Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
  • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
  • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
  • C07D207/452—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
• • 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
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
  • C07D207/36—Oxygen or sulfur atoms
  • C07D207/40—2,5-Pyrrolidine-diones
  • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
  • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
  • C07D207/456—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 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 other ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
  • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide

Definitions

• This disclosure relates to the field of active agents. More particularly, this disclosure relates to anti-inflammatory agents, anti-metastatic agents, antiproliferative agents and anticancer agents. The present disclosure also relates to methods for treating cancers using these agents.
• UBC Urothelial bladder cancer
• Ri is H, alkyl or halogen
• R 2 is H, or a substituted or unsubstituted member chosen from acetyl, propiolyl, butyryl, isobutyryl and benzoyl;
• Q is Q A or Q B ;
• R-5 is H, or a substituted or unsubstituted member chosen from acetyl, propiolyl, butyryl, isobutyryl and benzoyl;
• R-6 is H, Boc, or a substituted or unsubstituted member chosen from acetyl, propiolyl, butyryl, isobutyryl and benzoyl;
• R 7 is a substituted or unsubstituted member chosen from Ci-Cs alkyl, C3-C8 cycloalkyl, phenyl, furanyl, thiophenyl, pyridinyl, naphthyl, quinolyl and isoquinolyl;
• R 3 and R4 are independently chosen from H, -SR 8 and -NR 9 R1 0 , or R 3 and R4 are joined together to form a 5-7 membered ring that optionally comprises an heteroatom chosen from N, S and O;
• R 9 is H or Ci-C 8 alkyl
• Rio is H, Ci-Cg alkyl, acetyl, propiolyl, butyryl, isobutyryl, or benzoyl; wherein R 2 , R 5 , R 6 and R 7 , when substituted, are substituted with at least one substituent chosen from -OR 9 , -F, -CI, -Br, -I, acetyl, propiolyl, butyryl, isobutyryl, benzoyl, -N0 2 , Ci-Cs alkyl, methoxycarbonyl-, or alkyloxycarbonyl-;
• Q is Q A or Q B ;
• R 2 is H, or a substituted or unsubstituted member chosen from acetyl, propiolyl, butyryl, isobutyryl and benzoyl;
• R5 is H, or a substituted or unsubstituted member chosen from acetyl, propiolyl, butyryl, isobutyryl and benzoyl;
• R6 is H, Boc, or a substituted or unsubstituted member chosen from acetyl, propiolyl, butyryl, isobutyryl and benzoyl;
• R 7 is a substituted or unsubstituted member chosen from Ci-Cg alkyl, C3-C8 cycloalkyl, phenyl, furanyl, thiophenyl, pyridinyl, naphthyl, quinolyl and isoquinolyl;
• R 9 is H or Ci-C 8 alkyl
• n 1, 2 or 3;
• R 2 , R5, R.6 and R 7 when substituted, are substituted with at least one substituent chosen from -OR 9 , -F, -CI, -Br, -I, acetyl, propiolyl, butyryl, isobutyryl, benzoyl, -N0 2 , Ci-Cs alkyl, methoxycarbonyl-, or alkyloxycarbonyl-;
• composition comprising a pharmaceutically acceptable carrier and at least one compound of the present disclosure.
• a method for treating cancer or at least one cancer chosen from breast cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, and melanoma comprising administering to a subject in need thereof an effective amount of at least one compound of the present disclosure.
• a method for reducing the risks of developing cancer or for reducing the risk of developing at least one cancer in a subject comprising administering to the subject an effective amount of at least one compound of the present disclosure.
• a method for inhibiting cancer cell growth comprising administering to a subject in need thereof an effective amount of at least one compound of the present disclosure.
• the cancer can be chosen from breast cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, and melanoma.
• a method for inhibiting cancer cell growth comprising contacting cancer cells with an effective amount of at least one compound of the present disclosure.
• the cancer can be chosen from breast cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, and melanoma.
• a method for inhibiting cancer tumor growth and/or cancer tumor size comprising administering to a subject in need thereof an effective amount of at least one compound of the present disclosure.
• the cancer can be chosen from breast cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, and melanoma.
• a method for decreasing and/or preventing cancer tumor metastases comprising administering to a subject in need thereof an effective amount of at least one compound of the present disclosure.
• the cancer can be chosen from breast cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, and melanoma.
• At least one compound of the present disclosure for treating cancer or for treating at least one cancer chosen from breast cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, and melanoma.
• At least one compound of the present disclosure for reducing the risks of developing cancer or for reducing the risks of developing at least one cancer chosen from breast cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, and melanoma.
• the cancer can be chosen from breast cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, and melanoma.
• At least one compound of the present disclosure for inhibiting cancer tumor growth and/or cancer tumor size of at least one cancer chosen from breast cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, and melanoma.
• At least one compound of the present disclosure for decreasing and/or preventing cancer tumor metastases of at least one cancer chosen from breast cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, and melanoma.
