbon numbering of miliusane molecule as used herein includes reference to a compound comprising the numbering system shown as below:
  • the core structure of miliusane includes reference to a compound comprising the basic structure shown as below:
  • the methyl group and the ethyl group form a tetrahydrofuran ring (1-oxa-spiro [4.5] decane and 2-oxa-spiro [4.5] decane) .
  • the methyl group and the ethyl group form a tetrahydro-thiophene ring (1-thia-spiro [4.5] decane and 2-thia-spiro [4.5] decane) .
  • the methyl group and the ethyl group form a pyrrolidine ring (1-aza-spiro [4.5] decane, 2-aza-spiro [4.5] decane, 1-aza-spiro [4.5] dec-1-ene, 2-aza-spiro [4.5] dec-1-ene and 2-aza-spiro [4.5] dec-2-ene) .
  • hydrocarbyl as used herein includes reference to a moiety consisting of hydrogen and carbon atoms; such a moiety may comprise an aliphatic and/or an aromatic moiety. The moiety may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.
  • hydrocarbyl groups include C 1-6 alkyl (e.g. C 1 , C 2 , C 3 or C 4 alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl) ; C 1-6 alkyl substituted by aryl (e.g.
  • benzyl or by cycloalkyl (e.g. cyclopropylmethyl) ; cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) ; aryl (e.g. phenyl, naphthyl or fluorenyl) and the like.
  • cycloalkyl e.g. cyclopropylmethyl
  • cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
  • aryl e.g. phenyl, naphthyl or fluorenyl
  • alkyl and C 1-6 alkyl as used herein include reference to a straight or branched chain alkyl moiety having 1, 2, 3, 4, 5 or 6 carbon atoms. This term includes reference to groups such as methyl, ethyl, propyl (n-propyl or isopropyl) , butyl (n-butyl, sec-butyl or tert-butyl) , pentyl, hexyl and the like.
  • the alkyl moiety may have 1, 2, 3 or 4 carbon atoms.
  • alkenyl and C 2-6 alkenyl as used herein include reference to a straight or branched chain alkyl moiety having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at least one double bond, of either E or Z stereochemistry where applicable. This term includes reference to groups such as ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, and the like.
  • alkynyl and C 2-6 alkynyl as used herein include reference to a straight or branched chain alkyl moiety having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at least one triple bond. This term includes reference to groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, and the like.
  • alkoxy and C 1-6 alkoxy as used herein include reference to -O-alkyl, wherein alkyl is straight or branched chain and comprises 1, 2, 3, 4, 5 or 6 carbon atoms. In one class of embodiments, alkoxy has 1, 2, 3 or 4 carbon atoms. This term includes reference to groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like.
  • cycloalkyl as used herein includes reference to an alicyclic moiety having 3, 4, 5, 6, 7 or 8 carbon atoms.
  • the group may be a bridged or polycyclic ring system. More often cycloalkyl groups are monocyclic. This term includes reference to groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbomyl, bicyclo [2.2.2] octyl, and the like.
  • aryl as used herein includes reference to an aromatic ring system comprising 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring carbon atoms.
  • Aryl is often phenyl but may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes reference to groups such as phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl, and the like.
  • Cyclic group means a ring or ring system, which may be unsaturated or partially unsaturated but is usually saturated, typically containing 3 to 13 ring-forming atoms, for example a 3-, 4-, 5-or 6-membered ring.
  • the ring system may be a bridged or polycyclic ring system.
  • the ring or ring system may be substituted with one or more hydrocarbyl groups. Cyclic groups includes carbocyclyl and heterocyclyl moieties.
  • carbocyclyl as used herein includes reference to a saturated (e.g. cycloalkyl) or unsaturated (e.g. aryl) ring moiety having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 carbon ring atoms.
  • carbocyclyl includes a 3-to 10-membered ring or ring system and, in particular, 5-or 6-membered rings, which may be saturated or unsaturated.
  • the ring or ring system may be substituted with one or more hydrocarbyl groups.
  • a carbocyclic moiety is, for example, selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo [2.2.2] octyl, phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl, and the like.
  • heterocyclyl as used herein includes reference to a non-aromatic (e.g. heterocycloalkyl) or an aromatic (e.g. heteroaryl) heterocyclic ring moiety having from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, silicon and sulfur.
  • heterocyclyl includes a 3-to 10-membered ring or ring system and more particularly a 5-or 6-membered ring, which may be saturated or unsaturated.
  • the ring or ring system may be substituted with one or more hydrocarbyl groups.
