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WO2019111265A1 - Composés et procédés de traitement du cancer - Google Patents

Composés et procédés de traitement du cancer Download PDF

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Publication number
WO2019111265A1
WO2019111265A1 PCT/IL2018/051346 IL2018051346W WO2019111265A1 WO 2019111265 A1 WO2019111265 A1 WO 2019111265A1 IL 2018051346 W IL2018051346 W IL 2018051346W WO 2019111265 A1 WO2019111265 A1 WO 2019111265A1
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Prior art keywords
compound
another embodiment
cells
acid
formula
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PCT/IL2018/051346
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English (en)
Inventor
Yehoshua KORCHIA-MAOR
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Share Gal Research And Development Ltd
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
    • 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
    • C07D405/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel compounds, compositions and methods of preparation thereof, as well as uses thereof for treating cancer of various types, including: pancreatic, liver, breast, colon, brain and lung cancer.
  • Cancer is a maj or public health problem worldwide and is the second leading cause of death in the United States.
  • pancreatic adenocarcinoma is one of the most lethal due to its rapid growth and propensity to invade adjacent organs and metastasize.
  • Ephedra is a genus of gymnosperm shrubs which belongs to the family of Ephedracea with over 30 registered species. As the majority of the gymnosperm plants, instead of fruits, it has bisexual strobilus which serves as food for birds. The leaves are degenerated and located in a sort of reddish membranous sheath on the stem which is green all year round. The various species of Ephedra are widespread throughout many lands. However, they are found in more abundance in southern Europe, Middle West, central Asia and northern China.
  • Ephedra species especially E. sinica
  • E. sinica have traditionally been used by the Chinese for a variety of medical purpose for at least 5000 years (Dewick, P.M.; 2009, Medicinal natural products, a biosynthetic approach, 3 rd edition, Wiley).
  • Last studies have revealed to have anti-invasive, antiangiogenic and antitumor activities of Ephedra sinica extract (Nam, N.H. et al.; Phytother. Res. 2003 ,17, 70-76).
  • Ephedra genus contains alkaloids as ephedrine (E) and pseudoephedrine (PE) which have been considered the primary pharmacologically active substances in Ephedra.
  • E ephedrine
  • PE pseudoephedrine
  • Ephedra foeminea a particular species of the genus Ephedra, namely Ephedra foeminea, draw attention and interest as a potential agent for cancer treatment mainly due to two reasons: a) Surprisingly, no ephedrine alkaloids were identified in its chemical profile composition (Ibragic, S. et al.; Bosn. J. Basic. Med. Sci., 15), b) reports from patients diagnosed with different types of cancer that were apparently healed from their ailments by drinking an infusion prepared with Ephedra foeminea stalks, and a report on reducing various cancerous cells’ viability (Ben-Arye, E.; et al.; J. Cancer Res. Clin. Oncol. 2016, 142(7), 1499-1508; and Mendelovich, M. et al.; J. Med. Pla. Res. 2017, 11(43), 690-702, respectively).
  • pancreatic adenocarcinoma Due to its rapid growth and prognostic to invade adjacent organs and metastasize pancreatic adenocarcinoma is considered one of the most lethal forms of cancer. The early stages of this cancer do not usually produce symptoms, so the disease is generally advanced when it is diagnosed (Lillemoe, K. D. et al.; Ca. Can. J. Clin. 2000, 50, 241-268). It is estimated that ninety-nine percent of patients with adenocarcinoma of the pancreas will die within 5 years of diagnosis (Jemal, A. et al.; Can. stat. 2003, 53, 5-26).
  • Pancreatic cancer is the fourth leading cause of cancer-related death in the United States and is the seventh most common cause of death worldwide (Lillemoe, K. D. et al.; Ca. Can. J. Clin. 2000, 50, 241- 268). Treatment for pancreatic cancer is rarely effective because surgical excision offers the only possibility for a cure, and fewer than 15% of patients are candidates for tumor resection at the time of diagnosis. Chemotherapy provides only a slight survival advantage over surgical resection alone, and radiation therapy has not been demonstrated to be beneficial (Hazard, L.; Gast. Can. Res., 2009, 3, 20-28). More effective treatments are needed to improve the prognosis of patients with pancreatic cancer.
  • this invention provides compounds, compositions, their preparation and uses in the treatment of cancer, especially their use in the treatment of pancreatic cancer.
  • this invention provides a compound represented by the structure of formula (I): x'-x 2 -x
  • X 1 is a cinnamic acid moiety or derivative thereof
  • X 2 is an amino acid or an amine linker
  • X 3 is a hydroxy or polyhydroxy-substituted flavone, flavanone or derivative thereof.
  • n is an integer between 1 and 4;
  • n is 1-4. In another embodiment, n is 1. In another embodiment, n is 2. In another embodiment, n is 3. In another embodiment of this invention, n is 4. Each possibility represents a separate embodiment of this invention.
