WO2023170724A1 - Use of substituted quinolone derivatives for treating cancer - Google Patents

Use of substituted quinolone derivatives for treating cancer Download PDF

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WO2023170724A1
WO2023170724A1 PCT/JO2022/050004 JO2022050004W WO2023170724A1 WO 2023170724 A1 WO2023170724 A1 WO 2023170724A1 JO 2022050004 W JO2022050004 W JO 2022050004W WO 2023170724 A1 WO2023170724 A1 WO 2023170724A1
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obu
cancer
oet
ome
alkyl
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PCT/JO2022/050004
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French (fr)
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Mohammed Ameen Fouad Saleh AL-KUBAISI
Yusuf ALHIARI
Violet KASABRI
Rula DARWISH
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The University Of Jordan
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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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to a novel use of substituted quinolone derivatives for the treatment of cancer, and more particularly for treating skin cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, and leukemia.
  • Cancer is a collection of diseases with uncontrolled growth and spread of irregular cells. The result is death if the spread is uninhibited. There are a lot of issues that increase the occurrence rate of cancer despite the main cause is unknown. These reasons are divided into modifiable and those that are not. Cancer was considered the second cause of death among both gender in 2005, also from 58 million deaths, worldwide cancer has a percentage of 13 % of those deaths. It affects individuals from different sex, ages, and races.
  • Quinolones and their salts are wide-range antimicrobial agents that have a unique mechanism of action. Fluoroquinolones are among most promising nitrogen containing heterocyclic compounds depicting broad spectrum and potent anti -infective act. As synthetic compounds, these agents have been established generally to increase antimicrobial activity, pharmacokinetic properties, and safety of the drug. Therefore, numerous attempts have been done to discover new potential uses of these compounds. For instance, the international patent application PCT/J02020/050006 discloses substituted quinolone derivatives having antimicrobial activity against gram positive and gram-negative bacteria, and a method of preparation thereof.
  • EPl 080725 discloses the use of a fluoroquinolone for the treatment of atherosclerosis, and a method of preparation thereof.
  • Ri is selected from OH,OEt,OMe,OPr-n,OPr-i,OBu-n,OBu-i,OBu-s,OBu-t;
  • R2 is selected from (C2 - C10) alkyl, (C3 - Cs) cycloalkyl, heteroaryl or heterocycle unsubstituted or substituted;
  • R 3 IS selected from H, NH 2 , NO 2 , OH, OMe, OEt, OPr, OBu, SH, CN, CF 3 , CC1 3 , OSO 3 H, F, Cl, Br, diazonium ion, or linked to NH with (C 3 -Cs) heterocyclic ring;
  • R4 is selected from H, OMe, OH, OEt, OBu, OHx, (Ci - C10) alkyl;
  • Rs is selected from H, OMe, OH, OEt, OBu, OHx, (Ci - C10) alkyl;
  • Re is selected from H, OH, OMe, OEt, OBu, OHx,(Ci - C10) alkyl;
  • R4, Rs, Re are mono-, di-, or tri- substituted with H, OMe, OH, OEt, OBu, OHx, (Ci - C10) alkyl;
  • X is selected from fluorine, chlorine, or hydrogen atom.
  • the compound may be used for treating different types of cancer.
  • the different types cancer may be skin cancer, breast cancer, prostate cancer, lung cancer, pancreatic cancer, and leukemia.
  • FIG. 1 illustrates IC50 values of tested substituted quinolone derivatives vs. reference drug against K562 leukemia cell line.
  • FIG. 2 illustrates IC50 values of tested substituted quinolone derivatives vs. reference drug against MCF7 breast cancer cell line.
  • FIG. 3 illustrates IC50 values of tested substituted quinolone derivatives vs. reference drug against T47D breast cancer cell line.
  • FIG. 4 illustrates IC50 values of tested substituted quinolone derivatives vs. reference drug against A549 lung cancer cell line.
  • Embodiments of the present disclosure provide a use of substituted quinolone derivatives for treating different types of cancer: Wherein Ri is selected from OH,OEt,OMe,OPr-n,OPr-i,OBu-n,OBu-i,OBu-s,OBu-t;
  • R2 is selected from (C2 - C10) alkyl, (C3 - Cs) cycloalkyl, heteroaryl or heterocycle unsubstituted or substituted;
  • R 3 IS selected from H, NH 2 , NO 2 , OH, OMe, OEt, OPr, OBu, SH, CN, CF 3 ,
  • R4 is selected from H, OMe, OH, OEt, OBu, OHx, (Ci - C10) alkyl;
  • Rs is selected from H, OMe, OH, OEt, OBu, OHx, (Ci - C10) alkyl;
  • Re is selected from H, OH, OMe, OEt, OBu, OHx,(Ci - C10) alkyl;
  • R4, Rs, Re are mono-, di-, or tri- substituted with H, OMe, OH, OEt, OBu, OHx, (Ci -
  • X is selected from fluorine, chlorine, or hydrogen atom.
  • the different types of cancer may be skin cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, and leukemia.
