WO1994002145A2 - 2-aryl-4-quinolones as antitumor compounds - Google Patents
2-aryl-4-quinolones as antitumor compounds Download PDFInfo
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- WO1994002145A2 WO1994002145A2 PCT/US1993/006893 US9306893W WO9402145A2 WO 1994002145 A2 WO1994002145 A2 WO 1994002145A2 US 9306893 W US9306893 W US 9306893W WO 9402145 A2 WO9402145 A2 WO 9402145A2
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- 0 *c1ccc([*-]=O)cc1 Chemical compound *c1ccc([*-]=O)cc1 0.000 description 3
- LUGPSBWXDAHDMQ-UHFFFAOYSA-N C1Oc2cc(NC(CC3)c4ncccc4)c3cc2O1 Chemical compound C1Oc2cc(NC(CC3)c4ncccc4)c3cc2O1 LUGPSBWXDAHDMQ-UHFFFAOYSA-N 0.000 description 1
- UXAXQKYXADBMJU-UHFFFAOYSA-N CN(C(C1)c(cc2)ccc2O)c(cccc2)c2C1=O Chemical compound CN(C(C1)c(cc2)ccc2O)c(cccc2)c2C1=O UXAXQKYXADBMJU-UHFFFAOYSA-N 0.000 description 1
- KJMRWDHBVCNLTQ-UHFFFAOYSA-N CN(c(cccc1)c1C(O1)=O)C1=O Chemical compound CN(c(cccc1)c1C(O1)=O)C1=O KJMRWDHBVCNLTQ-UHFFFAOYSA-N 0.000 description 1
- MBYSOSGWDGZIBA-UHFFFAOYSA-N O=C(C=C(c1ncccc1)Nc1c2)c1cc1c2OCO1 Chemical compound O=C(C=C(c1ncccc1)Nc1c2)c1cc1c2OCO1 MBYSOSGWDGZIBA-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- 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
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
-
- 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
- C07D215/38—Nitrogen atoms
-
- 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
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Definitions
- the present invention relates to 2-aryl-4-quinolone compounds, and to use of the compounds as anti-tumor agents.
- Quinolones have been widely studied as antibacterial agents.
- the antibacterial activity of quinolones appears to be related, at least in part, to the ability of the compounds to bind to and inhibit DNA gyrase.
- the inhibitory activity of the compound can be altered by the R-group substituents at ring positions 6, 7, and 8 (seen in Figure 2A). Fluorine in position 6 is particularly effective in enhancing antibacterial ability (Neu).
- 2-phenyl-4-quinolone which can tautomerize to 2-phenyl-4-hydroxyquinoline.
- Several methods of synthesis of 2-phenyl-hydroxyquinoline have been proposed. For example condensation of an arylamine with ethyl benzoylacetate in the presence of polyphosphoric acid yields small amounts of the corresponding beta-arylaminocinnamates, which can then be cyclized to 2-phenylhydroxyquinoline in the presence of polyphosphoric acid (Staskun, et al.; see also Venturella, et al., 1975).
- 4-Methoxy-2-quinoline in particular, can be thermally
- a method for synthesizing 4-quinolones directly involves a variation of the von Niementowski
- the invention includes a method of treating a tumor in a mammalian subject, by administering to the subject, a 2-aryl-4-quinolone compound, in an amount effective to reduce tumor growth in the subject.
- the 2-aryl-4- quinolone compound has one of the forms:
- R 0 , R 1 , R 2 , and R 3 are each selected from the group consisting of H, F, Cl, Br, I, OH, OCH 3 , OCF 3 , OCH 2 CH 3 , CH 3 , CF 3 , CH 2 CH 3 , SCH 3 , SCH 2 CH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHCH 2 CH 2 N(CH 3 ) 2 , NHC(O)CH 3 ,
- R 4 , R 5 , R 6 , R 7 , and R 8 are each selected from the group consisting of H, F, Cl, Br, I, OH, OCH 3 , OCF 3 , OCH 2 CH 3 , CH 3 , CF 3 , CH 2 CH 3 , SCH 3 , SCH 2 CH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , OCH 2 Ph; or two of said R 4 , R 5 , R 6 , R 7 , and R 8 together are OCH 2 CH 2 O, OCH 2 CHPhO, or NCH 2 CH 2 O; and X is O, S, or NH.