  • the compound of this invention is selected from:
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as described hereinabove and a pharmaceutical acceptable carrier.
  • this invention provides a method of treating a disease or a medical condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound as described hereinabove.
  • the disease is cancer.
  • the cancer is pancreatic, liver, breast, colon, brain or lung cancer.
  • the cancer is pancreatic cancer.
  • Figures 1A-1B depict morphology and viability evaluation of Aspcl cells at the end point of the real time cytotoxic detection assay, 32 hours after treatment with compounds 1 or 2.
  • Figure 1A Representative micrographs before MTT assay; and
  • Figure IB MTT assay.
  • Figures 2 depicts real time cytotoxicity detection assay during the course of 72 hours on Aspcl cells treated with 300 mM of compound 10 (grey) or 2 (black). Measurement of fluorescent signals was calculated from the percentage of the control.
  • Figures 3A-3B depict Western blot analysis of protein expression profile of Aspcl cells treated with 150mM of compounds of this invention for 24 hours. Control and treated groups were analyzed in triplicates.
  • Figure 3A compound 10; and Figure 3B: compound 2.
  • Figures 4A-B depict ROS formation in Aspcl cells treated with compound 10 or 2 and then with dichlorofluorescin (DCFH). Aspcl cells were treated with compound 10 or 2 and the fluorescence intensity of dichlorofluorescein (DCF) was measured after 2 hours of incubation.
  • Figure 4A 24 hours treatment with compound 10 or 2; or
  • Figure 4B 96 hours treatment with compound 10 or 2. Solid - treatment, diagonal lines - control.
  • Figure 5 depicts effect of compound 10 on tumor formation. Treatment with compound 10 started 24 hours after cells seeding (before tumor formation) and persisted for 72 hours. White arrows indicate examples of secondary tumor formation.
  • Figure 6 depicts effect of compound 10, irinotectan or carboplatin on tumor formation. Treatment with compound 10, irinotectan or carboplatin started 72 hours after cells seeding (before tumor formation) and persisted for additional 72 hours. Black dots represent necrotic areas.
  • Figure 7 depicts effect of compound 2, naringenin and p-coumaric acid on tumor formation.
  • Treatment with compound 2, naringenin and p-coumaric acid started 24 hours after cells seeding (before tumor formation) and persisted for 72 hours. Black dots represent necrotic areas.
  • Figure 8 depicts tumor area size of subcutaneous Aspc 1 tumors daily treated with compound 10 (30mg/Kg mice) (T) or treated only with vehicle (C).
  • Figure 9 depicts subcutaneous Aspcl tumors removed from nude mice treated with compound 10 after 3 weeks. A necrosis area is observed in the center of treated tumors.
  • Figure 10 depicts average necrosis percentage of subcutaneous Aspcl tumors removed from nude mice daily treated with compound 10.
  • Figure 11 depicts average percentage of natural killers (NK) cells from blood of nude mice daily treated with compound 10 (Treated) or alternatively with vehicle only (Control).
  • Figure 12 depicts tumor area size of subcutaneous A549 tumors daily treated with compound 10 (30mg/Kg mice) (treated) or treated only with vehicle (control).
  • Figure 13 depicts average of tumor size area from day 15 of subcutaneous A549 tumors daily treated with compound 10 (30mg/Kg mice) (Treated) or alternatively treated with vehicle only (Control).
  • Figure 14 depicts tumor size area of subcutaneous T98G tumors daily treated with compound 10 (30mg/Kg mice) (Treated) or alternatively treated with vehicle only (Control).
  • Figure 15 depicts average of tumor size area from day 7 of subcutaneous T98G tumors daily treated with compound 10 (30mg/Kg mice) (Treated) or alternatively treated with vehicle only (Control).
  • this invention provides a compound represented by the structure of formula (I): x'-x 2 - X 3
  • X 1 is a cinnamic acid moiety or derivative thereof
  • X 2 is an amino acid or an amine linker
  • X 3 is a hydroxy or polyhydroxy- substituted flavone, flavanone or derivative thereof.
  • n is an integer between 1 and 4;
  • n is 1-4. In another embodiment, n is 1. In another embodiment, n is 2. In another embodiment, n is 3. In another embodiment of this invention, n is 4. Each possibility represents a separate embodiment of this invention.
  • X 1 within formula (I) of the compound of this invention is represented by the structure of formula (Ila):
  • R'-R 3 are each independently H, OH, OR, F, Cl, Br or I;
  • R is a Ci-Cs linear or branched, substituted or unsubstituted alkyl group or a C 3 -Cs substituted or unsubstituted cycloalkyl group.
  • X 1 is represented by the structure of formula (lib):
  • R ' -R 3 are each independently H, OH, OR, F, Cl, Br or I;
  • R is a Ci-Cs linear or branched, substituted or unsubstituted alkyl group or a C 3 -Cs substituted or unsubstituted cycloalkyl group.