  • the reaction mixture was refluxed under anhydrous conditions, at a temperature of about 65-70°C, for 2-3 days. Consequently, the resulting mixture was monitored until no starting material remained and was then left to crystallize at room temperature. The obtained bright orange crystals were filtered, washed, and left to dry in dark place.
  • Table 1 describes the 16 synthesized fluoroquinolone derivatives 3a-5f.
  • a series of nitrofluoroquinolones (3a-3f), reduced fluoroquinolones (4a-4d), and triazolo-fluoroquinolones (5a-5f) were prepared. All compounds were used as pure samples after verification over the TLC system with a mobile phase mixture of 94:5: 1 chloroform-methanol-formic acid (CHCh-MeOH-FA) and 50:50 n-hexane - Ethyl acetate. The compounds were each characterized to make sure that no oxidation or degradation occurred and then dissolved in DMSO to obtain a final stock solution concentration of 10 mg/mL.
  • CHCh-MeOH-FA chloroform-methanol-formic acid
  • the fluoroquinolone derivatives were developed to have a high lipophilic character in order to ease and facilitate their accessibility into the hydrophobic cell membrane of various cancer cell lines. This is because the developed fluoroquinolones includea lipophilic alkane chain at one terminal and one or more substituted anisidines at another terminal.
  • each fluoroquinolone derivative was evaluated by using 1, 1- diphenyl-2-picrylhydrazyl (DPPH) scavenging assay.
  • DPPH 1, 1- diphenyl-2-picrylhydrazyl
  • a DPPH solution (0.2 mM in MeOH) was mixed with each fluoroquinolone derivative as well as ascorbic acid in a concentration ratio of 1:1 using a 96-well plate.
  • the formed sample mixtures were then incubated for about 1 hour in a dark room, away from light.
  • a change in absorbance at 517 nm wavelength was measured using a microplate reader.
  • the ability of each fluoroquinolone compound (3a-5f) to scavenge the DPPH radicals was calculated using the following equation:
  • %Radical scavenging activity (%RS A) x 100
  • Ao is the absorbance of the reagent blank and Ai is the absorbance of the sample.
  • compound 3 c had the lowest IC50 value and thus the strongest anti-oxidant activity in the nitro-fluoroquinolone series.
  • compound 4b In the reduced fluoroquinolone series, compound 4b exhibited the highest radical scavenging and anti-oxidant activity out of all developed fluoroquinolones.
  • the triazolo-fluoroquinolone series all of the developed compounds demonstrated a very weak anti-oxidant activity in comparison to ascorbic acid.
  • a mouse macrophage cell line, RAW 264.7 (ATCC® TIB-71), was obtained and cultured in high glucose DMEM supplemented with 10% (FBS), penicillin (100 U/mL), streptomycin (100 pg/mL), and L-glutamate (100 pg/mL). The cell was incubated, in a humidified incubator, in an atmosphere of 5% CO2 at 37 °C.
  • the cells were seeded onto a 96-well plate (2/ 10 5 cells/well) and incubated for 24 hours with about 20 pg/mL of macrophage prompting lipopolysaccharide (LPS) and indomethacin (25-200 pg/mL) to form a positive control as well as different concentrations (5-200 pg/mL) of each fluoroquinolone derivative 3a-5f to form samples.
  • LPS macrophage prompting lipopolysaccharide
  • indomethacin 25-200 pg/mL
  • Nitric oxide production was assayed by measuring nitrite in the supernatants of cultured RAW 264.7 cells.
  • the amount of nitrite in the culture medium was measured using the Griess reagent (50 pL of 1 % Sulfanilamide in 5 % phosphoric acid and 50 pL of 0.1 % napthylethyllenediamine-HCL).
  • a volume of about 100 pL of the Griess reagent cell was mixed with aliquots of 100 pL of the cell culture media. Subsequently, the mixture was incubated at room temperature for 10 minutes and the absorbance was measured at 550 nm in a microplate reader.
  • the quantity of nitrite was determined from a sodium nitrite standard curve and the ability of each fluoroquinolone compound (3a-5f) to scavenge NO radicals was calculated using the following equation:
  • %Radical scavenging activity (%RS A) x 100
  • Ao is the absorbance of the positive control and Ai is the absorbance of the sample
  • IC50 concentration of each fluoroquinolone erivative required to inhibit 50% of nitric radical was expressed as IC50 (pM), where their values can be found below in Table 3. All IC50 values were compared to a reference NO- scavenging agent (indomethacin).
  • compound 3d has a lower IC50 value and thus a higher anti-inflammatory potency than the reference agent indomethacin.
  • compounds 4b and 4e exhibited a substantially greater NO- scavenging than indomethacin. It can be noticed that compound 4e is themost potent antiinflammatory developed fluoroquinolone.
  • compound 5 c demonstrated a promising equipotency to indomethacin without similar DPPH scavenging effectiveness. The remaining triazolo-fluoroquinolones were found to be ineffective radical scavengers in comparison to either ascorbic acid or indomethacin (p ⁇ 0.01- 0.001).