  • a heterocyclic moiety is, for example, selected from oxiranyl, azirinyl, 1, 2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolizidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, morph
  • heterocycloalkyl as used herein includes reference to a heterocyclic moiety having 3, 4, 5, 6 or 7 ring carbon atoms and 1, 2, 3, 4, or 5 ring heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur. Heterocycloalkyl can have one or more carbon-carbon double bonds or carbon-heteroatoms double bonds as long as the ring is not aromatic.
  • the group may be a polycyclic ring system but more often is monocyclic.
  • This term includes reference to groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl, imidazolyl, indolizidinyl, piperazinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, quinolizidinyl, and the like.
  • the ring or ring system may be substituted with one or more hydrocarbyl groups.
  • heteroaryl as used herein includes reference to an aromatic heterocyclic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen and sulfur.
  • the group may be a polycyclic ring system, having two or more rings, at least one of which is aromatic, but is more often monocyclic.
  • the ring or ring system may be substituted with one or more hydrocarbyl groups.
  • This term includes reference to groups such as pyrimidinyl, furanyl, benzo [b] thiophenyl, thiophenyl, pyrrolyl, imidazolyl, pyrrolidinyl, pyridinyl, benzo [b] furanyl, pyrazinyl, purinyl, indolyl, benzimidazolyl, quinolinyl, phenothiazinyl, triazinyl, phthalazinyl, 2H-chromenyl, oxazolyl, isoxazolyl, thiazolyl, isoindolyl, indazolyl, purinyl, isoquinolinyl, quinazolinyl, pteridinyl, and the like.
  • halogen as used herein includes reference to F, Cl, Br, or I.
  • halogen containing moiety includes reference to a moiety comprising 1 to 30 plural valence atoms selected from carbon, nitrogen, oxygen and sulfur which moiety includes at least one halogen.
  • the moiety may be hydrocarbyl for example C 1-6 alkyl or C 1-6 alkoxy, or carbocyclyl for example aryl.
  • substituted as used herein in reference to a moiety means that one or more, especially up to 5, more especially 1, 2 or 3, of the hydrogen atoms in said moiety are replaced independently of each other by the corresponding number of the described substituents.
  • optionally substituted as used herein means substituted or un-substituted. It will, of course, be understood that substituents are only at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort whether a particular substitution is possible.
  • enantiomer as used herein means one of two stereoisomers that have mirror images of one another.
  • racemate as used herein means a mixture of equal amounts of enantiomers of a chiral molecule.
  • diastereomer as used herein means one of a class of stereoisomers that are not enantiomers, but that have different configurations at one or more of the equivalent chiral centers.
  • Example of diasteromers are epimers that differ in configuration of only one chiral center.
  • stereoisomer as used herein means one of a class of isomeric molecules that have the same molecular formula and sequence of bonded atoms, but different three-dimensional orientations of their atoms in space.
  • tautomer means isomeric molecules that readily interconvert by a chemical reaction. The reaction commonly results in the migration of a hydrogen atom, which results in a switch of a single bond and adjacent double bond.
  • a prodrug is a medication that is administered as an inactive (or less than fully active) chemical derivative that is subsequently converted to an active pharmacological agent in the body, often through normal metabolic processes.
  • the present invention provides compounds of formula (I) , or (II) :
  • R 19 and R 20 are each independently hydrogen or selected from hydrocarbyl, heterocyclyl or - (CH 2 ) k -heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, cyano, amino, hydroxy, C
  • X is oxygen or sulfur
  • R is hydrogen or selected from hydrocarbyl, heterocyclyl or - (CH 2 ) k -heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, cyano, amino, hydroxy, C 1-6 alkyl and C 1-6 alkoxy; wherein k is an integer between 1 and 6 (e.g. 1, 2 or 3) ; dashed line “----” denotes a single or double bond; or a pharmaceutically acceptable salt or prodrug thereof.
  • the compounds of the present invention are represented by formula (IX) or formula (X) :
  • R 1 is alkyl
  • R 2 is aryl
  • the compound is an optically pure stereoisomer.
  • the compound has formula (X) .
  • the compound of formula (X) has the relative stereochemistry indicated below:
  • the compound of formula (X) has the absolute stereochemistry indicated below:
  • R 2 is phenyl
  • the compound has formula (IX) .
  • the compound of formula (IX) has the relative stereochemistry indicated below:
  • the compound of formula (IX) has the absolute stereochemistry indicated below:
  • R 1 is C 1-6 alkyl, C 2-6 alkyl, C 3-6 alkyl, or C 3-5 alkyl. In certain embodiments, R 1 is C 4 alkyl. In certain embodiments, R 1 is n-butyl.
  • the compound is a tautomer of the compound of Formula (IX) or (X) .