• at least one compound of the present disclosure in the manufacture of a medicament for treating cancer or for treating at least one cancer chosen from breast cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, and melanoma.
• At least one compound of the present disclosure in the manufacture of a medicament for reducing the risks of developing cancer or for reducing the risks of developing at least one cancer chosen from breast cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, and melanoma.
• the cancer can be chosen from breast cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, and melanoma.
• the use of at least one compound of the present disclosure in the manufacture of a medicament for inhibiting cancer tumor growth and/or cancer tumor size can be chosen from breast cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, and melanoma.
• the use of at least one compound of the present disclosure in the manufacture of a medicament for decreasing and/or preventing cancer tumor metastases can be chosen from breast cancer, uterine cancer, ovarian cancer, prostate cancer, bladder cancer, and melanoma.
• the ratio of phosphorylated/no phosphorylated proteins was calculated from densitometric analysis of each sample to evaluate the relative activation of pSTATl or pSTAT3.
• Compounds 4 and 5 efficiently inhibited IFNy-induced STAT1 activation and IL6- induced STAT3 activation.
• * p ⁇ 0.05 and ** p ⁇ 0.01 denote significant differences between treatments;
• Fig. 2 represents images (a) and graphical analysis (b) showing flow cytometry analysis to determine the expression level of MHC-II and CD40 surface antigens in resting and IFNy-activated human macrophages untreated and pretreated with compounds 4 (10 ⁇ ) and 5 (25 ⁇ ).
• Compounds 4 and 5 efficiently inhibited IFNy- induced CD40 and MHC-II expression.
• * p ⁇ 0.05 and ** p ⁇ 0.01 denote significant differences between treatments;
• Fig. 3 represents images (a) and graphical analysis (b) showing scratch wound healing assays to determine the motility of human macrophages monolayers cultured for 3 h with vehicle (DMSO) or compounds 4 (10 uM) and 5 (25 uM), and then activated for 48 h with vehicle (PBS) or 25 ng/mL IL6.
• Compounds 4 and 5 efficiently inhibited IFNy-induced STAT1 activation and IL6-induced STAT3 activation. * p ⁇ 0.05 and ** p ⁇ 0.01 denote significant differences between treatments;
• Fig. 4 is a graphical representation of NO production in the macrophage-like J774A.1 cells following a pro-inflammatory stimulation by IFNy and TNFa after pretreatment with vehicle (DMSO) and the derivatives 4 and 5.
• DMSO vehicle
• Compounds 4 and 5 efficiently inhibited combined IFNy/TNFa -induced NO synthesis.
• * p ⁇ 0.05 and ** p ⁇ 0.01 denote significant differences between treatments;
• Fig. 5 is a graphical representation of NO production by the murine UBC cell line MB49-I following a pro-inflammatory stimulation by IFNy and TNFa after pretreatment with vehicle (DMSO) and derivatives 4 and 5.
• Compounds 4 and 5 at 10 and 50 ⁇ efficiently inhibited combined IFNy/TNFa-induced NO synthesis.
• * p ⁇ 0.05 and ** p ⁇ 0.01 denote significant differences between treatments;
• Fig. 6 is a graphical representation of relative cell viability on the murine UBC cell line MB49-I following a pro-inflammatory stimulation by IFNy and TNFa after pretreatment with vehicle (DMSO) and anti-inflammatory derivatives 4 and 5 at different concentrations.
• Fig. 7 refers to relative cell viability on MB49 and MB49-I cell lines 24-hour post treatment (3h) with either vehicle (DMSO) or compound 4 at different concentrations (0, 10, 15, 20, 30, and 50 ⁇ ).
• vehicle DMSO
• compound 4 at different concentrations (0, 10, 15, 20, 30, and 50 ⁇ ).
• the negative effects of compound 4 on cell survival would not be caused by an increase in cell mortality of UBC MB49 or MB49-I cells but rather by stopping cell proliferation.
• * p ⁇ 0.05 denote significant difference compared to control (without compound 4);
• Fig. 8 refers to (a) Western blot analysis: compound 4 efficiently inhibited TNFa/NFKB and IL6/STAT3 signaling pathways in murine UBC MB49-I cells at doses as lower as 10 ⁇ ; and (b) Luciferase assay: compound 4 at 50 ⁇ efficiently inhibited NFKB activation.
• MB49-I cells were transfected with an NFi B-responsive luciferase construct encoding the firefly luciferase reporter gene under the control of CMV promoter and tandem repeats of the NFKB transcriptional response element.
• * p ⁇ 0.01 denote significant difference compared to control;
• Fig. 9 refers to (a) microinvasion assays: compound 4 efficiently inhibited Ml- induced human UBC T24 cell invasion (matrigel in Boyden chamber); and (b) motility assays: compound 4 at 30 ⁇ efficiently inhibited IL6-induced motility (scratch assay) in human UBC T24 cells.
• motility assays compound 4 at 30 ⁇ efficiently inhibited IL6-induced motility (scratch assay) in human UBC T24 cells.