  • the developed compounds 3 a - 5f were tested for their in vitro antitumor activity against seven different cell lines: two breast cancer cell lines MCF7 (ATCC® HTB-22) and T47D (ATCC® HTB-133), human skin cancer cell line A375 ((ATCC® CRL-1619), pancreatic cancer cell line PANCI (ATCC® CRL-1469), lung cancer cell line A549 ((ATCC® CCL- 185), prostate cancer cell line PC3 (ATCC® CRL-1435TM), and chronic leukemia cell line K562 (ATCC® CCL-243).
  • the cell lines were cultured in high glucose DMEM containing 10% FBS, HEPES Buffer (10 rnM), L-glutamine (2 rnM), gentamicin (50 pg/mL), penicillin (100 U/mL), and streptomycin sulfate (100 mg/mL).
  • each cell line was incubated for 72 hours with different concentrations of substituted fluoroquinolones (5-200 pg/mL).
  • the cytotoxicity measurements were determined using sulforhodamine (SRB) colorimetric assay for cytotoxicity screening.
  • SRB sulforhodamine
  • ICso values were calculated from curves constructed by plotting cell survival (%) versus drug concentration. The reading values were then converted to the percentage of control (% cell survival). Cytotoxic effects were expressed as IC50 (pM) in Table 4. Calculation of the %cytotoxicity was determined by the following equation:
  • triazo-fluoroquinolones exhibited the least antineoplastic activity.
  • the only exceptions in the triazo-fluoroquinolone series were observed with compounds 5a and 5f.
  • the rest of the triazo-fluoroquinolone series were significantly ineffective in lung cancer A549, breast cancer MCF7, pancreatic cancer Panc-1, and prostate cancer PC-3 cell lines in comparison to the reference drug cisplatin.
  • compound 4c In comparison to the reference drug cisplatin, compound 4c exhibited comparable IC50 value and effectiveness against A549 cancer cell line, eight compounds (3a, 3c, 3e, 4a, 4b, 4c, 4f, 5a) exhibited stronger IC50 value and effectiveness against MCF7 cancer cell line, eight compounds (3b,3d,3e,4a,4b,4c,4e,4f) exhibited stronger IC50 value and effectiveness against PC3 cancer cell line, six compounds (3b,4a,4c,4d,4e,5f) exhibited stronger IC50 value and effectiveness against K562 cancer cell line, and 3 compounds (3e,4c,5a) exhibited stronger IC50 value and effectiveness against T47D cancer cell line.
  • FIG. 1-4 illustrates cytotoxicity IC50 values of developed compounds against K562 cancer cell line.
  • the results show that most of the developed fluoroquinolones, particularly the reduced fluoroquinolone series, have superior activity against leukaemia K562 cell line in comparison to other cancer cell lines tested, with compound 4c showing the strongest IC50 value of 3.51 pM.
  • FIG. 2 and FIG. 3 illustrate cytotoxicity IC50 values of developed compounds against MCF7 and T47D cancer cell lines, respectively. In both cell lines, reduced fluoroquinolone compounds, particularly 4c and 4f, demonstrated the highest antitumor activity.
  • FIG. 4 illustrates the cytotoxicity IC50 values of developed compounds against lung A549 cancer cell line.
  • Selectivity ratio also known as selectivity index (SI) is a term that describes the safety of a tested compound. SI was calculated by dividing ICsoof the tested compound on normal periodontal ligament fibroblasts (PDL) cell line by the lowest IC50 value of the same compound on a specific pathological cell line. The lowest IC50 value of each compound on a specific cancer cell line was selected from table 4. Their selectivity indices for safety examination were calculated using normal periodontal ligament fibroblasts (PDL) in comparison to cisplatin’s lack of differential cytotoxicity. The selectivity indexes of developed fluoroquinolones 3a-5f are reported in table 5.
  • the term “about”, when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1%, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.
  • the terms “treat,” “treating,” or “treatment,” refer to reducing the severity of cancer, delayed onset of cancer, alleviated growth of cancer, alleviated cell metastasis of cancer, shortened duration of cancer, hindered development of cancer. It includes causing cancer regression, alleviating the condition caused by cancer, or stopping the symptoms caused by cancer.
  • the terms “treat,” “treat,” or “treatment” include, but are not limited to, prophylactic and / or therapeutic treatment.

Abstract

There is provided a novel use of a substituted quinolone compound of the general formula (I), or a pharmaceutically acceptable salt thereof for treatment of cancer. The prepared substituted quinolones with dual anti-inflammation/free radical scavenging and antiproliferation propensities can be used as authentic agents for the treatment of many different types of cancer, particularly skin cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, and leukemia. Formula (I) Wherein R1 is selected from OH,OEt,OMe,OPr-n,OPr-i,OBu-n,OBu-i,OBu-s,OBu-t; R2 is selected from (C2 – C10) alkyl, (C3 – C8) cycloalkyl, heteroaryl or heterocycle unsubstituted or substituted; R3 is selected from H, NH2, NO2, OH, OMe, OEt, OPr, OBu, SH, CN, CF3, CCl3, OSO3H, F, Cl, Br, diazonium ion, or linked to NH with (C3-C8) heterocyclic ring; R4 is selected from H, OMe, OH, OEt, OBu, OHx, (C1 – C10) alkyl; R5 is selected from H, OMe, OH, OEt, OBu, OHx, (C1 – C10) alkyl; R6 is selected from H, OH, OMe, OEt, OBu, OHx,(C1 – C10) alkyl; R4, R5, R6 are mono-, di-, or tri- substituted with H, OMe, OH, OEt, OBu, OHx, (C1 – C10) alkyl; and X is selected from fluorine, chlorine, or hydrogen atom.