- the 2-aryl-4- quinolone is a dioxalane 2-aryl-4-quinolone having one of the forms:
- R 4 , R 5 , R 6 , R 7 , and R 8 are each selected from the group consisting of H, F, Cl, Br, I, OH, OCH 3 , OCF 3 , OCH 2 CH 3 , CH 3 , CF 3 , CH 2 CH 3 , SCH 3 , SCH 2 CH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , OCH 2 Ph; or two of said R 4 , R 5 , R 6 , R 7 , and R 8 together are OCH 2 CH 2 O, OCH 2 CHPhO, or NCH 2 CH 2 O; and X is O, S, or NH.
- the invention includes, in a treatment regimen for inhibiting growth of a tumor in a
- a method for inhibiting the growth of the tumor by administering to the subject, a 2-aryl-4-quinolone compound, in an amount effective to inhibit tumor growth in the treated subject.
- the invention also includes a pharmaceutical composition which contains a 2-aryl-4-quinolone compound of the invention, for use in inhibiting the growth of tumor cells.
- the invention includes novel anti-tumor compounds having structures I-VIII shown above.
- the hovel compounds include structures I-IV having alkylated amino groups at the 5, 6, 7, or 8 quinolone ring position, and the dioxalane quinolone compounds having structures V-VIII.
- Figure 1 shows a general structure for the compounds useful in the method of the invention
- Figures 2A-2D illustrate four embodiments of the Fig. 1 structure which are useful for treatment of tumor cells (structures I-IV);
- FIGS 3A-3D illustrate four additional
- Figure 4 illustrates one preferred method of synthesis of compound I shown in Figure 1A;
- FIG. 5 shows the synthetic method for
- Figure 6 illustrates a method of synthesis of a pyridine analog of benzoyl acetate ethyl ester for use in the reaction scheme of Figure 4, for synthesis of a 2-pyridino-4-quinolone compound;
- Figure 7 shows an alternate synthesis of a 2-phenyl-4-quinolone compound
- Figure 8 shows another synthesis scheme which is useful for preparing 2-aryl-4-quinolone compounds of the invention.
- Figure 9 illustrates a method of synthesis of a compound having structure V shown in Figure 3A;
- FIGS. 10A and 10B illustrate two exemplary dioxalane 2-aryl-4-quinolone compounds of the
- FIG. 11 illustrates methods for alkylating 2-phenol-4-quinolone at the ring nitrogen and 4-position oxygen.
- This section describes synthetic methods for preparing 2-aryl-4-quinolone compounds useful for treatment of tumors.
- the 2-aryl-4-quinolone compounds of the invention have the general structure shown in Figure 1.
- the compounds includes a quinolone fused-ring structure, substituent groups attached to ring atoms 5, 6, 7, and 8, and a selected aryl group (Ar) attached to ring atom 2.
- Figures 2A-2D show four general embodiments of the structure shown in Figure 1.
- substituents R 0 through R 3 on ring atoms 5, 6, 7, and 8 are each selected from the group consisting of H, F, Cl, Br, I, OH, OCH 3 , OCF 3 , OCH 2 CH 3 , CH 3 , CF 3 , CH 2 CH 3 , SCH 3 , SCH 2 CH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHCH 2 CH 2 N(CH 3 ) 2 ,
- the 2-aryl group is a phenyl ring in which substituents R 4 through R 8 are selected from the group consisting of H, F, Cl, Br, I, OH, OCH 3 , OCF 3 , OCH 2 CH 3 , CH 3 , CF 3 , CH 2 CH 3 , SCH 3 , SCH 2 CH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , OCH 2 Ph.
