WO2012083866A1 - Quinoline derivatives as anti-cancer agents - Google Patents

Abstract

Quinoline derivatives showing anticancer activities against cancer cell lines of hepatocellular carcinoma (Hep3B), lung carcinoma (A549), esophageal squamous cell carcinoma (HKESC-1, HKESC-4 and KYSE150). The quinoline derivatives have a backbone structure of the following formulas:

Description

QUINOLINE DERIVATIVES AS ANTI-CANCER AGENTS

CROSS REFERENCE TO RELATED APPLICATION

[1] This application claims benefit of U.S. Provisional Application No. 61/425,767, filed December 22, 2010, the content of which is incorporated herein in its entirety by references.

FIELD OF THE INVENTION

[2] This invention relates to a novel genus of compounds useful as anti-cancer agents. Particularly, it relates to a group of substituted quinoline derivatives which show potent anti-cancer effects.

BACKGROUND OF THE INVENTION

[3] Substituted quinoline-type alkaloids are known for possessing interesting biological activities. For example, 8-hydroxyquinoline derivatives were reported to possess activities against (i) Alzheimer's disease, (ii) rat mesenchymal stem cells (rMSCs) proliferation and (iii) antifungal properties. The compound, 8- aminoquinoline (sitamaquine), has been suggested to be a candidate agent for treating visceral leishmania leishmaniasis. The 8-hydroxyquinoline and its derivatives have been reported to possess good antifungal properties and can help the treatment of neurodegenerative disease.

[4] Asymmetric hydrogenation offers a new method for structural modification of this compound type to produce new chiral structural moiety and associated bioactivity. Zhou, Chan and others reported their effort in the asymmetric production of chiral tetrahydroquinoline with high enantioselectivities. However, there is no known report of the substituted quinoline-type alkaloids of the present invention that are useful for cancer treatment with good solubility and acceptable cell toxicity.

SUMMARY OF THE INVENTION

[5] The present invention provides quinoline derivatives of formula I - IV and their salts for anti-tumor activities.

I II

Ri Re Ri Re

III IV

Formula I - IV [6] where A, B, C, D and W, X, Y and Z in the ring moieties is C, O, N, P, or S.

[7] Rj ,R₂ ,R₃ ,R4 ,R5 ,R6 _/R7 and R₈ are each independently H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkoxy or substituted alkoxy, hydroxyl or substituted hydroxyl, amino or substituted amino, thio or substituted thio, sulfonyl or substituted sulfonyl, sulfinyl or substituted sulfinyl, sulfonylamino or substituted sulfonylamino, halo, SO₃H, amine, CN, CF₃, acyl or substituted acyl, aryl or substituted aryl, heterocyclyl or substituted heterocyclyl, alkoxy or substituted alkoxy, aldehyde or substituted aldehyde or substituted phosphine; COR^a, CSR^a and CONHR^a where R^a is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, hydroxyl or substituted hydroxyl, aryl or substituted aryl, optionally heterocyclyl ring or substituted heterocyclyl ring; OR^b, SR^b or NR^bR^c where R^b and R^c are H or independently each other, alkyl or substituted alkyl, alkenyl or substituted alkenyl, acyl or substituted acyl, heterocyclyl ring or substituted heterocyclyl ring, CN; Q to C₄NR^dR^e, HCNNR^dR^e or HCNOR^d where R^d and R^e are H or independently each other, alkyl or substituted alkyl, alkenyl or substituted alkenyl, acyl or substituted acyl, heterocyclyl ring or substituted heterocyclyl ring; SR^f, OR^f or NR^fR^g, where R^f and R^g are H or independently each other, alkyl or substituted alkyl, alkenyl or substituted alkenyl, acyl or substituted acyl, heterocyclyl ring or substituted heterocyclyl ring; SOzNR^ where R^h and R' are H or independently each other, alkyl or substituted alkyl, alkenyl or substituted alkenyl, acyl or substituted acyl, heterocyclyl ring or substituted heterocyclyl ring.

[8] Preferably, the aforementioned A, B, C, D,W, X, Y and Z is each

independently C or N. More preferably, the quinoline derivative of the present invention is the following formula:

formula B formula A

[9] wherein Rj, R₂ and R₃ are each independently H or Br; R₅, R₇ and R₈ are

H; R₆ is selected from the group consisting of CH₃, CH₂CH₃, OBn, CH₂CH₂Ph, CH₂OH; and R₄is a substituted phenyl group, OBn, OH or OAc wherein said phenyl group is of the following formula:

[10] wherein Ra is COH₂, Rb is H, and Rc is Ph, F, CI, OCF₃, CF₃, CN, OMe or NO₂; or Ra is COH₂, Rb is Ph, F, CI, OCF₃, CN, OMe or NO₂, and Rc is H.