Description

USE OF SUBSTITUTED QUINOEONE DERIVATIVES FOR TREATING
CANCER
TECHNICAL FIELD
[01] The present disclosure relates to a novel use of substituted quinolone derivatives for the treatment of cancer, and more particularly for treating skin cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, and leukemia.
BACKGROUND
[02] Cancer is a collection of diseases with uncontrolled growth and spread of irregular cells. The result is death if the spread is uninhibited. There are a lot of issues that increase the occurrence rate of cancer despite the main cause is unknown. These reasons are divided into modifiable and those that are not. Cancer was considered the second cause of death among both gender in 2005, also from 58 million deaths, worldwide cancer has a percentage of 13 % of those deaths. It affects individuals from different sex, ages, and races.
[03] Quinolones and their salts are wide-range antimicrobial agents that have a unique mechanism of action. Fluoroquinolones are among most promising nitrogen containing heterocyclic compounds depicting broad spectrum and potent anti -infective act. As synthetic compounds, these agents have been established generally to increase antimicrobial activity, pharmacokinetic properties, and safety of the drug. Therefore, numerous attempts have been done to discover new potential uses of these compounds. For instance, the international patent application PCT/J02020/050006 discloses substituted quinolone derivatives having antimicrobial activity against gram positive and gram-negative bacteria, and a method of preparation thereof.
[04] The European patent application EPl 080725 discloses the use of a fluoroquinolone for the treatment of atherosclerosis, and a method of preparation thereof.
SUMMARY
[05] Therefore, it is an object of the present disclosure to provide a novel use of a compound of the general formula (I), or a pharmaceutically acceptable salt therefore for treating cancer:
Figure imgf000004_0001
Formula (I)
Wherein Ri is selected from OH,OEt,OMe,OPr-n,OPr-i,OBu-n,OBu-i,OBu-s,OBu-t;
R2 is selected from (C2 - C10) alkyl, (C3 - Cs) cycloalkyl, heteroaryl or heterocycle unsubstituted or substituted;
R3 IS selected from H, NH2, NO2, OH, OMe, OEt, OPr, OBu, SH, CN, CF3, CC13, OSO3H, F, Cl, Br, diazonium ion, or linked to NH with (C3-Cs) heterocyclic ring;
R4 is selected from H, OMe, OH, OEt, OBu, OHx, (Ci - C10) alkyl;
Rs is selected from H, OMe, OH, OEt, OBu, OHx, (Ci - C10) alkyl;
Re is selected from H, OH, OMe, OEt, OBu, OHx,(Ci - C10) alkyl;
R4, Rs, Re are mono-, di-, or tri- substituted with H, OMe, OH, OEt, OBu, OHx, (Ci - C10) alkyl; and
X is selected from fluorine, chlorine, or hydrogen atom.
[06] In aspects of the present disclosure, the compound may be used for treating different types of cancer.
[07] In some aspects, the different types cancer may be skin cancer, breast cancer, prostate cancer, lung cancer, pancreatic cancer, and leukemia. BRIEF DESCRIPTION OF THE DRAWINGS
[08] The disclosure will now be described with reference to the accompanying drawings, which illustrate embodiments of the present disclosure, without however restricting the scope of the disclosure thereto, and in which:
[09] FIG. 1 illustrates IC50 values of tested substituted quinolone derivatives vs. reference drug against K562 leukemia cell line.
[010] FIG. 2 illustrates IC50 values of tested substituted quinolone derivatives vs. reference drug against MCF7 breast cancer cell line.
[Oil] FIG. 3 illustrates IC50 values of tested substituted quinolone derivatives vs. reference drug against T47D breast cancer cell line.
[012] FIG. 4 illustrates IC50 values of tested substituted quinolone derivatives vs. reference drug against A549 lung cancer cell line.
DETAILED DESCRIPTION
[013] Embodiments of the present disclosure provide a use of substituted quinolone derivatives for treating different types of cancer:
Figure imgf000005_0001
Wherein Ri is selected from OH,OEt,OMe,OPr-n,OPr-i,OBu-n,OBu-i,OBu-s,OBu-t;
R2 is selected from (C2 - C10) alkyl, (C3 - Cs) cycloalkyl, heteroaryl or heterocycle unsubstituted or substituted;
R3 IS selected from H, NH2, NO2, OH, OMe, OEt, OPr, OBu, SH, CN, CF3,
CC13, OSO3H, F, Cl, Br, diazonium ion, or linked to NH with (C3-Cs) heterocyclic ring;
R4 is selected from H, OMe, OH, OEt, OBu, OHx, (Ci - C10) alkyl;
Rs is selected from H, OMe, OH, OEt, OBu, OHx, (Ci - C10) alkyl;
Re is selected from H, OH, OMe, OEt, OBu, OHx,(Ci - C10) alkyl;
R4, Rs, Re are mono-, di-, or tri- substituted with H, OMe, OH, OEt, OBu, OHx, (Ci -
C10) alkyl; and
X is selected from fluorine, chlorine, or hydrogen atom.