  • X 1 is represented by the structure of formula (He):
  • X 1 of the compound of this invention is any derivative of formula IIC (i.e. p-coumaric acid) .
  • the term“amino acid” of X 2 within formula (I) of the compound of this invention is herein defined as any compound having at least one N-terminal (amino moiety, NH2/NH 3 + depending on pKa/pH) and one C-terminal (carboxyl moiety, CO2H/CO2 depending on pKa/pH).
  • the amino acid of X 2 within formula (I) of the compound of this invention is standard or non standard.
  • non-limiting examples of the amino acids consist of:
  • glycine serine, leucine, tyrosine, threonine, alanine, 5-aminovaleric acid, 2-aminocaprylic acid, carnosine, arginine, histidine, lysine, aspartic acid, glutamic acid, asparagine, glutamine, cysteine, selenocysteine, proline, valine, isoleucine, methionine, phenylalanine, tryptophan, gama- aminobutyric acid, carnitine, levo thyroxine, hydroxyproline, selenomethionine, hypusine, 2- aminoisobutyric acid, ornithine, citrulline, and b-alanine.
  • the amino acid is selected from glycine, serine, leucine, tyrosine, threonine, alanine, 5-aminovaleric acid, 2- aminocaprylic acid, carnosine.
  • X 2 of the compound of this invention is any derivative of the amino acids as described hereinabove.
  • X 2 of the compound of this invention is an amine linker.
  • the amine is alkyl amine or dialkylamine.
  • one of the carbon atoms of the alkyls within the alkylamine or dialkylamine is oxygen or nitrogen.
  • non limiting examples for amines are selected from methylamine, ethylamine, propylamine, butylamine, dimethylamine, diisopropylamine, diethylamine, N-ethylethylenediamine and 2-ethoxyethaneamine. Each possibility represents a separate embodiment of this invention.
  • X 2 of the compound of this invention is any derivative of the amines as described hereinabove.
  • X 3 within formula (I) of the compound of this invention is represented by the structure of formula (Ilia):
  • R 4 -R 13 are each independently H, OH, R, OR, F, Cl, Br, I, NO 2 , CF3 or an oxygen atom which is directly attached to X 2 ;
  • R is a Ci-Cs linear or branched, substituted or unsubstituted alkyl group or a C 3 -Cs substituted or unsubstituted cycloalkyl group;
  • At least one of R 4 -R 13 is an oxygen atom which is directly attached to X 2 ;
  • X 3 is represented by the structure of formula Illb, IIIc, Hid, Hie, Illf or Illg:
  • non- limiting examples of hydroxy or polyhydroxy-substituted flavone or flavanone of X 3 of the compound of this invention consist of: apigenin, acacetin, genkwanin, wogonin, norwogonin, tangeretin, 3-hydroxyflavone, kaempferol, morin, quercetin, rhamnazin, butin, hesperetin, naringenin and sterubin.
  • the compound of this invention is selected from:
  • the compound of this invention is selected from:
  • R 1 - R 3 ⁇ 4 of formulae Ila and lib are each independently H, OH, OR, F, Cl, Br or I.
  • R 1 , R 2 and/or R 3 are each independently H.
  • R 1 , R 2 and/or R 3 are each independently OH.
  • R 1 , R 2 and/or R 3 are each independently OR.
  • R 1 , R 2 and/or R 3 are each independently F.
  • R 1 , R 2 and/or R 3 are each independently Cl.
  • R 1 , R 2 and/or R 3 are each independently Br.
  • R 1 , R 2 and/or R 3 are each independently I. Each possibility represents a separate embodiment of this invention.
  • R 4 -R 13 of formula Ilia are each independently H, OH, R, OR, F, Cl, Br, I, NO2, CF3 or an oxygen atom which is directly attached to X 2 .
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and/or R 13 are each independently H.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and/or R 13 are each independently OH.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and/or R 13 are each independently R.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and/or R 13 are each independently OR.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and/or R 13 are each independently F.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and/or R 13 are each independently Cl.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and/or R 13 are each independently Br. In another embodiment, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and/or R 13 are each independently I. In another embodiment, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and/or R 13 are each independently NO2.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and/or R 13 are each independently CF3.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and/or R 13 are each independently an oxygen atom which is directly attached to X 2 .
  • Each possibility represents a separate embodiment of this invention.
  • R is a Ci-Cs linear or branched, substituted or unsubstituted alkyl group or a Ci-Cs substituted or unsubstituted cycloalkyl group.
  • R is Ci-Cs linear or branched, substituted or unsubstituted alkyl group.
  • R is C-Cs substituted or unsubstituted cycloalkyl group.
  • an alkyl group refers, in some embodiments, to any straight- or branched-chain alkyl group containing up to about 30 carbons unless otherwise specified.
  • an alkyl includes C1-C5 carbons.
  • an alkyl includes Ci-C 6 carbons.
  • an alkyl includes Ci-Cs carbons.
  • an alkyl includes C1-C10 carbons.