• * p ⁇ 0.05 denote significant difference compared to control (Ml DMSO);
• Fig. 10 refers to cellular analysis of 3D spheroid-based tumor invasion assays: compound 4 at 30 ⁇ efficiently inhibited the invasiveness activity of MDA-MB-241 cells, a highly invasive human breast cancer cell line, thus demonstrating that the anti- invasion effects of compound 4 is not cell-specific.
• * p ⁇ 0.01 denote significant difference compared to day 0;
• Fig. 12 represents images showing liver histological analysis in C57B1/6J mice at the end of treatment by periodic i.p. injections of compound 4 at different concentrations (0, 90, 150, and 300 ⁇ ) during 3 weeks. Treatment, even at higher dose, does not induce features of liver dysfunction such as hepatocellular injury, inflammation, fibrosis and steatosis (haematoxylin and eosin, 100 x and 400 x magnification). These results showed no evidence of toxicity from the anti -inflammatory treatment, indicating that compound 4 concentrations up to 300 ⁇ were well tolerated in these mice;
• Treatment at 150 ⁇ significantly reduce the size of subcutaneously implanted MB49-I tumors (a) and the number of lung metastases (b).
• Histological examination of lung specimens demonstrated that MB49-I tumor cell infiltration induced multifocal fibrotic lesions in the lungs of control mice (as indicated by the arrows), whereas no metastatic foci and a well- alveolized normal histology was seen in the lungs of mice treated with 150 ⁇ compound 4.
• (a) Represents images of bladders from normal age-matched mice and bladders that were chirurgically recovered at the end of the study (day 16 after tumor implantation) from control (Ctl) and treated tumor- bearing mice
• (b) Graphical representation showing i.p. injections of compound 4 biweekly at 150 ⁇ during two weeks completely abolished the development of muscle-invasive MB49-I tumors (n 6). *p ⁇ 0.5 compared to Ctl.
• Fig. 16 refers to the regulatory effects of pro-inflammatory IL6 and TNFa in the production of iNOS proteins (a) and NO molecules (b) by MB49 and MB49-I cells.
• Fig. 17 refers to in vivo study showing loss of basal and TNFa-induced iNOS expression (a) and NO production (b) by shRNA affects luciferase-expressing MB49- I tumor development (c) ectopically implanted in the bladder of C57B1/6J female mice.
• Fig. 19 refers to the anti-inflammatory effects of compound 4 in peritoneal macrophages after in vivo therapeutic targeting of ectopically implanted MB49 tumors in C57B1/6J male mice.
• Treatment at 90 and 150 ⁇ significantly decrease NO production (a) and urea synthesis and release (b) in peritoneal macrophages.
• Peritoneal macrophages were recovered at the end of the study (day 26 after tumor implantation).
• Polarization to pro-inflammatory Ml macrophages is characterized by NO production through iNOS activity while urea synthesis through arginase-1 activity is related to polarization to anti-inflammatory M2 macrophages.
• Fig. 20 refers to structure-function relationship study on the anti-inflammatory activity of compound 4.
• Fig. 21 refers to the comparative effects of compounds 4, 8, 10, and 11 in NO production in MB49-I cells, (a) Chemical structures of compounds 4, 8, 10, and 11; (b) Graphical representation of IFNy/LPS-induced NO production in MB49-I cells after pretreatment with vehicle (DMSO) and the compounds 4, 8, 10, and 11 at 20 and 37.5 ⁇ .
• DMSO vehicle
• * p ⁇ 0.05 and ** p ⁇ 0.01 denote significant differences between treatments;
• Fig. 22 represents images (a) and graphical analysis (b) showing Western blot analysis to determine the expression level of phosphorylated STAT1 in murine macrophages (RAW 264.7 cells) pretreated for 90 min with vehicle (DMSO) or compounds 4, 8, 10, and 11 (at 20 and 37.5 ⁇ ), and then washed and recovered after 15 min of activation with 5 ng/mL IFNy.
• vehicle DMSO
• compounds 4, 8, 10, and 11 at 20 and 37.5 ⁇
• the ratio of p-STATl/STATl was calculated from densitometric analysis of each sample to evaluate the relative activation of the transcription factor STAT1.
• FIG. 23 represents images (a) and graphical analysis (b) showing Westem blot analysis to determine the expression level of phosphorylated ⁇ in murine macrophages (RAW 264.7 cells) pretreated for 90 min with vehicle (DMSO) or compounds 4, 8, 10, and 11 (at 20 and 37.5 ⁇ ), and then washed and recovered after 15 min of activation with 100 ng/mL LPS.
• the ratio of p-IkB/IkB was calculated from densitometric analysis of each sample to evaluate the relative deactivation of ⁇ proteins, the negative regulator of the transcription factor NFKB.
• Fig. 24 represents images and graphical analysis showing the comparative effects of compounds 4 and 8 in cell viability of murine UBC MB49-I cells (a), murine macrophages RAW 264.7 cells (b) and human macrophages THP-1 cells (c).