  • the compound has the same relative stereochemistry at the C-1, C-1’, and C-5 carbons as miliusane.
  • the compound has the same absolute stereochemistry at the C-1, C-1’, and C-5 carbons as miliusane.
  • the compound is an enantiomer.
  • the compound is a racemate.
  • the compound is a diastereomer.
  • the compound is a tautomer.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and at least one pharmaceutical acceptable carrier.
  • X 1 and X 2 are carbon atoms either joined by double bond or joined by a single bond constituents of an epoxide ring or a hydroxyethylene moiety
  • X 3 and X 4 are carbon atoms either joined by double bond or joined by a single bond comstituents of an epoxide ring or a hydroxyethylene moiety
  • R 1 is selected from the group consisting of branched alkyl chains, unbranched alkyl chains, cycloalkyl groups, aromatic groups, alcohols, ethers, amines, and substituted or unsubstituted ureas, esters, aldehydes and carboxylic acids
  • R 2 is selected from the group consisting of H, OH and NHR 3 , wherein R 3 is a nitrogen protecting group
  • R 1 , R 3 and R 4 are selected from the group consisting of branched alkyl chains, unbranched alkyl chains, cycloalkyl groups, aromatic groups, alcohols, ethers, amines, and substituted or unsubstituted ureas, esters, aldehydes and carboxylic acids; m is an integer between 0 and 5;
  • D represents hydrogen or represents a C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl radical or represents a C 3 -C 7 -cycloalkyl or 4-to 7-membered monocyclic heterocyclyl radical, where the radicals mentioned may optionally be mono-or polysubstituted by identical or different substituents selected from the group consisting of halogen and hydroxyl and C 1 -C 3 -alkyl, halo-C 1 -C 3 -alkyl, or C 1 -C 3 -alkoxy;
  • X represents halogen, nitro or cyano or represents an optionally monohalogen-or polyhalogen-substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy, C 3
  • V 1 and V 2 together with the carbon atoms to which they are attached form a saturated or unsaturated cycle T 1 which optionally contains at least one further heteroatom and has 4 to 7-ring atoms and whose ring-forming atoms may be mono-or polysubstituted by identical or different substituents selected from the group consisting of halogen and a C 1 -C 6 -alkyl radical.
  • each compound may be in the form of the free compound, an enantiomer, an acid or base addition salt, or a prodrug.
  • the present invention provides 17 compounds with potent anti-cancer activity and synthesis thereof.
  • the compounds of the present invention are synthesized and evaluated for their anticancer activity, namely 4 ⁇ - (N-phenyl) miliusate, 4 ⁇ - (N-phenyl) miliusate, 4 ⁇ - (N-benzoyl-N-phenyl) miliusate, 4 ⁇ - (N-benzoyl-N-phenyl) miliusate, hexahydro-miliusate, 3, 4-dihydro-miliusate, 2′, 3′, 6′, 7′-tetrahydro-miliusate, 2-hydroxy-3, 4-dihydro-miliusate, 2-acetoxy-3, 4-dihydro-miliusate, 8′-oxo-miliusate, 8′-hydroxy-miliusate, 10′-hydroxy-8′-oxo-miliusate, 8′, 10′-dihydroxy-miliusate, 5 ⁇ - (p-trimethylammonio-benzoy
  • miliusane compounds have been evaluated for their anticancer activity against a panel of cancer cell lines comprising KB, HCT116, LNCaP, A549, MCF-7 and A375.
  • 4 ⁇ - (N-Phenyl) miliusate demonstrates cell killing activity with IC 50 values ranging from 0.2-2.0 ⁇ M.
  • 4 ⁇ - (N-Phenyl) miliusate demonstrated cell killing activity with IC 50 values ranging from 1.1-6.5 ⁇ M.
  • 4 ⁇ - (N-Benzoyl-N-phenyl) miliusate demonstrates cell killing activity with IC 50 values ranging from 0.5-2.5 ⁇ M.
  • 5 ⁇ - (p-Trimethylammonio-benzoyl) miliusol iodide demonstrates cell killing activity with IC 50 values ranging from 0.05-1.2 ⁇ M.
  • 5 ⁇ - (p-Dimethyl-allyl-ammonio-benzoyl) miliusol bromide demonstrates cell killing activity with IC 50 values ranging from 0.1-1.5 ⁇ M.
  • N- (n-butyl) -miliusol lactam demonstrates cell killing activity with IC 50 values ranging from 0.5-4.2 ⁇ M.