  • an alkyl is a C1-C12 carbons.
  • an alkyl is a C1-C20 carbons.
  • branched alkyl is an alkyl substituted by alkyl side chains of 1 to 5 carbons.
  • the alkyl group may be unsubstituted.
  • the alkyl group may be substituted by F, Cl, Br, I, CF 3 , OH, O(alkyl) (i.e. alkoxy), CHO, C(0)NH 2 , C(0)NH(alkyl), C(0)N(alkyl) 2 , CN, NO2, CO2H, NH 2 , NH(alkyl), N(alkyl) 2 , SH, and/or S(alkyl).
  • the alkyl group is methyl.
  • the alkyl group is ethyl. In another embodiment, the alkyl group is propyl. In another embodiment, the alkyl group is butyl. In another embodiment, the alkyl group is t-Butyl. In another embodiment, the alkyl group is neopentyl. In another embodiment, the alkyl group is isopropyl. In another embodiment, the alkyl group is isobutyl. . Each possibility represents a separate embodiment of this invention.
  • cycloalkyl group refers, in some embodiments, to a ring structure comprising carbon atoms as ring atoms, which may be either saturated or unsaturated, substituted or unsubstituted, single or fused.
  • the cycloalkyl is a 3-8 membered ring.
  • the cycloalkyl is a 3-10 membered ring.
  • the cycloalkyl is a 3-12 membered ring.
  • the cycloalkyl is a 6 membered ring.
  • the cycloalkyl is a 5-7 membered ring.
  • the cycloalkyl is a 3-8 membered ring.
  • the cycloalkyl group may be unsubstituted or substituted by F, Cl, Br, I, CFs, OH, O(alkyl) (i.e. alkoxy), CHO, C(0)NH 2 , C(0)NH(alkyl), C(0)N(alkyl) 2 , CN, N0 2 , C0 2 H, NH 2 , NH(alkyl), N(alkyl) 2 , SH, and/or S(alkyl).
  • the cycloalkyl ring may be fused to another saturated or unsaturated cycloalkyl.
  • the cycloalkyl ring is a saturated ring. In some embodiments, the cycloalkyl ring is an unsaturated ring. In another embodiment, the cycloalkyl ring is cyclohexyl. In another embodiment, the cycloalkyl ring is cyclohexenyl. In another embodiment, the cycloalkyl ring is cyclopropyl. In another embodiment, the cycloalkyl ring is cyclopropenyl. In another embodiment, the cycloalkyl ring is cyclopentyl. In another embodiment, the cycloalkyl ring is cyclopentenyl.
  • the cycloalkyl ring is cyclobutyl. In another embodiment, the cycloalkyl ring is cyclobutenyl. In another embodiment, the cycloalkyl ring is cycloctyl. In another embodiment, the cycloalkyl ring is cycloctadienyl (COD). In another embodiment, the cycloalkyl ring is cycloctaene (COE). Each possibility represents a separate embodiment of this invention.
  • this invention provides compounds of formula I in the form of salts, in particular base salts.
  • Suitable salts include those formed with both organic and inorganic bases.
  • Such base addition salts will normally be pharmaceutically acceptable although non- pharmaceutically acceptable salts may be of utility in the preparation and purification of the compounds in question.
  • the term’’derivative refers to compound which can be provided based on a previous compound (which is derived from) following a few known synthetic steps; e.g. 1-3 steps selected from: alkylation reactions, nucleophilic, electrophilic or aromatic substitution reactions, acid/base reactions, aldol reaction and similar condensations, esterification, trans-esterification, animation, amidation, hydrolysis, Schiff base/imine/enamine formation reactions etc.
  • this invention provides methods for preparing the compounds as described hereinabove.
  • a method for the preparation of compound of formula (I), beginning from compound of formula (IVa), is illustrated below in Scheme 1.
  • DCC is dicyclohexylcarbodiimide
  • NHS is N-hydroxysuccinimide
  • R'-R 3 is H, OH, OR, F, Cl, Br or I;
  • R 4 -R 13 are each independently H, OH, R, OR, F, Cl, Br, I, N0 2 or CF 3 ;
  • R is a Ci-C 8 linear or branched, substituted or unsubstituted alkyl group or a C 3 -Cs substituted or unsubstituted cycloalkyl group;
  • n is an integer between 1 and 4;
  • R 4 -R 13 is OH; and is a single or a double bond.
  • “ ⁇ ” is a single bond.
  • “ ” is a double bond.
  • DCC is dicyclohexylcarbodiimide
  • NHS is N-hydroxysuccinimide
  • RfrR 3 is H, OH, OR, F, Cl, Br or I;
  • R 4 -R 13 are each independently H, OH, R, OR, F, Cl, Br, I, N0 2 or CF 3 ;
  • R is a Ci-Cs linear or branched, substituted or unsubstituted alkyl group or a C 3 -Cs substituted or unsubstituted cycloalkyl group;
  • n is an integer between 1 and 4;
  • R 4 -R 13 is OH; and a ⁇ > ⁇ > is a single or a double bond. In another embodiment, a ⁇ > ⁇ > is a single bond. In another
  • “ ” is a double bond.