- Figures 3A-3D show four additional embodiments of the Figure 1 structure, wherein a methylenedioxy moiety (-OCH 2 O-) forms a five-membered ring with the 6- and 7-ring atoms of the quinolone backbone
- Figure 4 shows one general synthetic scheme for producing compounds of the type illustrated in Figure 2A. This approach is detailed in Example 1. Briefly, aniline (IX) is condensed with benzoyl acetate ethyl ester (X) to produce the intermediate product XI, followed by a thermal cyclization in diphenyl ether at 240-250°C, to produce the desired 2-aryl-4-quinolone (I H ).
- aniline (IX) is condensed with benzoyl acetate ethyl ester (X) to produce the intermediate product XI, followed by a thermal cyclization in diphenyl ether at 240-250°C, to produce the desired 2-aryl-4-quinolone (I H ).
- 6-substituted 2-aryl-4-quinolones and 8-substituted 2-aryl4-quinolones can be prepared from p-substituted anilines and o-substituted anilines, respectively.
- 5- and 7-Substituted 2-phenyl-4-quinolones can be prepared from m-substituted aniline starting
- Figure 5 illustrates synthesis of 2-phenyl-4-quinolone compounds having an OH substitution at the 5, 6, 7, or ,8 position (XII). As seen, these compounds can be prepared directly by demethylation of the corresponding methoxy precursors (XIII) with KOH in ethylene glycol (Venturella). Details are given in Example 2 .
- the methoxy precursors can be prepared as described in Example 1.
- Table 1 identifies several exemplary 2-phenyl-4-quinolones (structure I in Figure 2A) formed by the above methods.
- R N indicates substitutions at the ring nitrogen
- R O substitutions at the 4'-position of the pendant ring
- R 1 , R 2 , and R 3 indicate substituents at the 6-8 ring positions, respectively ( Figure 1)
- Re indicates substitutions on the 2-phenyl ring.
- 2-aryl-4-quinolone compounds in which the pendant aryl group is a pyridine ring can be prepared by similar methods.
- the pyridine analog (XV) of benzoyl acetate ethyl ester can be formed by reaction of nicotinic acid ethyl ester (XIV) with ethyl acetate in ethanol, in the presence of sodium ethoxide, according to published methods (Hurd).
- Compound XV is then reacted with aniline or a substituted aniline, as illustrated in Figure 4, to yield the desired 2-pyridyl-4-quinolone compound (III).
- the position of the ring nitrogen in the compound is determined by the ring position of the ethyl ester group on the pyridine ring, as can be appreciated.
- Figure 7 illustrates an alternative method for producing 2-aryl-4-quinolone compounds, and in particular, compounds substituted in the pendant phenyl ring.
- this method the hydroxyl group of p-hydroxyacetophenone (XVII) is protected by treatment with methoxymethyl chloride in the presence of NaH to give p-methoxymethoxy acetophenone (XVIII).
- Figure 8 illustrates a synthesis scheme for preparing 2-aryl-4-quinolone compounds which contain alkylated amine substituents (e.g., dimethylamine, morpholine, piperidine, and the like) attached at ring positions 5, 6, 7, and 8.
- alkylated amine substituents e.g., dimethylamine, morpholine, piperidine, and the like
- quinolone compound having a p-substituted 2-phenyl group the appropriate p-substituted benzoyl chloride compound can be used.
- indole-3-carboxylic acid chloride can be used instead of a benzoyl chloride compound.
- 2-furan, 2-thiophene, or 2-pyrrole quinolone compound the appropriate acid chloride derivative is used.
- FIGS. 10A and 10B show two exemplary dioxalane
- Figure 11 illustrates modifications of 2-phenyl-4-quinolone (I) to produce alkylation with various R groups (see Table 2) at the ring nitrogen or the 4-position oxygen.
- I 2-phenyl-4-quinolone
- m/z 235, M+ Elemental and mass spectral
- Table 2 identifies several exemplary O-substituted 2-phenyl-4-quinolones formed by the above methods, which are detailed for compounds 44, 45 and 46 in Example 4.