  • 5 ⁇ - (p-Trimethylammonio-benzoyl) miliusol iodide, 5 ⁇ - (p-dimethyl-allyl-ammonio-benzoyl) miliusol bromide, and 4 ⁇ - (N-phenyl) miliusate demonstrate more potent cell killing activity than that of miliusol. All other compounds show no cell killing activity at a concentration of 20 ⁇ M.
  • the measured average tumor size (L ⁇ W ⁇ W) is suppressed by 30.5%with treatment of 4 ⁇ - (N-phenyl) miliusate at the dose of 20 mg/kg (p ⁇ 0.01) in comparison with the vehicle control group (paclitaxel, the clinically used anticancer drug, shows 23.3%inhibition of tumor growth at the dose of 10 mg/kg) .
  • the vehicle control group paclitaxel, the clinically used anticancer drug
  • reaction mixture is then diluted with CH 2 Cl 2 (30 mL) , and washed sequentially with 5%NaHCO 3 (1 ⁇ 10 mL) , H 2 O (1 ⁇ 10 mL) , and brine (1 ⁇ 10 mL) , followed by removal of solvent in vacuo, leading to crude products, which can be purified using silica gel column chromatography to afford the 2′, 3′, 6′, 7′-tetrahydro-miliusane derivative. Unreacted, partially reacted or unwanted compounds as disclosed herein can be removed from the reaction product.
  • the combined EtOAc solution is washed sequentially with H 2 O (10 mL) and brine (10 mL) , dried over Na 2 SO 4 , and concentrated in vacuo.
  • the reaction mixture is subjected to chromatography separation on a silica gel column, eluted with a solvent system such as petroleum ether : EtOAc 2: 1 to afford the 2-hydroxy-miliusane derivative. Unreacted, partially reacted or unwanted compounds as disclosed herein can be removed from the reaction product.
  • a chloroform (CHCl 3 ) solution of an amino group containing miliusane derivative such as 5 ⁇ - (p-dimethylamino-benzoyl) miliusol (10 mg, 0.022 mmol) and an alkyl halide such as methyl iodide or allyl bromide (10 mL) is refluxed under N 2 atmosphere for 72 hours.
  • Products can be detected by TLC, HPLC and LC-MS.
  • the reaction product is evaporated in vacuo to dryness to afford a mixture, which is subjected to a Si gel column separation to afford miliusane ammonium salt product. Unreacted, partially reacted or unwanted compounds as disclosed herein can be removed from the reaction product.
  • a miliusane such as miliusol (6.1 mg, 0.02 mmol)
  • a primary amine such as n-butylamine (5.9 ⁇ L, 0.06 mmol) or aniline (5.5 ⁇ L, 0.06 mmol)
  • 1-butyl-3-methylimidazolium tetrafluoroborate [bmim] BF 4 , 3.7 ⁇ L, 0.02 mmol
  • the cooled reaction mixture is then diluted with 5 mL of EtOAc and washed with saturated aqueous NH 4 Cl.
  • the collected EtOAc solution is concentrated in vacuo, and purified over a silica gel column to afford miliusane lactam product. Unreacted, partially reacted or unwanted compounds as disclosed herein can be removed from the reaction product.
  • Hexadehydro-miliusate is obtained as a white powder with a molecular formula of C 20 H 32 O 5 determined by positive HRESIMS and NMR studies .
  • N- (n-Butyl) -miliusol lactam is obtained as a white powder with a molecular formula of C 22 H 33 NO 3 determined by positive HRESIMS .
  • HRTOF positive ESIMS m/z calcd for C 22 H 34 NO 3 : 360.2539 [M+1] + , found: 360.2530 [M+1] + .
  • N-Phenyl-miliusol lactam is obtained as a white powder with a molecular formula of C 24 H 29 NO 3 determined by positive HRESIMS .
  • HRTOF positive ESIMS m/z calcd for C 24 H 34 NO 3 : 380.2226 [M+1] + , found: 380.2235 [M+1] + .
  • cytotoxicity assays involving oral epidermoid (KB) , colon (HCT116) , prostate (LNCaP) , breast (MCF-7) , lung (A549) and melanoma (A375) carcinoma cell lines, are performed using sulforhodamine B according to established protocols (Zhang HJ, Ma CY, Hung NV, Cuong NM, Tan GT, Santarsiero BD, Mesecar AD, Soejarto DD, Pezzuto JM, Fong HHS. Miliusanes, a class of cytotoxic agents from Miliusa sinensis.
  • KB cells are maintained in DMEM medium.
  • LNCaP cells are maintained in RPMI1640 medium with hormone-free 10%heat-activated FBS (fetal bovine serum) supplemented with 0.1 nM testosterone.
  • MCF-7 cells are maintained and assayed in MEME medium containing 10 mg/L of insulin.