  • DCC is dicyclohexylcarbodiimide
  • NHS is N-hydroxysuccinimide
  • R 4 -R 13 are each independently H, OH, R, OR, F, Cl, Br, I, NO2 or CF 3 ;
  • R is a Ci-Cs linear or branched, substituted or unsubstituted alkyl group or a C 3 -Cs substituted or unsubstituted cycloalkyl group;
  • n is an integer between 1 and 4;
  • R 4 -R 13 is OH; and a g . , ⁇ > ⁇ > is a single bond.
  • “ ” is a double bond.
  • LG is Cl, Br, I, mesylate, tosylate or triflate
  • DCC is dicyclohexylcarbodiimide
  • NHS is N-hydroxysuccinimide
  • R'-R 3 is H, OH, OR, F, Cl, Br or I;
  • R 4 -R 13 are each independently H, OH, R, OR, F, Cl, Br, I, NO2 or CF 3 ;
  • R is a Ci-Cs linear or branched, substituted or unsubstituted alkyl group or a C 3 -Cs substituted or unsubstituted cycloalkyl group;
  • n is an integer between 1 and 4;
  • R 4 -R 13 is OH; and g . , is a single bond.
  • “ ” is a double bond.
  • LG is Cl, Br, I, mesylate, tosylate or triflate
  • DCC is dicyclohexylcarbodiimide
  • NHS is N-hydroxysuccinimide
  • RhR 3 is H, OH, OR, F, Cl, Br or I;
  • R 4 -R 13 are each independently H, OH, R, OR, F, Cl, Br, I, N0 2 or CF 3 ;
  • R is a Ci-C 8 linear or branched, substituted or unsubstituted alkyl group or a C 3 -Cs substituted or unsubstituted cycloalkyl group;
  • n is an integer between 1 and 4;
  • At least one of R 4 -R 13 is OH
  • LG is Cl, Br, I, mesylate, tosylate or triflate
  • DCC is dicyclohexylcarbodiimide
  • NHS is N-hydroxysuccinimide
  • R 4 -R 13 are each independently H, OH, R, OR, F, Cl, Br, I, N0 2 or CF 3 ;
  • R is a Ci-Cs linear or branched, substituted or unsubstituted alkyl group or a C 3 -Cs substituted or unsubstituted cycloalkyl group;
  • n is an integer between 1 and 4;
  • R 4 -R 13 is OH; and is a single or a double bond. In another embodiment, is a single bond. In another
  • “ ” is a double bond.
  • a solvent(s) is/are employed in the methods which are described in Schemes 1-6.
  • any solvent as known in the art can be employed.
  • non limiting examples of solvents include: water, tetrahydrofuran (THF), acetonitrile, sulfolane, diethyl ether, N,N-dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), dioxane, ethanol, methanol and any combination thereof.
  • THF tetrahydrofuran
  • acetonitrile acetonitrile
  • sulfolane diethyl ether
  • N,N-dimethylformamide DMF
  • DMA dimethylacetamide
  • DMSO dimethyl sulfoxide
  • dioxane ethanol
  • methanol dimethyl sulfoxide
  • the solvent is water.
  • the solvent is tetrahydrofuran (THF).
  • a base is employed in step 2 of the methods which are described in schemes 1-3.
  • any base as known in the art can be employed.
  • non limiting examples of bases include: Na CCh, NaHCCh, K2CO3, KHCO3, LbCCh, LiHC(3 ⁇ 4, NaOH, LiOH, KOH and any combination thereof. Each possibility represents a separate embodiment of this invention.
  • the base is Na 2 C0 3 .
  • steps 1-4 of the methods which are described in scheme 1-3 are performed without an excess of employed reagent (compared to reactant).
  • an excess of reagent is used.
  • an excess of between 5-150% is used.
  • an excess of between 5-15% is used.
  • an excess of between 15- 30% is used.
  • an excess of between 30-50% is used.
  • an excess of between 50-75% is used.
  • an excess of between 75-100% is used.
  • an excess of between 100-125% is used.
  • an excess of between 125-150% is used.
  • an excess of 30% is used.
  • DCC is dicyclohexylcarbodiimide
  • NHS is N-hydroxysuccinimide
  • THF is tetrahydrofuran
  • DMF is N,N-dimethylformamide.
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of this invention as described hereinabove and a pharmaceutical acceptable carrier.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration.
  • the most suitable route may depend upon the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of this invention (an "active ingredient") with the carrier which constitutes one or more suitable diluents, adjuvants, excipients, or stabilizers, and can be in solid or liquid form such as, tablets, capsules, powders, solutions, suspensions, or emulsions. Each possibility represents a separate embodiment of this invention.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • the composition may be prepared in the form of a ready-made drink, or as a powder that can be combined with hot water and then ingested like a tea by an individual. Each possibility represents a separate embodiment of this invention.