- R identifies the alkyl moiety of a 4-position -OR group.
- the invention includes a method of treating a tumor in a mammalian subject, by administering to the subject, a 2-aryl-4-quinolone compound, in an amount effective to inhibit tumor cells in the subject.
- the 2-aryl-4-quinolone compound has the structure given in Figures 2A-2D, including substitutions at ring positions 5-8, and on the pendant (2-position) phenyl group.
- the compounds have the general structure given in Figure 3A-3D, including
- Selected 2-phenyl-4-quinolones and related compounds (22-50 in Tables 1 and 2) were assayed for cytotoxicity in vitro against six tumor cell lines, including human lung carcinoma (A-549), ileocecal carcinoma (HCT-8), melanoma (RPMI-7951), and
- compound 33 demonstrated potent cytotoxicity, with EC 50 values ⁇ 1.0 ⁇ g/ml in virtually all cases. This indicates that several substituents at position 6 (R 1 ) (F, Cl, OH, CH 3 , and OCH 3 ) , position 7 (R 2 ) (F, Cl, OCH 3 , and OH), and position 8 (R 3 ) (F) of the basic 2-phenyl-4-quinolone structure (e.g. 22) are possible with minimal effects in general cytotoxicity obtained with this class of compound. More generally, a preferred embodiment of the invention contemplates 2-ary1-4-quinolone compounds in which R 1 and R 2 are each H, F, Cl, OH, CH 3 , or OCH 3 , and R 3 is H, F, or Cl.
- the 6-hydroxy compound (32) showed selectivity towards the KB and L1210 lines.
- Introduction of an OH group at C-8 (34) or the introduction of alkyl groups at N-1 (35 and 50) and at the C-4 oxygen (36-43) all led to poorly active compounds.
- the C-4 O-mesylated compound (44) was also minimally cytotoxic.
- TGI is the log concentration of molarity of compound which reduces viable cell number to the level at the start of the experiment
- LC 50 is the log compound molarity which reduces the viable cell number to 50% of the level at the start of the experiment.
- the three compounds were further tested against the cell lines MRC-3 (normal human lung fibroblast), HTBD U -145 (human prostate carcinoma), HE p -2 (human lung carcinoma), BT549 (human breast carcinoma), HeLaS 2 (human cervical carcinoma), A549 (human lung carcinoma), SW480 (human colon carcinoma), HepG 2 (human liver carcinoma), and HepG 2 -T 14 (Hep-G 2
- Example 6B Details of the compound test method are given in Example 6B. The results are seen in Table 5, which shows that all three compounds show about the same cytotoxicity potency to the several cell lines.
- XXV and XXVI were compared with that of compound 27 against the tumor cell lines shown at the left-hand column in Table 6 below.
- Various concentrations of compounds XXV, XXVI, and 27 were added into 96 well multi-dish in triplicate. 1 ⁇ 10 4 cells were added to each well. After three days of continuous exposure of the cells to the drugs, a final concentration of 0.5 mg/ml MTT in PBS was added and then these were incubated at 37°C Four hours later, the cells were lysed with isopropanol containing 0.06 N HC1 and read by an ELISA reader with wavelength set at 570 nm for attached cells and 570 nm-630 nm for suspension cells. Inhibition of cell proliferation was expressed as the O.D. of drug treated mean/O.D. of the control mean.
- IC 50 was estimated by the curve plotted by concentration of the drug versus
- the two dioxalane compounds show high activity against the cell lines tested.
- Compound XXV showed highest activity in general, with compounds XXVI being substantially more active than compound 27 in the first two cell lines.