• Cells were pretreated for 90 min, with vehicle (DMSO) and compounds 4 and 8 at different concentrations, and then washed and counted after a 24-hour period of incubation to estimate the number of viable cells.
• DMSO vehicle
• * p ⁇ 0.05 denote significant differences between treatments.
• Fig. 25 refers to the comparative anticancer activities of compounds 4 and 8 in the development of MB49-I tumors ectopically implanted in C57B1/6J male mice.
• * p ⁇ 0.05 and ** p ⁇ 0.01 denote significant differences between treatments.
• the present disclosure concerns the discovery of small aminobenzoic acid derivatives showing anti-inflammatory, anti-metastatic, anti-proliferative and anticancer properties in vitro and in vivo. It describes the synthetic methodology to make these derivatives from readily available ortho-, meta- and para-benzoic acid and their biological applications for the treatment of a several types of cancers.
• this disclosure relates to different pharmaceutical compositions comprising these compounds.
• the compounds and the pharmaceutical composition of this disclosure have been shown to possess anticancerous activity on various types of cancers.
• this disclosure provides novel treatment modalities against cancer.
• the unique biological properties of these compounds may be advantageously used to provide compounds with anticancer activity against cancers including but not limited to breast, prostate, ovarian and bladder cancers.
• sufficient amount of a compound of the present disclosure is a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, including clinical results, and, as such, an "effective amount” or synonym thereto depends upon the context in which it is being applied. For example, in the context of treating cancer, for example, it is an amount of the compound sufficient to achieve such treatment of the cancer as compared to the response obtained without administration of the compound.
• the amount of a given compound of the present disclosure that will correspond to an effective amount will vary depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.
• a “therapeutically effective amount” , “effective amount” or a “sufficient amount” of a compound of the present disclosure is an amount which inhibits, suppresses or reduces a cancer (e.g., as determined by clinical symptoms or the amount of cancerous cells) in a subject as compared to a control.
• subject includes all members of the animal kingdom including human. According to one embodiment, the subject is a human.
• alkyl as used herein means straight and/or branched chain, saturated alkyl groups containing from one to n carbon atoms and includes (depending on the identity of n) methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, t- butyl, 2,2-dimethylbutyl, n-pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-hexyl and the like, wherein n is the maximum number of carbon atoms in the group.
• an alkyl component of a naturally occurring amino acid refers to the portion of a naturally occurring amino acid that is comprised between the carbon of the carbonyl group of the amino acid and the nitrogen atom of the amino acid.
• compound(s) of the present disclosure refers to compounds of formulae I, IA, IB, IC, ID, IE, IIA, IIB and IIC presented in the present disclosure, isomers thereof, such as stereoisomers (for example, enantiomers, diastereoisomers, including racemic mixtures) or tautomers, or to pharmaceutically acceptable salts, solvates, hydrates and/or prodrugs of these compounds, isomers of these latter compounds, or racemic mixtures of these latter compounds.
• the expression “compound(s) of the present disclosure” also refers to mixtures of the various compounds or variants mentioned in the present paragraph.
• halogen as used herein comprises fluoro, chloro, bromo and iodo.
• the compounds of the disclosure may have at least one asymmetric centre. Where the compounds according to the present document possess more than one asymmetric centre, they may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present disclosure. It is to be understood that while the stereochemistry of the compounds of the present disclosure may be as provided for in any given compound listed herein, such compounds of the disclosure may also contain certain amounts (for example less than 30%, less than 20%, less than 10%, or less than 5%) of compounds of the present disclosure having alternate stereochemistry.
• suitable reaction conditions means that the selection of the particular group or conditions would depend on the specific synthetic manipulation to be performed and the identity of the molecule but the selection would be well within the skill of a person trained in the art. All process steps described herein are to be conducted under conditions suitable to provide the product shown. A person skilled in the art would understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so.
• pharmaceutically acceptable salt means an acid addition salt or basic addition salt which is suitable for or compatible with the treatment of subjects such as animals or humans.
• pharmaceutically acceptable acid addition salt means any non-toxic organic or inorganic salt of any compound of the present disclosure, or any of its intermediates.
• Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
• Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as /3 ⁇ 4?ra-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form.
• mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as
• the acid addition salts of the compounds of the present disclosure are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
• the selection of the appropriate salt will be known to one skilled in the art.
• Other non-pharmaceutically acceptable salts e.g. oxalates, may be used, for example, in the isolation of the compounds of the present disclosure, for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
• the pharmaceutically acceptable acid addition salt is the hydrochloride salt.
• compositions of the disclosure include any non-toxic organic or inorganic base addition salt of any acid compound of the disclosure, or any of its intermediates.
• Acidic compounds of the disclosure that may form a basic addition salt include, for example, where R is C0 2 H.
• Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide.
• Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.
• Other non- pharmaceutically acceptable basic addition salts may be used, for example, in the isolation of the compounds of the disclosure, for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
• a desired compound salt is achieved using standard techniques. For example, the neutral compound is treated with an acid or base in a suitable solvent and the formed salt is isolated by filtration, extraction or any other suitable method.