  • formulations of the compound of this invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non- aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste. Each possibility represents a separate embodiment of this invention.
  • a tablet may be made by compression or molding, optionally with one or more carriers.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein. Each possibility represents a separate embodiment of this invention.
  • formulations for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient.
  • Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose of multi- dose containers, for example sealed ampoules and vials, and may be stored in a freeze- dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use.
  • a sterile liquid carrier for example saline, phosphate-buffered saline (PBS) or the like.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Each possibility represents a separate embodiment of this invention.
  • formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
  • formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
  • lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
  • preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.
  • this invention provides a method of treating a disease or a medical condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of this invention, as described hereinabove.
  • the method comprises administering more than one compound of this invention.
  • the disease is cancer.
  • the cancer is pancreatic, liver, breast, colon, brain or lung cancer.
  • the cancer is pancreatic cancer.
  • the cancer is liver cancer.
  • the cancer is breast cancer.
  • the cancer is colon cancer.
  • the cancer is brain cancer.
  • the cancer is lung cancer.
  • the disease is a hyper-proliferative and/or a neoplastic disease.
  • “treating” is alleviating a neoplastic or cancerous symptoms and/or disturbances.
  • “treating” is inhibiting tumor growth.
  • “treating” is reducing tumor size.
  • “treating” is destroying the tumor.
  • “treating” is inhibiting malignancy.
  • this invention provides one or more compounds to be used in the methods as described above.
  • the compound is utilized as a medicament.
  • the compound is used as a chemotherapeutic agent, targeted at a cancerous cell, a neoplastic cell, a malignant cell or any combination thereof.
  • the chemotherapeutic agent has low toxicity to non-malignant tissues.
  • the compound has a chemotherapeutic effect.
  • subject or patient refers to any mammalian patient, including without limitation, humans and other primates, dogs, cats, horses, cows, sheep, pigs, rats, mice, and other rodents.
  • the subject is male.
  • the subject is female.
  • Each possibility represents a separate embodiment of this invention.
  • the methods as described herein may be useful for treating either males or females.
  • administering When administering the compounds of the present invention, they can be administered systemically or, alternatively, they can be administered directly to a specific site where cancer cells or precancerous cells are present. Thus, administering can be accomplished in any manner effective for delivering the compounds or the pharmaceutical compositions to the cancer cells or precancerous cells.
  • Exemplary modes of administration include, without limitation, administering the compounds or compositions orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes.
  • parenterally subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes.
  • mucous membranes such as, that of the nose, throat, and bronchial tubes.
  • the compounds of this invention shows strong biological activity by significant reducing viability of many different cancer cell lines where the human pancreatic Aspcl cells present the most sensitive behavior.
  • in vitro results show that the compounds are able to significantly change the expression pattern of key proteins in cancer metabolism such as GLUT-4 receptor and E-cadherin.
  • GLUT-4 is responsible for the glucose uptake which was showed to be impaired in treated cells generating a significant stress response.
  • E-cadherin upregulation impairs cancer cells migration and invasion of the surrounding tissues (i.e. metastasis).
  • in vivo tests see e.g.
  • Example 8 below performed on nude mice daily treated with compounds of this invention showed a significant increase of NK (natural killer) cells production which are very functional in the process of tumor regression.
  • NK cells inhibit angiogenesis process. It is therefore contemplated, without being bound to any mechanism, that treated cells remain attached in situ lacking essential nutrients for normal growth and recede through necrosis. It is noteworthy that the involvement of NK cells and therefore the immune system to combat cancer is just one additional feature of this small molecule which behaves as a target therapy.
  • the compounds of this invention could be classified as belonging to a class of chemotherapeutic compounds known as antimetabolites, which are defined as molecules able to interfere with mechanisms related to cell growth and replication and their efficacy as anticancer agents has been widely demonstrated (Shewach, D. S. et al.; Chem Rev. 2009, 109, 2859-2861; and Mihlon, F. et al.; Semin. Intervent. Radiol. 2010, 27, 384-390).
  • Antimetabolite compounds can induce ligands for NK cell-activating receptors in mammalian tumor cells and promote NK cell-mediated tumor cytotoxicity (e.g.
  • compound 10 may also be inducing the expression of NK receptors ligands, which can explain the significantly increased amount of NK cells in treated mice serum (e.g. Example 8, Figure 11). Nonetheless, the mechanisms involved in the induction of ligands for NK cell- activating receptors are only partially understood.
  • Adherent Human carcinoma cell lines were cultured according to standard mammalian tissue culture protocols and sterile technique.
  • Caco2, HepG2, MCF-7 cell lines were cultured in high glucose Dulbecco's Modified Eagle Medium
  • HT29 cells were cultured in McCoy's 5 A medium
  • Aspcl, A549, Mia Paca, U87MG and T98MG cells line were cultured in RPMI medium 1640 and HFF was culture in BIOAMF media. All media was supplemented with 10% fetal bovine semm, streptomycin (100 mg/ml), penicillin (100 U/ml) and Nystatin (12.5 U/ml).