- KB cells non-resistant human nasopharyngeal carcinoma (KB) cells and KB cells resistant to VP-16 (KB REV and KB 7 ) and KB cells resistant to vincristine (KB VCR ). Cytotoxicity was measured after exposure to the test compound as described in Example 6B, with the results shown in Table 8 below. As seen, comparable levels of cytotoxicity activity were observed for both KB cells and KB cells resistant to VP-16 (KB REV and KB 7 ) and KB cells resistant to vincristine (KB VCR ). Cytotoxicity was measured after exposure to the test compound as described in Example 6B, with the results shown in Table 8 below. As seen, comparable levels of cytotoxicity activity were observed for both
- podophyllotoxin and combretastatin A-4. These three natural products all bind at the colchicine site of tubulin (Hamel, 1990; Lin, et al . , 1990).
- the unsubstituted compound 22 had significant inhibitory activity in the tubulin polymerization assay, with an IC 50 value of 7.3 ⁇ M, measured for the extent of polymerization after 20 minutes.
- maximum enhancement of activity occurred with a substitution at position 6.
- the substituent group was methoxy (26), chloride (24), or fluoride (23).
- the 6-methoxy substituent appeared to be slightly more inhibitory than the compounds with halides at position 6, the differences between the compounds were within the experimental error of the assay.
- a substituent at position 7 also enhanced activity about 2-fold relative to the unsubstituted 22.
- methoxy, and hydroxyl groups, respectively, at position 7 had IC 50 values of 3.7, 4.8, and 3.4 ⁇ M. With chloride and especially methoxy substituents, somewhat lower IC 50 values were obtained when the substituent was at position 6 as compared with position 7. With the hydroxyl substituent, in contrast, position 7 appeared to be more favorable (IC 50 value of 3.4 ⁇ M for 33 as compared with 16 ⁇ M for 32).
- a 2-aryl-4-quinolone compound of the type described above is administered in a pharmaceutically effective amount, to reduce tumor growth in a mammalian
- pharmaceutically effective amount is meant a concentration at the tumor site or in the bloodstream which is effective to inhibit growth of tumor cells. This concentration can be determined from EC 50 values from in vitro growth inhibition studies, such as those described, using either known tumor cell lines, and related to the patient's tumor type.
- the present invention provides a method of inhibiting tumor cell growth in the subject.
- a 2-aryl-4-quinolone compound is administered in an amount effective to inhibit tumor growth.
- Drug resistance in the initial phase of the regimen is evidenced by an increasingly larger drug dose needed to inhibit tumor growth. That is, the tumor becomes increasingly more refractory to growth inhibition by the drug.
- the effective drug dose of aryl quinolone is generally no higher than that required before drug resistance develops.
- the compound itself is readily synthesized, and can be administered either orally or parenterally, e.g., by intravenous administration.
- the mode of action of the compound, inhibiting tubulin formation necessary for cell mitosis, would tend to confine the effects of the compound to actively dividing cell.
- studies carried out in support of the invention show that exemplary compounds 24, 26, and 27 produced no detectable breaks in protein-linked DNA, unlike VP-16.
- the compounds do not appear to share cross-resistance with a number of common anti-tumor agents, including doxorubicin, vincristine, and VP-16, and thus are useful particularly in a treatment regimen where anti-tumor resistance has developed, or in combination with other anti-tumor compounds, such as doxorubicin, cis-platin, vincristin, or VP-16.
- p-Hydroxyacetophenone (46) (13.6 g, 0.1 mole) was dissolved in dry tetrahydrofuran (THF) (200 ml), and NaH (80% in oil, 3.0 g, 0.1 mole) was added.
- Candidate compounds (22-50) were assayed for in vitro cytotoxicity with a panel of human and murine tumor cell lines at the School of Medicine, UNC-CH. These cell lines include lung carcinoma (A-549), ileocecal carcinoma (HCT-8), epidermoid carcinoma of the nasopharynx (KB), melanoma (RPMI-7951), and murine leukemia (P-388 and L-1210). All cell lines were obtained from the American Type Culture
- Cytotoxicity studies in human and murine tumor cell lines were performed in a 96 well format. Each well was deposited with approximately 1 ⁇ 10 5 cells and overnight stabilization, testing chemicals, in appropriate dilution, were added to each of the wells (each concentration performed in quadruplicate).