• solvate means a compound of the present disclosure, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
• a suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a "hydrate”.
• solvates of the compounds of the present disclosure will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions.
• prodrugs include prodrugs.
• prodrugs of the compounds of the present disclosure may be conventional esters formed with available hydroxy, or amino group.
• an available OH or nitrogen in a compound of the present disclosure may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. an acid chloride in pyridine).
• inert solvent e.g. an acid chloride in pyridine.
• Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C8-C24) esters, acyloxymethyl esters, carbamates and amino acid esters.
• the prodrugs of the compounds of the present disclosure are those in which one or more of the hydroxy groups in the compounds is masked as groups which can be converted to hydroxy groups in vivo.
• Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985.
• Compounds of the present disclosure include radiolabeled forms, for example, compounds labeled by incorporation within the structure 2 H, 3 H, 14 C, 15 N, or a radioactive halogen such as 125 I.
• a radiolabeled compound of the compounds of the present disclosure may be prepared using standard methods known in the art.
• beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
• Treatment or “treating” can also mean prolonging survival as compared to expected survival if not receiving treatment.
• “Palliating" a disease or disorder means that the extent and/or undesirable clinical manifestations of a disorder or a disease state are lessened and/or time course of the progression is slowed or lengthened, as compared to not treating the disorder.
• R 2 , R 3 , R4 and Q are as previously defined.
• R 2 , R5 and R6 are as previously defined.
• R 2 , R3, R4 and R 7 are as previously defined.
• R 2 and R 7 are as previously defined.
• R 2 is H, unsubstituted member chosen from acetyl and propiolyl;
• Q is Q A ;
• R5 is H, unsubstituted member chosen from acetyl and propiolyl
• R6 is Boc, H, or an unsubstituted member chosen from acetyl and propiolyl.
• R 2 is H or unsubstituted member chosen from acetyl and propiolyl
• R 7 is an unsubstituted member chosen from Ci-Cs alkyl, C3-C6 cycloalkyl, phenyl, furanyl, thiophenyl, pyridinyl, naphthyl, quinolyl and isoquinolyl.
• the compound of formula I is as previously defined with the proviso that the compound is different from
• the above three excluded compounds are not to be excluded from the scope of the various uses and methods as previously described. [0055] According to another embodiment, the above three excluded compounds are to be excluded from the scope of the various uses and methods as previously described.
• the compound can be chosen from
• the compounds can be chosen from
• the compounds can be chosen from:
• the compounds can be chosen from:
• Schemes 1 to 4 represent examples of synthetic routes used for the preparation of the compounds of the present disclosure.
• the reaction conditions of each step are presented directly in the schemes.
• Example 1 shows the preparation of compounds 4 and 5. This reaction sequence can be used to produce other derivatives starting from unsubstituted or substituted ortho-, meta- and para- benzoic acid starting materials.
• Reagents and conditions a) Maleic anhydride (MA), dry acetone, methanol, 22 °C, 1 h; b) 1) Ac 2 0, AcONa, 50 °C, 2 h; 2) H 2 0, 70 °C, 2 h; c) 1) wo-butyl chloroformate, Et 3 N, CH 2 C1 2 0 °C, 1 h and 22 °C, 1 h; 2) fert-butyl carbazate, CH 2 C1 2 22 °C, 12 h; d) HC1, dioxane, 22 °C, 5 h.
• MA Maleic anhydride
• Reagents and conditions a) TFA, CH 2 C1 2 22 °C, 0.5 h; b) Relevant anhydride or acid chloride, EtOAc, 22 °C, 30 min to 2 h; c) H 2 Pd/C, CH 3 OH, 22 °C, 3 h.
• compound 5 can be treated with a relevant aldehyde (alkyl aldehydes (linear or branched), benzaldehyde or substituted benzaldehydes or other arylaldehydes) under acidic conditions at reflux in butanol (or other solvent) to give the desired derivatives of general structure 13.
• aldehyde alkyl aldehydes (linear or branched), benzaldehyde or substituted benzaldehydes or other arylaldehydes
• R alkyl or aromatic (unsubstituted or substituted)
• Reagents and conditions a) RCHO, H + , Butanol, reflux, 1 to 5 h.
• derivative 4 (or any other maleimides described herein) can be reacted with an appropriate diene (butadiene (unsubstituted or substituted), cyclopentadiene, cyclohexadiene cycloheptadiene, furane, thiophene, pyrrole, N- alkylpyrrole) to give the desired cycloadducts (Diels-Alder products) such as 14, 15 and 16.
• Diels-Alder products such as 14, 15 and 16.
• This reaction can be performed by heating the pure reagents (diene and dienophile) either neat or in solution, with or without pressure as it is described in example 10.
• n 1, 2 or 3
• diene butadiene (unsubstituted or substituted), cyclopentadiene, cyclohexadiene, furane, thiophene, pyrrole, W-alkyl pyrrole.
• Reagents and conditions a) Relevant diene, toluene, ⁇ , 3 h.