[11] The various features of novelty which characterize the invention are pointed out with particularity in the claims annexed to and forming a part of this disclosure. For a better understanding of the invention, its operating advantages, and specific objects attained by its use, reference should be made to the drawings and the following description in which there are illustrated and described preferred embodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[12] FIG. 1 shows the results of the MTS assays for compounds (+)-2b and (-)-2b on the carcinoma cell lines compared with CDDP

[13] FIG. 2 shows tumor volume change of subcutaneous KYSE150 xenografts with i.p. injection of (-) isomers of 2b and PEG control

DETAILED DESCRIPTION OF THE INVENTION

[14] The term "alkyl or substituted alkyl" denotes such radicals as straight chain, branched chain or cyclic hydrocarbon groups with 1 to 10 carbon atoms. These alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[15] The term "alkenyl or substituted alkenyl" denotes such radicals as straight chain, branched chain or cyclic hydrocarbon groups with at least one C=C double bond. These alkenyl groups are vinyl, allyl, propenyl, butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, cyclopentenyl, 1-methyl- cyclopentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, cyclohexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1,4-pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3- cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, as well as the straight and branched chain of the trienes.

[16] The term "acyl or substituted acyl" denotes such radicals as aromatic, aliphatic or heterocyclic acyl group, the example the acyl groups are carbamoyl, straight or branch chain alkanoyl, such as, formyl, acetyl, propanoyl, butanoyl, isopropanoyl, pentanoyl, hexnoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl; alkoxycarbonyl, such as,

methoxycarbonyl, ethoxycarbonyl, fefr-butoxy carbonyl, fefr-pentyloxycarbonyl or heptyloxycarbonyl; cycloalkylcarbonyl, such as, cyclopropylcarbonyl,

cyclobutylcarbonyl, cyclopentyl, carbonyl or cyclohexylcarbonyl; alkylsulfonyl, such as, methylsulfonyl or ethylsulfonyl; alkoxysulfonyl, such as, methoxysulfonyl or ethoxysulfonyl; aroyl, such as, benxoyl, toluoyl or naphthoyl; aralkanoyl, such as, phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutyl, phenylpentanoyl, phenylhexanoyl, naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl; aralkenoyl, such as, phenylpropenoyl, phenylpentenoyl, phenylhexenoyl, naphthylpropenoyl, naphthylbutenoyl, naphthylpentenoyl; aralkoxy carbonyl, such as,

benzyloxy carbonyl; aryloxy carbonyl, such as, phenoxyacetyl, naphthyloxy carbonyl; aryloxyalkanoyl, such as, phenoxyacetyl, phenoxypropionyl; ary carbamoyl, such as, phenylcarbamoyl, arylthiocarbamoyl, such as, phenylthiocarbamoyl; arylglyoxyloyl, such as, phenylglyoxyloyl, naphthylglyoxyloyl; arylsulfonyl, such as,

phenylsulfonyl, naphthylsulfonyl; heterocycliccarbonyl, heterocylclicalkanoyl, such as, thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl,

thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl, or tetrazolylacetyl,

heterocyclicalkenoyl, such as, heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl or heterocyclichexenoyl or heterocyclicglyoxyloyl, such as, thiazolylglyoxyloyl thienyglyoxyloyl.

[17] The term "aryl or substituted aryl" denotes such radicals as carbocyclic aromatic or heterocyclic aromatic system, such as, phenyl, naphthyl,

tetrahydronaphthyl, indane or biphenyl. These systems may be unsubstituted of substituted by one or more groups, such as, halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy, thio or thioalkyl.

[18] The term "heterocyclyl ring or substituted heterocyclyl ring" refers to monocyclic or poly cyclic heterocyclic groups containing at least one heteroatom, such as, N-containing saturated and unsaturated heterocyclic groups, for example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl; pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl; indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl or tetrazolopyridazinyl; O-containing saturated and unsaturated heterocyclic groups, for example, pyranyl, furyLoxazolyl, isoxazolyl, oxadiazolyl, morpholinyl, benzoxazolyl or benzoxadiazolyl; S-containing saturated and unsaturated heterocyclic groups, for example, thienyl, thiazolyl, thiadiazolyl, thiazolidinyl or thiazolidinyl.

[19] The term "halo or halogen" refer to fluorine, chlorine, bromine or iodine atom which can be one or more halogen atoms.

[20] The term "hydroxyl" refers to a hydrogen bond to an oxygen atom, the term "substituted hydroxyl" denotes a hydroxyl group substituted with one or more groups, such as, halogen, protected hydroxyl, cyano, nitro, alkyl or substituted alkyl, alkenyl or substituted alkenyl, acyl or substituted acyl, aryl or substituted aryl, heterocyclyl ring or substituted heterocyclyl ring, alkoxy or substituted alkoxy, acyloxy or substituted acyloxy, carboxy or protected carboxy, carboxymethyl or protected carboxymethyl, hydroxymethyl or protected hydroxymethyl, amino or protected amino, carboxamide or protected carboxamide.