  • Cells were incubated in 5% C02 at 37 °C.
  • tissue culture were maintained in 25cm ⁇ Nunc ⁇ cell culture treated EasYFlask ⁇ M (ThermoFisher scientific) and all the media and supplements were obtained from Biological Industries. Treatment were performed by plating cells in a Nunc ⁇ M 95 micro we ll delta surface plates (ThermoFisher scientific) in a starting confluence of 1 x 10 ⁇ cells/well. After 24h of incubation, the compound of interest was added in different concentrations as shown in the presented results.
  • Viability of the cells following treatment was determined using a commercially available MTT assay kit (ABCAM, abl46345) and performed according to manufacturer's instmctions.
  • the quantification was determined by measuring the optical density at 570 nm in an enzyme-linked immunosorbent assay (Spark, Tecan) reader. Data was presented as proportional viability (%) by comparing the group treated with the tested compound with the untreated cells, the viability of which is assumed to be 100%.
  • HT29 human colon cancer cell line The spheroid formation potential of HT29 human colon cancer cell line was evaluated in 3D nonadherent culture condition. Initially the HT29 human cells were grown as a monolayer after which they were counted, re- suspended and plated with 1,500 cells per well in a 96-well plate pre-coated with a thin layer of 1.5% agarose (w/v) in McCoy's 5A medium containing 10% FBS and incubated at 37°C in a humidified atmosphere of 5% C02. Cell culture media was replaced every 2-3 days with fresh medium to remove cellular debris and the spheroids that were not well-formed.
  • the tested compound was added at various concentrations (0.2, 0.4 and 0.6 mg/ml) and incubated for 24, 48 and 72 h. The number and diameter of colonies within each well were photographed and counted every day under the microscope (Olympus BX-51 ; Olympus, Hamburg, Germany), and the images of the representative fields were captured. Each sample was analyzed in triplicate, and all the experiments were performed three times. The viability of cells growing on the spheroids was measured by the APH (acid phosphatase) assay, which was performed according to manufacturer's instructions.
  • APH acid phosphatase
  • PCR Quantitative polymerase chain reaction
  • Immunoblot analysis was performed using antibodies against GAPDH (1:6000 dilution; abl289l5, Abeam), E-cadherin (1: 10000 dilution; ab40772, Abeam), GLUT-4 (1:1000 dilution; G4048, SIGMA), and then species-specific HRP-labeled secondary antibodies were added.
  • the blots were visualized using enhanced chemiluminescence (biological industries) and quantitated using ImageQaunt LAS 4000 mini, General Electric).
  • Tested compounds were evaluated for their ability to influence on cell viability and proliferation.
  • a broad screening was performed using ten different cell lines as described in table 1, and four different concentrations were used (37.5, 75, 150 and 300mM) to treat cells for 24 hours and determine the proliferation inhibitory profile of each novel chemical entity.
  • This molecule showed a substantial effect in decreasing cell viability on pancreatic (Aspcl) and lung (A549) cancer cell lines.
  • a concentration of 150mM reduced cell viability by around 50% in both cell lines.
  • compound 10 was capable to significantly reduce cell viability of MiaPaca
  • pancreatic cells pancreatic cells
  • T98G cells T98G cells (51.5% with 150mM) which are derived from a relatively resistant brain tumor.
  • Normal human skin/foreskin-derived fibroblasts (HFF) were barely influenced by compound 10 (around 80% with 150mM), indicating the specificity of this molecule in treating cancer cells.
  • Compound 1 is structurally very similar to compound 2, the only difference between these compounds are two hydroxyl moieties (OH) as compound 1 has quercetin in the polyphenol position instead of Naringenin (see compounds’ stmcture described hereinabove).
  • This small modification barely alters the decrease in viability of Aspcl cells when comparing the treatment with compound 2 (56%) to compound 1 (62.5%).
  • this modification grants to this novel entity a high specificity to HepG2 cells, leading to a remarkable reduction in cell viability (21%) when these cells were treated with 150mM of compound 1 for 24 hours in comparison to healthy cells (HFF) where there was almost no effect (90% of viability).
  • Compound 8 is composed of quercetin linked to p-coumaric acid by a long chain molecule namely aminocapryic acid (see structure defined hereinabove). This compound was effective in reducing viability in Aspcl cells (52% viability with 150mM) with similar strength as the other molecules mentioned above (1, 2 and 10). Nonetheless, this novel entity was able to significantly reduce cell viability (62%) in U87MG, another brain cancer cell line.
  • Compound 11 is structurally similar to compound 10. Instead of quercetin in the polyphenol position, compound 11 has a molecule of Naringenin (see structure defined hereinabove). Despite the high similarity, it was only able of reducing cell viability in Aspcl cells in a very moderate fashion (80% viability with 150mM). Regarding the other entities shown in table 1 (compounds 3-6 and 9), no significant results in cell viability were observed.