• the compounds of the present disclosure may be modified by appending appropriate functionalities to enhance selective biological properties.
• modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
• the compounds of the present disclosure may contain one or more asymmetric carbon atoms and thus may occur as racemates and racemic mixtures, single enantiomer, diastereomeric mixtures and individual diastereoisomers. All such isomeric forms of these compounds are expressly included in the present disclosure.
• Each stereogenic carbon may be of the R or S configuration.
• the small aminobenzoic acid derivatives herein disclosed display anti -inflammatory, anti -metastatic, anti -proliferative and/or anticancer properties as well as favorable toxicity profiles, and may be used for example in treating malignancies, for example muscle-invasive and superficial UBC tumors, for example in humans.
• An aspect herein provided is a method for treating cancer or at least one cancer chosen from melanoma, breast cancer, uterine cancer, ovarian cancer, prostate cancer and bladder cancer, the method comprising administering to a subject in need thereof an effective amount of at least one compound as defined herein,
• Another aspect is a method for reducing the risks of developing cancer or for reducing the risk of developing at least one cancer in a subject, the cancer being, for example, chosen from melanoma, breast cancer, uterine cancer, ovarian cancer, prostate cancer and bladder cancer, the method comprising administering to the subject an effective amount of at least one compound as defined herein.
• the method comprising administering to a subject in need thereof an effective amount of at least one compound as defined herein.
• the cancer cell growth is inhibited by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70% or about 80% relative to an untreated subject.
• Another aspect is a method for inhibiting tumor growth and/or reducing tumor size, the method comprising administering to a subject in need thereof an effective amount of at least one compound as defined herein.
• the tumor size is measured in weight and/or volume.
• the tumor growth and/or tumor size is decreased by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% relative to an untreated subject.
• administration of an effective amount of at least one compound disclosed herein to a subject in need thereof increases time to progression of at least one cancer chosen from melanoma, breast cancer, uterine cancer, ovarian cancer, prostate cancer and bladder cancer.
• the compound herein disclosed is for use in reducing risks of developing at least one cancer chosen from melanoma, breast cancer, uterine cancer, ovarian cancer, prostate cancer and bladder cancer.
• the compound is for use in the treatment of at least one cancer chosen from melanoma, breast cancer, uterine cancer, ovarian cancer prostate cancer and bladder cancer.
• the compound is for use as an anticancer agent.
• the compound is for use as an anti-inflammatory agent.
• the compound is for use as an anti-metastatic agent.
• the compounds presently disclosed display antiinflammatory properties.
• UBC cells tested with compounds 4 and 5 were conducted to investigate the antiinflammatory properties of the compounds on pro-inflammatory cytokines.
• IFNy-induced STATl activation and IL6-induced STAT3 activation were decreased in pretreated human macrophages.
• compounds 4 and 5 were found effective in reducing IFNy-induced CD40 and MHC-II expressions, as shown in Fig. 2.
• scratch wound healing assays were conducted and compounds 4 and 5 were found effective in inhibiting IFNy-induced STATl activation and IL6-induced STAT3 activation in human macrophages.
• An aspect provided is a method for decreasing anti-inflammatory properties of cancer cells, the method comprising contacting the cancer cells with at least one compound as defined herein.
• the relative STATl activation of cells treated with a compound herein disclosed is decreased by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70% or about 80% relative to untreated cells.
• the relative STAT3 activation of cells treated with a compound herein disclosed is decreased by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70% or about 80% relative to untreated cells.
• the CD40 expression of cells treated with a compound herein disclosed is decreased by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70% or about 80% relative to untreated cells.
• the MHC-II expression of cells treated with a compound herein disclosed is decreased by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70% or about 80% relative to untreated cells.
• Fig. 4 and 5 anti-inflammatory activity of compounds 4 and 5 was assessed by measuring nitric oxide (NO) production in murine macrophage-like cells stimulated with inflammatory signals, IFNy/TNFa. Compounds 4 and 5 were found effective in reducing IFNy/TNFa induced NO production.
• NO nitric oxide
• NO production in cells treated with a compound herein disclosed is decreased by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70% or about 80% relative to untreated cells.
• An aspect provided is a method for inducing anti-proliferative properties of cancer cells, the method comprising contacting the cancer cells with at least one compound as defined herein.
• the viability of cells treated with a compound herein disclosed is decreased by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70% or about 80% relative to untreated cells.
• the cancer cell growth is inhibited by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70% or about 80% relative to untreated cancer cells.
• the TNFOC/NFKB and/or IL6/STAT3 signaling pathways of cells treated with a compound herein disclosed is decreased by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70% or about 80% relative to untreated cells.
• the invasiveness of cells with a compound herein disclosed is decreased by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70% or about 80% relative to untreated cells.
• Similar body weight means no greater than a 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% difference in body weight loss.
• Similar hematocrit means no greater than a 5%, 4%, 3%, 2% or 1% difference in hematocrit level.
• the compounds herein disclosed display antiproliferative and anti-metastatic activity.