  • HCT116 cells are maintained in McCoy’s 5A medium supplemented with 10%fetal bovine serum.
  • A549 and A375 cells are maintained in RPMI-1640 medium supplemented with 10%FCS.
  • Serial dilutions of the compounds are prepared using 10%aqueous DMSO as solvent.
  • the 190 ⁇ L cell suspension (3 ⁇ 10 4 cells in 1 ml media) is incubated with10 ⁇ L sample solutions, in triplicate, in 96-well tissue culture plate at 37 °C in a humidified atmosphere of 5%CO 2 in air for 72 hours. 10 ⁇ L 10%aqueous DMSO is used as control group.
  • the cells are fixed to plastic substratum by the addition of 100 ⁇ L cold 20%aqueous trichloroacetic acid and washing with water after incubation at 4 °C for 30 min. After staining cells with 100 ⁇ L of 0.4%sulforhodamine B in 1%aqueous AcOH for 30 min, unbound dye is removed by rinsing with 1%aqueous AcOH. The bound dye is solubilized with 200 ⁇ L 10 mM unbuffered Tris base, pH 10, and the optical density is measured at 515 nm using an ELISA plate reader. The average data are expressed as a percentage, relative to the control. The IC 50 values, the dose that inhibit cell growth by 50%, are calculated using nonlinear regression analysis (percent survival versus concentration) .
  • Antitumor animal study 4 ⁇ - (N-Phenyl) miliusate shows potent cell killing activity in our in vitro evaluation system.
  • HCT116 xenograft animal study is used to evaluate the anticancer activity of 4 ⁇ - (N-phenyl) miliusate in comparison with the clinically used anticancer drug paclitaxel. All animal studies are approved and performed according to Animal Care and Use Guidelines of the Animal Ethics Committee at Hong Kong Institution and performed following Animal Care and Use guidelines set by NIH (National Institute of Health, USA) .
  • BALB/c nude mice, SPF class, male or female, 7-8 weeks old, are purchased from Charles River Laboratories.
  • mice are kept for one week of acclimatization to SPF class laboratory conditions.
  • 4 ⁇ - (N-Phenyl) miliusate was tested for its antitumor activity against HCT116 cancer cells using a number of nude mice (Balc/nu/nu, female) in comparison of paclitaxel.
  • HCT116 cancer cells are subcutaneously implanted with 5 ⁇ 10 6 cells in the rear flank of each mouse. After 10 days, solid tumors with average size of about 80mm 3 appeared at the implanted sites.
  • references cited herein are incorporated by reference herein in their entirety to indicate the state of the art as of their publication or filing date and it is intended that this information can be employed herein, if needed, to exclude specific embodiments that are in the prior art.
  • composition of matter are claimed, it should be understood that compounds known and available in the art prior to Applicant's invention, including compounds for which an enabling disclosure is provided in the references cited herein, are not intended to be included in the composition of matter claims herein.
  • the different functions discussed herein may be performed in a different order and/or concurrently with each other. Furthermore, if desired, one or more of the above-described functions may be optional or may be combined.
  • the present invention discloses new anticancer agents based on the miliusane natural products.
  • the present invention also includes its preparation and application method for treating cancer.

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Abstract

L'invention concerne des composés de lactame miliusane anticancéreux, leur préparation et leur procédé d'application dans le traitement du cancer.
PCT/CN2017/104966 2017-06-01 2017-09-30 Lactames de miliusane anticancéreux WO2018218841A1 (fr)

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CN201780089677.9A CN110730775A (zh) 2017-06-01 2017-09-30 抗癌密瘤杀内酰胺

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US15/610,926 US9822071B2 (en) 2012-06-05 2017-06-01 Anticancer miliusane lactams

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130324580A1 (en) * 2012-06-05 2013-12-05 Hong Kong Baptist University Anti-Cancer Agents Synthesized Based On Miliusane Compounds
US20160046594A1 (en) * 2012-06-05 2016-02-18 Hong Kong Baptist University Anticancer Miliusane Derivatives
US20170267635A1 (en) * 2012-06-05 2017-09-21 Hong Kong Baptist University Anticancer Miliusane Lactams

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130324580A1 (en) * 2012-06-05 2013-12-05 Hong Kong Baptist University Anti-Cancer Agents Synthesized Based On Miliusane Compounds
US20160046594A1 (en) * 2012-06-05 2016-02-18 Hong Kong Baptist University Anticancer Miliusane Derivatives
US20170267635A1 (en) * 2012-06-05 2017-09-21 Hong Kong Baptist University Anticancer Miliusane Lactams

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