  • a real time cytotoxicity detection assay of Aspcl treated with compounds 2 or 10 was performed during the course of 72 hours on Aspcl cells after treatment with compounds 2 or 10.
  • Aspcl cells treated with compounds 2 or 10 for 24 hours at various doses (18-300mM) results in a significant decrease on cell viability in a time and dose-dependent manner, nonetheless, apoptotic bodies were not identified by microscopy analysis ( Figure 1A), indicating that probably treated cells are inducing cell cycle arrest and stopping proliferation instead of inducing death by apoptosis.
  • Aspcl cells were incubated with a non-toxic dye that binds to the DNA of died or damage cells. After 24 hours of incubation, cells were treated with compound 1 or 2. The effect observed in cells treated with compound 10 was immediately, after 30 minutes of treatment the measurement of the fluorescence of died cells achieved its maximum level and persists constant until the end of the assay (70 hours after cells seeding) ( Figure 2, grey). Compound 2 exhibits a similar pattern only that its effect was more delayed and moderate ( Figure 2, black).
  • MTT viability assay was performed with the cells at the end point of the real-time cytotoxic detection assay in order to confirm the results ( Figure 1B). The level of the fluorescence signal was correlated with the viability level.
  • the small GTPases of the RHO subfamily are signaling molecules that are primarily involved in several critical cellular processes, including cell proliferation, motility, and invasion (Bishop, L. A. et al.;Biochem. J. 2000. 348 part 2, 241-255). Recent reports revealed that the activity of RHO protein could be modulated by a functional interaction with catenin pl20, which is found in cytosolic pools. Moreover, it was demonstrated that cadherins could titrate out pl20 molecules from the cytosol, reducing their ability to affect RHO signaling (Anastasiadis, P. Z. et al. J. Cell Sci. 2000, 113 pt.
  • ROS reactive oxygen species
  • ROS in cancer are involved in cell cycle progression and proliferation, cell survival and apoptosis, energy metabolism, cell morphology, cell-cell adhesion, cell motility, angiogenesis and maintenance of tumor sternness.
  • ROS levels are still higher than those observed in normal cells.
  • cancer cells may be more sensitive than normal cells to the accumulation of ROS, which offers an interesting therapeutic window (Liu, J. et ak; Oxid. Med. Cell. Longev. 2015, 294303).
  • Targeting the enhanced antioxidant mechanisms and directly increasing ROS to reach a threshold that is incompatible with cell viability can selectively kill cancer cells, without affecting normal cells (Sosa, V. et ak; Ageing Res. Rev. 2013, 12, 376-390; and Gorrini, C. et al; Nat. Rev. drug Discov. 2013, 12, 931-947).
  • the cellular assays described above were performed in a monolayer system. Although monolayer systems partially reflect the microenvironment of cancer cells, there are currently more advanced culture methods that mimic in a better way the cellular interactions by the cells comprising the tumor (Freidrich, J. et. al.; Nat. Prot. 2009, 4, 309-324). Seeking to elucidate whether the compounds of this invention would also be able to hinder the growth of cancer cells, it was decided to proceed with assays in a 3D cell spheroid model. This assay can be applied to test whether the compounds treatment is able of impairing tumors formation or alternately to test the effect of the treatment in growing tumors.
  • FIT-29 cell line was used for this model due to its capacity to form spheroids in vitro.
  • Single dose (150mM) treatment of compound 10, 24 hours after cells seeding (before spheroid formation) did not significantly impair tumor formation
  • compound 10 avoided secondary tumors formation (Figure 5).
  • T98G subcutaneous tumors were less stable and spontaneously started to reduce after one week from cell injection, even without any treatment.
  • evaluation of the effect of tumor reduction between control and treated groups was performed at week 1 of treatment ( Figure 14).
  • no necrosis was observed, and the percentage of NK cells was similar in both groups.

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Abstract

La présente invention concerne de nouveaux composés, des compositions et des procédés de préparation de ceux-ci, ainsi que leurs utilisations pour le traitement du cancer de divers types, comprenant : le cancer du pancréas, du foie, du sein, du côlon, du cerveau et du poumon.
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CN113773295A (zh) * 2021-09-26 2021-12-10 广东省科学院动物研究所 单取代二氢色原酮合成方法及治疗copd等肺部炎症中应用
CN113773295B (zh) * 2021-09-26 2023-06-20 广东省科学院动物研究所 单取代二氢色原酮合成方法及治疗copd等肺部炎症中应用
CN116143744A (zh) * 2021-11-23 2023-05-23 陈艳莉 一种芳香酯类化合物及其用途
CN116063263A (zh) * 2022-11-30 2023-05-05 安徽德信佳生物医药有限公司 一种槲皮素苯丙烯酸酯及其制备方法和用途

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