[014] In some embodiments of the present disclosure, the different types of cancer may be skin cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, and leukemia.
[015] The disclosure is now further illustrated on the basis of examples and a detailed description from which further features and advantages may be taken. It is to be noted that the following explanations are presented for the purpose of illustrating and description only; they are not intended to be exhaustive or to limit the disclosure to the precise form disclosed.
Example 1
Preparation of substituted fluoroquinolone derivatives
[016] The compounds of the present disclosure comprising a fluoroquinolone derivative compound of general formula (I) was synthesized with reference to the method described in the international patent application number PCT/J02020/050006.
[017] The synthesis of the starting material, with a general formula of ethyl -l-butyl-6-fluoro-7- (substituted-methoxy-phenylamino)-8-nitro-4-oxo-l,4-dihydro-quinolone-3 -carboxylate (la- fl, was initiated by adding three molar equivalents of substituted anisidine (2.99g, 24.3 mmol) into a solution consisting of ethyl l-butyl-7-chloro-6-fluoro-8-nitro-4-oxo-l,4- dihydroquinolone-3 -carboxylate (3.0g, 8.1mmol) in 15 ml of dimethylsulfoxide (DMSO) solvent along with a few drops of pyridine. The reaction mixture was refluxed under anhydrous conditions, at a temperature of about 65-70°C, for 2-3 days. Consequently, the resulting mixture was monitored until no starting material remained and was then left to crystallize at room temperature. The obtained bright orange crystals were filtered, washed, and left to dry in dark place.
[018] The synthesis of the general scaffold of the nitro-fluoroquinolone derivative compounds (3a-3f), with a general formula of l-butyl-6-fluoro-7-(substituted methoxy-phenylamino)-8- nitro-4-oxo-l,4-dihydro-quinolone-3 -carboxylic acid (3a-f), was initiated by adding a vigorously stirred suspension of compound (2a-f) (2.0g, 4.37mmol) in 12N HC1 (30mL) and ethanol (15 mL) followed by heating at a temperature about 80-85 °C under reflux conditions. The progress of the ester hydrolysis was monitored by TLC and completed within 36h. Thereafter, the reaction mixture was cooled and poured onto crushed ice (250 g). The resulting pale orange precipitate was collected, washed, and left to dry.
[019] The synthesis of the general scaffold of the reduced fluoroquinolone derivative compounds (4a-4f), with a general formula of 8-amino-l-butyl-6-fluoro-7-( substituted methoxy-phenylamino)-4-oxo-l,4-dihydro-quinolone-3-carboxylic acid, was initiated by stirring a mixture of compound (3a-3f) (1.0g, 2.3 mmol) in 6.5mL of 12N HC1 in an ice bath for about 15 minutes. Stannous chloride (1.77g, 9.3mmol) was then added portion-wise into the reaction mixture, where the progress of the reaction was monitored by TLC until completion. After completion, the reaction mixture was poured onto crushed ice and the resulting brown-orange precipitate was collected, washed, and left to dry.
[020] The general scaffold of the triazolo-fluoroquinolone derivative compounds (5a- 5f), with a general formula of 9-butyl-4-fluoro-3-( substituted methoxy-phenyl)-6-oxo-6,9-dihydro- 3H-[l,2,3]triazolo[4,5-h]quinolone-7-carboxylic acid, was synthesized through cyclization/diazotization of preceding reduced acid (compound 4a). Compound 4a-f (0.50g, 1.25mmol) was placed in RBF, followed by addition of about 20ml aqueous HC1. The reaction mixture was left stirring in ice bath (0-5°C) for about 15 minutes. NaNCh (0.086g, Immol) dissolved in lOmL H2O was then added drop wise and the reaction mixture was left for stirring overnight. The progress of the cyclization reaction was monitored by TLC and was completed within 24 h. Thereafter, the reaction mixture was cooled and poured onto crushed ice. The resulting brown precipitate was collected, washed with cold water, and left to dry.
[021] Table 1 describes the 16 synthesized fluoroquinolone derivatives 3a-5f. A series of nitrofluoroquinolones (3a-3f), reduced fluoroquinolones (4a-4d), and triazolo-fluoroquinolones (5a-5f) were prepared. All compounds were used as pure samples after verification over the TLC system with a mobile phase mixture of 94:5: 1 chloroform-methanol-formic acid (CHCh-MeOH-FA) and 50:50 n-hexane - Ethyl acetate. The compounds were each characterized to make sure that no oxidation or degradation occurred and then dissolved in DMSO to obtain a final stock solution concentration of 10 mg/mL.
Table (1)
Figure imgf000008_0001
Figure imgf000009_0003
[022] The fluoroquinolone derivatives were developed to have a high lipophilic character in order to ease and facilitate their accessibility into the hydrophobic cell membrane of various cancer cell lines. This is because the developed fluoroquinolones includea lipophilic alkane chain at one terminal and one or more substituted anisidines at another terminal.