• UBC tumors and treated with compound 4 saw a significant decrease in tumor proliferation and in the number of metastases relative to untreated mice.
• Fig. 15 In female mice bearing orthotopically implanted urothelial bladder cancer tumors, as shown in Fig. 15, anti-proliferative properties of compound 4 were also seen. More particularly, the tumor development was stopped after two weeks of treatment. Similarly, mice ectopically implanted with urothelial bladder cancer tumors and treated with compound 4 saw a significant reduction of the tumor size, as illustrated in Fig. 18.
• tumors treated with a compound disclosed herein have a decrease in volume and/or a decrease in tumor growth of at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% relative to untreated tumors.
• Another aspect is a method for decreasing and/or preventing tumor metastases, the method comprising administering to a subject in need thereof an effective amount of at least one compound disclosed herein.
• the number of tumor metastases is decreased by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% relative to an untreated subject.
• Fig. 21 shows that these compounds were effective in inhibiting NO production.
• the compounds were also effective in inhibiting the IFNy-activated STAT1 signaling pathway and the LPS-activated NFKB signaling pathway in macrophage cells (Fig. 22 and 23).
• the LPS-activated NFKB signaling pathway of cells treated with a compound herein disclosed is decreased by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70% or about 80% relative to untreated cells.
• the compound is compound 4.
• the compound is compound 8.
• the compound is compound 10.
• the compound is compound 11.
• the subject is a mammal.
• the subject is a human.
• the cell is in vitro.
• the cell is in vivo.
• the cell is a cancer cell.
• the cancer is melanoma, uterine cancer, ovarian cancer, prostate cancer or bladder cancer.
• the bladder cancer is superficial UBC or muscle invasive
• the tumor is a melanoma tumor, uterine tumor, ovarian tumor, prostate tumor or bladder tumor.
• the bladder tumor is a superficial UBC tumor or a muscle invasive UBC tumor.
• the methods disclosed herein are effective for presenting the development of superficial UBC into muscle invasive UBC tumor.
• Multiplicities are described by the following abbreviations: s for singlet, d for doublet, dd for doublet of doublets, t for triplet, dt for doublet of triplets, q for quartet, dq for doublet of quartets, m for multiplet, #m for several multiplets, br for a broad signal.
• Step C Synthesis of TV'- [4-(2,5-dioxo-2,5-dihydro- pyrrol- l-yl)-benzoyl]- hydrazine carboxylic acid tert-butyi ester (4)
• ferf-butyl carbazate (128 mg, 0.97 mmol) dissolved in methylene chloride (0.8 mL) was added dropwise to the mixture and stirred for an additional 12 h at 22 ° C.
• the reaction mixture was diluted with ethyl acetate (55 mL) and methylene chloride (20 mL) and washed twice with saturated NaHC0 3 (2 x 50 mL), twice with 0.1 N HCl (2 x 50 mL), twice with saturated NaCl (2 x 50 mL), and finally with H 2 0 (50 mL).
• the organic phase was dried (MgS0 4 ) and evaporated to give crude derivative 4.
• Step D Synthesis of 4-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-benzoic acid hydrazide hydrochloride (or 4-nialeiniid benzoic acid hydrazide hydrochloride)
• Step E Synthesis of 4-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-benzoic acid hydrazide trifluoroacetic acid salt (6)
• Step C Synthesis of TV'- [3-(2,5-dioxo-2,5-dihydro- pyrrol- l-yl)-4-chloro- benzoyl]-hydrazine carboxylic acid tert-butyi ester (4a)
• Step C Synthesis of TV'- [3-(2,5-dioxo-2,5-dihydro- pyrrol- l-yl)-4-chloro- benzoyl]-hydrazine carboxylic acid tert-butyi ester (4b)
• compound 5 can be treated with a relevant aldehyde (alkyl aldehydes (linear or branched), benzaldehyde or substituted benzaldehydes) under acidic conditions at reflux in butanol (or other solvent) to give the desired alkylhydrazones or benzoylhydrazones derivatives.
• a relevant aldehyde alkyl aldehydes (linear or branched), benzaldehyde or substituted benzaldehydes) under acidic conditions at reflux in butanol (or other solvent)
• Derivative 4 (or any other maleimides described herein) can be reacted with an appropriate diene (butadiene (unsubstituted or substituted), cyclopentadiene, cyclohexadiene cycloheptadiene, furane, thiophene, pyrrole, N-alkylpyrrole) to give the desired cycloadducts (Diels-Alder products) such as for example 14, 15 and 16.
• Diels-Alder products such as for example 14, 15 and 16.
• This reaction can be performed by heating the pure reagents (diene and dienophile) either neat or in solution, with or without pressure.
• the intermediate 4-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-benzoic acid hydrazide trifluoroacetic acid salt (6) was prepared as described in example 1, step E using the following quantities: derivative 4 (100 mg, 0.303 mmol), trifluoroacetic acid 250 iL, dichloromethane (1 mL).