- Control wells received medium alone. After 3-4 days cultivation, the remaining cell number in each well was estimated by the formazan pigment formation assay. MTT was added to each well, and the plates were incubated overnight. The pigment formed was dissolved in DMSO, and the plates were analyzed on a Dynatech 360 ELISA reader at 570 nm. Actinomycin (Sigma Chemical Co., St. Louis, MO) was used as a positive control. The ED 50 of actinomycin for these cell lines is usually less than 0.01 ⁇ g/ml.
- test compound Various concentrations of the test compound were added together with 10 4 cells into 96 well multi dishes. After three days of continuous exposure of the cells to the compound, a final concentration of 0.5 mg/ml MTT (Mosmann) was added, with further incubation for 4 hours. At the end of this
- the monolayer cells were lysed with isopropanol containing 0.01N HCl, after aspiration of the medium, and read at 570 nm by an ELISA reader.
- isopropanol containing 0.01N HCl was added directly to the cells, and the cells were read at 570-630 nm by an ELISA reader after storage in the dark overnight at room temperature. Inhibition of cell proliferation is expressed as IC 50 by comparisons of the compound treated optical density with control (untreated cells) optical density.
- Tubulin Polymerization Activity Tubulin was purified from bovine brain as described previously (Hamel, et al . , 1984).
- Nonradiolabeled colchicine was obtained from Sigma, podophyllotoxin from Aldrich, and [ 3 H]colchicine from DuPont. Combretastatin A-4 was a generous gift of Dr. G.R. Pettit of Arizona State University.
- reaction mixture contained in a 0.24 mL volume 1.0 mg/mL (10 ⁇ M) tubulin, 1.0 M monosodium glutamate, 1.0 mM MgCl 2 , 4% (v/v) dimethyl sulfoxide, and varying concentrations of drugs (all
- reaction mixtures were preincubated at 37°C for 15 minutes and chilled on ice, and 10 ⁇ L of 10 mM GTP (required for
- IC 50 values defined as the drug concentration required to inhibit the extent of polymerization by 50% after a 20 minute
- spectrophotometers (sixteen samples) were used in each experiment. Each experiment had two control reaction mixtures, with the turbidity readings generally within 5% of each other.
Abstract
Description
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Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0664288A1 (en) * | 1992-10-09 | 1995-07-26 | Chugai Seiyaku Kabushiki Kaisha | Fluoroquinoline derivative |
WO1996010563A1 (en) * | 1994-09-30 | 1996-04-11 | The University Of North Carolina At Chapel Hill | 2-aryl-4-quinolones as antitumor compounds |
KR19990069876A (en) * | 1998-02-13 | 1999-09-06 | 성재갑 | Cyclin-Dependent Kinase Inhibitor Compounds Having 4-Quinolone Structure |
FR2781218A1 (en) * | 1998-07-15 | 2000-01-21 | Lafon Labor | Prevention of proliferation of clonogenic cells in tumors uses 2-quinolone derivatives as supplement to conventional chemotherapeutic treatment |
FR2797444A1 (en) * | 1999-08-13 | 2001-02-16 | Lafon Labor | PHARMACEUTICAL COMPOSITIONS COMPRISING 4-QUINOLONES |
WO2002000623A2 (en) * | 2000-06-26 | 2002-01-03 | Neurogen Corporation | Aryl fused substituted 4-oxy-pyridines |
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JP2012214501A (en) * | 2006-12-07 | 2012-11-08 | China Medical Univ | Compound of 2-phenyl-4-quinolone and use thereof as anticancer agent |