Example 2
DPPH free radical scavenger capability assay of the substituted fluoroquinolone derivatives
[023] The antioxidant activity of each fluoroquinolone derivative was evaluated by using 1, 1- diphenyl-2-picrylhydrazyl (DPPH) scavenging assay. According to this method, a DPPH solution (0.2 mM in MeOH) was mixed with each fluoroquinolone derivative as well as ascorbic acid in a concentration ratio of 1:1 using a 96-well plate. The formed sample mixtures were then incubated for about 1 hour in a dark room, away from light. A change in absorbance at 517 nm wavelength was measured using a microplate reader. The ability of each fluoroquinolone compound (3a-5f) to scavenge the DPPH radicals was calculated using the following equation:
%Radical scavenging activity (%RS A) =
Figure imgf000009_0001
x 100
Figure imgf000009_0002
Where Ao is the absorbance of the reagent blank and Ai is the absorbance of the sample.
All experiments were performed in triplicate. The concentration of each fluoroquinolone derivative required to inhibit 50% of DPPH radicals (at %RSA = 50%) was expressed as IC50 (pM), where their values can be found below in Table 2. All IC50 values were compared to a reference anti-oxidant agent (ascorbic acid).
[024] By referring to table 2, compound 3 c had the lowest IC50 value and thus the strongest anti-oxidant activity in the nitro-fluoroquinolone series. In the reduced fluoroquinolone series, compound 4b exhibited the highest radical scavenging and anti-oxidant activity out of all developed fluoroquinolones. The low IC50 value of compound 4b was very similar to that of reference agent ascorbic acid (IC50 of compound 4b = 3.61 > IC50 of ascorbic acid = 3.37). In the triazolo-fluoroquinolone series, all of the developed compounds demonstrated a very weak anti-oxidant activity in comparison to ascorbic acid.
Table (2)
Figure imgf000010_0001
Figure imgf000011_0001
* when P< 0.05, ** when P< 0.01 or 0.001, *** when P < 0.001 or 0.0001, **** when PO.OOOl, NS: not significantly different from reference drug, NI: non-inhibitory
Example 3
Anti-Inflammatory and NO-scavenging determination of the substituted fluoroquinolone derivatives
[025] The anti-inflammatory activity of the substituted fluoroquinolone derivatives, relevant to its NO inhibition ability, was measured using Griess assay.
[026] A mouse macrophage cell line, RAW 264.7 (ATCC® TIB-71), was obtained and cultured in high glucose DMEM supplemented with 10% (FBS), penicillin (100 U/mL), streptomycin (100 pg/mL), and L-glutamate (100 pg/mL). The cell was incubated, in a humidified incubator, in an atmosphere of 5% CO2 at 37 °C. To induce the RAW 264.7 macrophage cells to an inflammatory condition, the cells were seeded onto a 96-well plate (2/ 105 cells/well) and incubated for 24 hours with about 20 pg/mL of macrophage prompting lipopolysaccharide (LPS) and indomethacin (25-200 pg/mL) to form a positive control as well as different concentrations (5-200 pg/mL) of each fluoroquinolone derivative 3a-5f to form samples.
[027] Nitric oxide production was assayed by measuring nitrite in the supernatants of cultured RAW 264.7 cells. The amount of nitrite in the culture medium was measured using the Griess reagent (50 pL of 1 % Sulfanilamide in 5 % phosphoric acid and 50 pL of 0.1 % napthylethyllenediamine-HCL). A volume of about 100 pL of the Griess reagent cell was mixed with aliquots of 100 pL of the cell culture media. Subsequently, the mixture was incubated at room temperature for 10 minutes and the absorbance was measured at 550 nm in a microplate reader. The quantity of nitrite was determined from a sodium nitrite standard curve and the ability of each fluoroquinolone compound (3a-5f) to scavenge NO radicals was calculated using the following equation:
%Radical scavenging activity (%RS A) =
Figure imgf000012_0001
x 100
Figure imgf000012_0002
Where Ao is the absorbance of the positive control and Ai is the absorbance of the sample
All experiments were performed in triplicate. The concentration of each fluoroquinolone erivative required to inhibit 50% of nitric radical was expressed as IC50 (pM), where their values can be found below in Table 3. All IC50 values were compared to a reference NO- scavenging agent (indomethacin).
Table (3)
Figure imgf000012_0003
Figure imgf000013_0001
* when P< 0.05, ** when P< 0.01 or 0.001, *** when P < 0.001 or 0.0001, **** when PO.OOOl, NS: not significantly different from reference drug, NI: non -inhibitory
[028] In the nitro-fluoroquinolone series, compound 3d has a lower IC50 value and thus a higher anti-inflammatory potency than the reference agent indomethacin. In the reduced fluoroquinolone series, compounds 4b and 4e exhibited a substantially greater NO- scavenging than indomethacin. It can be noticed that compound 4e is themost potent antiinflammatory developed fluoroquinolone. In the triazolo-fluoroquinolone series, only compound 5 c demonstrated a promising equipotency to indomethacin without similar DPPH scavenging effectiveness. The remaining triazolo-fluoroquinolones were found to be ineffective radical scavengers in comparison to either ascorbic acid or indomethacin (p<0.01- 0.001).