• the intermediate 6 was dissolved in dichloromethane (2 mL) and treated with 4-hydroxy-3-methoxybenzaldehyde (vanillin, 46.1 mg, 0.303 mmol) and sodium bicarbonate (25.4 mg, 0.303 mmol).
• Dichloromethane (2-3 mL) was used to dissolve the aldehyde stuck to the reaction vessel wall.
• Cell culture - general Biological assays were performed using the human monocytic cell line THPl, the murine macrophage-like cell lines J774A.1 and RAW 264.7, and the murine UBC cell lines MB49 and MB49-I.
• the cells were maintained in RPMI medium supplemented with 10% heat-inactivated fetal bovine serum (FBS) and containing 1 mM sodium pyruvate, 10 mM 4-(2- hydroxyethyl)piperazine-l-ethanesulfonic acid (HEPES) and 50 ⁇ g/mL gentamycin (referred as 10% FBS RPMI-1640).
• FBS heat-inactivated fetal bovine serum
• HEPES 4-(2- hydroxyethyl)piperazine-l-ethanesulfonic acid
• gentamycin referred as 10% FBS RPMI-1640.
• THP1 cells were maintained at 37 °C in a moisture- saturated atmosphere containing 5% C0 2 .
• THP1 cells, RAW 264.7 cells and J774A.1 cells are the most widely used cell lines to investigate the function and differentiation of monocytes and macrophages in response to various inflammatory mediators. 17 ' 18 Undifferentiated THP1 cells resemble primary monocytes/macrophages isolated from healthy donors or donors with inflammatory diseases, such as diabetes mellitus and atherosclerosis. 19 After treatment with phorbol esters, THP1 cells differentiate into macrophage-like cells which mimic native monocyte-derived macrophages in several respects.
• GFP green fluorescent protein-expressing
• Luciferase assay To assess the transcriptional activity of NFKB in response to TNFa, MB49-I cells cultured in monolayers (7.5 * 10 4 cells/well in 24- well plates) were transiently transfected with an expression vector allowing the transcription of the firefly luciferase reporter gene under the control of CMV promoter and tandem repeats of the NFKB transcriptional response element.
• the luciferase gene encodes a 61-kDa enzyme that oxidizes D-luciferin in the presence of ATP, oxygen, and Mg ++ , yielding a fluorescent product that can be quantified by measuring the released light.
• MB49-I cells were pretreated for 30 min with vehicle (DMSO) and compound 4 (at 10 ⁇ or 30 ⁇ ); and then washed and recovered after 24 h of activation with 10 ng/mL or 50 ng/mL TNFa.
• Cell lysates were mixed with Luciferase assay reagent (a mixture of luciferine, coenzyme A, ATP and Mg 2+ ) and the light produced was measured using a luminometer.
• Luciferase assay reagent a mixture of luciferine, coenzyme A, ATP and Mg 2+
• THPl-derived human macrophages 750* 10 4 cells/mL were pretreated for 3 h with DMSO or compounds 4 and 5, and then left untreated (control) or treated for 48 h with 50 U/mL IFNy.
• the expression level of MHC-II and CD40 was evaluated by flow cytometry as described. 21"23
• T24 cells 50 x 10 3 cells
• polarized Ml macrophages 50 x 10 3 cells
• the polycarbonate filter with 0.4 ⁇ pores diameter is too small to left the cells move to the bottom of the lower wells.
• non-invading cells into the matrigel coat were removed and cells that migrated down to the polycarbonate filter were stained with Hoescht 33258 dye after a 48-h incubation period, visualized by fluorescence microscopy and counted.
• This method involves the detection of nitrite ions (N0 2 " ) formed by the spontaneous oxidation of NO under physiological conditions. According the manufacture procedure (Life Technologies; # G-7921), equal volumes of sulfanilic acid and N-(l-naphthyl)ethylenediamine are mixed together to form the Griess reagent. In the presence of N0 2 " , sulfanilic acid is converted to a diazonium salt, which in turn is coupled to N-(l-naphthyl)ethylenediamine to produce a pink coloration that is measured with a spectrophotometer (Biotek, synergy HT) at 548 nm. In the same manner, urea synthesis through arginase-1 activity was measured using commercially available kit.
• MTT methylthiazolyldiphenyl-tetrazolium bromide
• a blinded observer measured tumor length and width.
• the volume of the tumor was calculated from the formula: Length x width2 x 0.52, where length and width were tumor diameters measured with calipers in mutually perpendicular directions.
• a control group received PBS as treatment.
• other groups were treated at different doses (90, 150 or 300 ⁇ ) with an intraperitoneal (i.p.) injection of compounds 4 or 8 every 3-4 days for 18-20 days. 24 ' 27
• Dufresne M Dumas G, Asselin E, Carrier C, Pouliot M, Reyes-Moreno C, Pro-inflammatory type-1 and anti-inflammatory type-2 macrophages differentially modulate cell survival and invasion of human bladder carcinoma T24 cells, Mol. Immunol, 48, 1556-1567 (2011)

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