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3725413A (en) * | 1972-01-17 | 1973-04-03 | Warner Lambert Co | Process for the production of ethyl 8-hydroxy-1,3-dioxolo{8 4,5g{9 -quinoline-7-carboxylate |
FR2276049A1 (en) * | 1974-06-25 | 1976-01-23 | Chinoin Gyogyszer Es Vegyeszet | Bacteriostatic 5-substd.-oxolinic acids - prepn. by nitration of oxolinic acid and derivs, and opt redn. to the amino cpds. (NO260176) |
JPS567784A (en) * | 1979-06-28 | 1981-01-27 | Yoshitomi Pharmaceut Ind Ltd | Imidazoquinolone derivative |
EP0341104A2 (en) * | 1988-04-06 | 1989-11-08 | MERCK PATENT GmbH | Substituted flavonoid compounds, their salts, their manufacture and medicines containing these materials |
EP0343574A1 (en) * | 1988-05-24 | 1989-11-29 | Kirin Beer Kabushiki Kaisha | 4(1H)-quinolone derivatives |
US5126351A (en) * | 1991-01-24 | 1992-06-30 | Glaxo Inc. | Antitumor compounds |
-
1993
- 1993-07-22 AU AU47807/93A patent/AU4780793A/en not_active Abandoned
- 1993-07-22 WO PCT/US1993/006893 patent/WO1994002145A2/en active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3725413A (en) * | 1972-01-17 | 1973-04-03 | Warner Lambert Co | Process for the production of ethyl 8-hydroxy-1,3-dioxolo{8 4,5g{9 -quinoline-7-carboxylate |
FR2276049A1 (en) * | 1974-06-25 | 1976-01-23 | Chinoin Gyogyszer Es Vegyeszet | Bacteriostatic 5-substd.-oxolinic acids - prepn. by nitration of oxolinic acid and derivs, and opt redn. to the amino cpds. (NO260176) |
JPS567784A (en) * | 1979-06-28 | 1981-01-27 | Yoshitomi Pharmaceut Ind Ltd | Imidazoquinolone derivative |
EP0341104A2 (en) * | 1988-04-06 | 1989-11-08 | MERCK PATENT GmbH | Substituted flavonoid compounds, their salts, their manufacture and medicines containing these materials |
EP0343574A1 (en) * | 1988-05-24 | 1989-11-29 | Kirin Beer Kabushiki Kaisha | 4(1H)-quinolone derivatives |
US5126351A (en) * | 1991-01-24 | 1992-06-30 | Glaxo Inc. | Antitumor compounds |
Non-Patent Citations (8)
Title |
---|
CHEM. IND., no.4, 1981 page 121 A. KASAHARA ET AL. 'A new synthesis of 2-aryl-4-quinolones' * |
DATABASE WPI Week 8112, Derwent Publications Ltd., London, GB; AN 81-20215D & JP-A-56 007 784 (YOSHITOMI PHARM IND KK) 27 January 1981 * |
GAZZ. CHIM. ITAL., vol.100, no.7, 1970 pages 678 - 681 P. VENTURELLA ET AL. 'Synthesis of 1-methyl-2-phenyl-5-hydroxy-4-quinolone and improved synthesis of edulein' * |
J. HETEROCYCL. CHEM., vol.12, no.4, 1975 pages 669 - 673 P. VENTURELLA ET AL. 'On the reactions between ethyl benzoylacetate and anisidines' * |
J. MED. CHEM., vol.33, 1990 pages 1721 - 1728 J.B. JIANG ET AL. 'Synthesis and biological evaluation of 2-styrylquinazolin-4(3h)-ones, a new class of antimitotic anticancer agents which inhibit tubulin polymerization' * |
J. MED. CHEM., vol.36, no.9, 30 April 1993 pages 1146 - 1156 K. SHENG-CHU 'Synthesis and cytotoxicity of 1,6,7,8-substituted 2-(4'-substituted phenyl)-4-quinolones and related compounds: Identification as antimitotic agents interacting with tubulin' * |
SYNTHESIS, vol.5, 1987 pages 482 - 483 BANG-CHI CHEN 'A versatile synthesis of 2-alkyl and 2-aryl 4-quinolones' * |
TETRAHEDRON LETTERS, vol.33, no.3, 14 January 1992 pages 373 - 376 V.N. KALININ ET AL. 'A new route to 2-aryl-4-quinolones via palladium-catalyzed carbonylative coupling of o-iodoanilines with terminal arylacetylenes' * |
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