Example 4
In vitro antiproliferative assay of the substituted fluoroquinolone derivatives
[029] The developed compounds 3 a - 5f were tested for their in vitro antitumor activity against seven different cell lines: two breast cancer cell lines MCF7 (ATCC® HTB-22) and T47D (ATCC® HTB-133), human skin cancer cell line A375 ((ATCC® CRL-1619), pancreatic cancer cell line PANCI (ATCC® CRL-1469), lung cancer cell line A549 ((ATCC® CCL- 185), prostate cancer cell line PC3 (ATCC® CRL-1435™), and chronic leukemia cell line K562 (ATCC® CCL-243).The cell lines were cultured in high glucose DMEM containing 10% FBS, HEPES Buffer (10 rnM), L-glutamine (2 rnM), gentamicin (50 pg/mL), penicillin (100 U/mL), and streptomycin sulfate (100 mg/mL). Subsequently, each cell line was incubated for 72 hours with different concentrations of substituted fluoroquinolones (5-200 pg/mL). The cytotoxicity measurements were determined using sulforhodamine (SRB) colorimetric assay for cytotoxicity screening. As a robust and classical antineoplastic reference agent, cisplatin (1-200 pg/mL) was recruited for comparison purposes.
ICso values were calculated from curves constructed by plotting cell survival (%) versus drug concentration. The reading values were then converted to the percentage of control (% cell survival). Cytotoxic effects were expressed as IC50 (pM) in Table 4. Calculation of the %cytotoxicity was determined by the following equation:
% Cytotoxicity 100
Figure imgf000014_0001
where Ao is the absorbance of the control and Ai is the absorbance of the sample.
Table (4)
Figure imgf000014_0002
Figure imgf000015_0001
Figure imgf000016_0001
* when P< 0.05, ** when P< 0.01 or 0.001, *** when P < 0.001 or 0.0001, **** when P<0.0001, NS: not significantly different from reference drug, NI: lack of cytotoxicity within the tested 0.1- 200 pg/mL concentration range
[030] The developed fluoroquinolones were classified intro three different groups according to their relative IC50 value: 1) strong antiproliferative effect with ICso< 50 pM, 2) intermediate antiproliferative effect with 50 pM < ICso<lOO pM., and 3) weak antiproliferative effect with ICso> 100 pM. With reference to table 5, only 12 compounds (3a,3b,3c,3e,3f,4a,4c,4d,4e,4f,5a,5f) demonstrated strong antiproliferative effect against different cancer cell lines. Unlike nitro-fluoroquinolone and reduced fluoroquinolone series, triazo-fluoroquinolones exhibited the least antineoplastic activity. The only exceptions in the triazo-fluoroquinolone series were observed with compounds 5a and 5f. Compound 5a had an appreciable antiproliferative activity again skin melanoma A375 (IC50 of compound 5a=30.8 < IC50 of cisplatin = 0.7) and breast cancer T47D (IC50 of compound 5a=22.3 <ICso of cisplatin = 45.2) cancer cell lines. Similarly, compound 5f had an appreciable antiproliferative activity against leukemia K562 (IC50 of compound 5f=l 1 .9 <ICso of cisplatin= 29.3) cancer cell line. The rest of the triazo-fluoroquinolone series were significantly ineffective in lung cancer A549, breast cancer MCF7, pancreatic cancer Panc-1, and prostate cancer PC-3 cell lines in comparison to the reference drug cisplatin.
[031] In comparison to the reference drug cisplatin, compound 4c exhibited comparable IC50 value and effectiveness against A549 cancer cell line, eight compounds (3a, 3c, 3e, 4a, 4b, 4c, 4f, 5a) exhibited stronger IC50 value and effectiveness against MCF7 cancer cell line, eight compounds (3b,3d,3e,4a,4b,4c,4e,4f) exhibited stronger IC50 value and effectiveness against PC3 cancer cell line, six compounds (3b,4a,4c,4d,4e,5f) exhibited stronger IC50 value and effectiveness against K562 cancer cell line, and 3 compounds (3e,4c,5a) exhibited stronger IC50 value and effectiveness against T47D cancer cell line.
[032] Reference in this example is made to FIG. 1-4. FIG 1. illustrates cytotoxicity IC50 values of developed compounds against K562 cancer cell line. The results show that most of the developed fluoroquinolones, particularly the reduced fluoroquinolone series, have superior activity against leukaemia K562 cell line in comparison to other cancer cell lines tested, with compound 4c showing the strongest IC50 value of 3.51 pM. FIG. 2 and FIG. 3 illustrate cytotoxicity IC50 values of developed compounds against MCF7 and T47D cancer cell lines, respectively. In both cell lines, reduced fluoroquinolone compounds, particularly 4c and 4f, demonstrated the highest antitumor activity. FIG. 4 illustrates the cytotoxicity IC50 values of developed compounds against lung A549 cancer cell line. Compounds 4c and 4f have displayed the lowest cytotoxicity IC50 values (< 50 pM) with reference to cisplatin. Despite their IC50 values being higher than that of cisplatin, these compounds have displayed strong activity against lung cancer cell line. Additionally, it is worth mentioning that the A375 human skin cancer cell line was resistant to any reasonably moderate antiproliferative capacity of nitro- and reduced fluoroquinolones (IC50 values > 100 pM). Pancreatic PANC-1 carcinoma cells were similarly resistant to nitro-fluoroquinolones (IC50 values > 100 pM).
[033] Overall, it can be deduced that the reduced fluoroquinolone series 4a-4f demonstrated the greatest antitumor activity against various cancer lines and can act as potential drug leads. Example 5
Selectivity index of the substituted fluoroquinolone derivatives
[034] Selectivity ratio, also known as selectivity index (SI), is a term that describes the safety of a tested compound. SI was calculated by dividing ICsoof the tested compound on normal periodontal ligament fibroblasts (PDL) cell line by the lowest IC50 value of the same compound on a specific pathological cell line. The lowest IC50 value of each compound on a specific cancer cell line was selected from table 4. Their selectivity indices for safety examination were calculated using normal periodontal ligament fibroblasts (PDL) in comparison to cisplatin’s lack of differential cytotoxicity. The selectivity indexes of developed fluoroquinolones 3a-5f are reported in table 5.
Table (5)
Figure imgf000018_0001
Figure imgf000019_0001
* when P< 0.05, ** when P< 0.01 or 0.001, *** when P < 0.001 or 0.0001, **** when PO.OOOl, NS: not significantly different from reference drug, NI: lack of cytotoxicity within the tested 0.1- 200 pg/mL concentration range
[035] All developed compounds, particularly 4a-d, have demonstrated a larger selectivity index than that of cisplatin. Moreover, it was shown that the IC50 values of PDL fibroblast of all substituted fluoroquinolones exceeded the IC50 value of cisplatin. Such results have indicated the high selectivity and safety profile of these developed compounds as well as their ability to be considered as potential drug leads.
[036] While embodiments of the present disclosure have been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various additions, omissions, and modifications can be made without departing from the spirit and scope thereof.
[037] In describing and claiming the present invention, the following terminology was used.
[038] The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.
[039] As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a defacto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.
[040] As used herein, the term “about”, when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.
[041] As used herein, the terms "treat," "treating," or "treatment," refer to reducing the severity of cancer, delayed onset of cancer, alleviated growth of cancer, alleviated cell metastasis of cancer, shortened duration of cancer, hindered development of cancer. It includes causing cancer regression, alleviating the condition caused by cancer, or stopping the symptoms caused by cancer. The terms "treat," "treat," or "treatment" include, but are not limited to, prophylactic and / or therapeutic treatment.

Claims

CLAIMS What is claimed is:
1. A novel use of a compound of the general formula (I), or a pharmaceutically acceptable salt thereof, for treating different types of cancer:
Figure imgf000021_0001
Formula (I)
Wherein Ri is selected from OH,OEt,OMe,OPr-n,OPr-i,OBu-n,OBu-i,OBu-s,OBu-t;
R2 is selected from (C2 - C10) alkyl, (C3 - Cs) cycloalkyl, heteroaryl or heterocycle unsubstituted or substituted;
R3 IS selected from H, NH2, NO2, OH, OMe, OEt, OPr, OBu, SH, CN, CF3,
CC13, OSO3H, F, Cl, Br, diazonium ion, or linked to NH with (C3-Cs) heterocyclic ring;
R4 is selected from H, OMe, OH, OEt, OBu, OHx, (Ci - C10) alkyl;
Rs is selected from H, OMe, OH, OEt, OBu, OHx, (Ci - C10) alkyl;
Re is selected from H, OH, OMe, OEt, OBu, OHx,(Ci - C10) alkyl;
R4, R5, Re are mono-, di-, or tri- substituted with H, OMe, OH, OEt, OBu, OHx, (Ci - C10) alkyl; and
X is selected from fluorine, chlorine, or hydrogen atom.
2. The use of the compound of claim 1, wherein cancer treatment includes skin cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, and leukemia.
PCT/JO2022/050004 2022-03-08 2022-03-08 Use of substituted quinolone derivatives for treating cancer WO2023170724A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090124617A1 (en) * 2003-07-24 2009-05-14 Astellas Pharma Inc. Quinolone derivative or salt thereof
WO2015179958A1 (en) * 2014-05-29 2015-12-03 The University Of British Columbia Antithrombotic compounds, methods and uses thereof
WO2017027379A1 (en) * 2015-08-07 2017-02-16 Thomas Helledays Stiftelse För Medicinsk Forskning Method for diagnosisng cancer or cancer-associated thrombosis by measuring levels of h3cit in plasma

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090124617A1 (en) * 2003-07-24 2009-05-14 Astellas Pharma Inc. Quinolone derivative or salt thereof
WO2015179958A1 (en) * 2014-05-29 2015-12-03 The University Of British Columbia Antithrombotic compounds, methods and uses thereof
WO2017027379A1 (en) * 2015-08-07 2017-02-16 Thomas Helledays Stiftelse För Medicinsk Forskning Method for diagnosisng cancer or cancer-associated thrombosis by measuring levels of h3cit in plasma

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