[21] The term "alkoxy or substituted alkoxy" refers to straight or branch chain oxo-containing atoms with alkyl, for example, methoxy, ethoxy, propoxy, butoxy, and tert-butoxy.

[22] The term "thio or substituted thio" refers to radicals containing -SH or -S- group, for examples, methylthio, ethylthio, propylthio, butylthio, hexylthio. [23] The term "sulfonyl or substituted sulfonyl" refers to radicals containing - S(0)₂- group, for examples, methylsulfonyl, ethylsulfonyl, propylsulfonyl,

trinuoromethanesulfonyl, trichloromethanesulfonyl or other halogen-substituted alky- or aryl-sulfonyl.

[24] The term "sulfinyl or substituted sulfinyl" refers to radicals containing - S(=0)-group, for examples, methylsulfinyl, ethylsulfinyl, butylsulfinyl, hexylsulfinyl.

Synthesis of Substituted Quinoline

[25] a) 5,7-Dibromo-2-methylquinolin-8-ol (2a): 2-methyl-8-quinolinol la (1.6 g, 10 mmol) was dissolved in 150 mL MeOH. 1 ml Br₂ in MeOH was added into the solution dropwise. After completed reaction, Na₂SO₃ was added and the product was extracted by DCM to give the crude product. The crude product was purified by silica gel column chromatography to give the pure product, ¹H-NMR (500 MHz, CDCI3): δ 2.75 (s, 3H), 7.39 (d, 1H, / = 8.5 Hz), 7.79 (s, 1H), 8.26 (d, 1H, / = 8.5 Hz); ¹³C- NMR (125 MHz, CDC1₃): δ 25.40, 104.23, 110.64, 124.60, 125.47, 133.30, 136.64, 138.63, 149.76, 159.46; HRMS (ESI): Calcd. for C₁₀H₈NOBr₂ [M+H]⁺, 315.8973; found

315.8981 ; Yield = 64.4%.

[26] b) 5,7-Dibromo-8-hydroxyquinoline-2-carbaldehyde (3a): 5,7-Dibromo-2- methylquinolin-8-ol 2a (950mg, 3 mmol), selenium dioxide (418mg, 3.8 mmol), 100 ml of pre-dried 1,4-dioxane, and 0.5 ml of water were mixed and stirred in a 500 mL round bottom flask. The resulting solution was refluxed for 24 h and the reaction was monitored until completion using TLC method. Then the mixture was filtered off, and the selenium metal was washed with DCM, and the combined filtrates were evaporated off under reduced pressure, the crude product was purified by silica gel chromatography to yield the pure product, ¾-NMR (500 MHz, CDC1₃): δ 8.06 (s, 1H), 8.17 (d, 1H, / = 8.5 Hz), 8.64 (d, 1H, / = 8.5 Hz), 10.25 (s, 1H); ¹³C-NMR (125 MHz, CDCI3): δ 106.02, 111.08, 119.83, 129.23, 137.30, 138.63, 138.78, 150.97, 151.72, 192.32; HRMS (ESI): Calcd. for C₁₀H₆NO₂Br₂ [M+H]⁺, 329.8765; found 329.8765 ; Yield = 98.0%.

[27] c) 5,7-Dibromo-l,2,3,4-tetrahydro-2-methylquinolin-8-ol (2b): A mixture of [Ir(COD)Cl]₂ (l.Omg, 0.0015mmol) and the P-Phos (2.1mg, 0.0032mmol) or other C₂- symmetric bidendate chiral diphosphines ligands in dried solvent (e.g. THF) (l.OmL) was stirred at room temperature for 30 minutes in a glovebox. The mixture was transferred by a syringe to stainless steel autoclave, in which I₂ (4mg, 0.015mmol) and 5,7-dibromo-2-methylquinolin-8-ol 2a (95mg, 0.3mmol) in 0.5mL dried solvent were placed beforehand. The hydrogenation was performed at room temperature under H₂ for 20 h. After carefully releasing the hydrogen, the reaction mixture was quenched with saturated sodium carbonate solution (2.0mL) for 15 minutes. The aqueous layer was extracted with EA (3 x 3 mL). The combined organic layer was dried with sodium sulfate and concentrated in vacuo to give the crude product.

Purification by a silica gel column eluted with hexane/ E A gave the pure product. The enaiomeric excesses (ee) were determined by HPLC with chiral column, ¾- NMR (500 MHz, CDC1₃): δ 1.26 (d, 3H, / = 6.0 Hz), 1.53-1.61 (m, 1H), 1.96-2.01 (m, 1H), 2.59-2.66 (m, 1H), 2.80-2.85 (m, 1H), 3.35-3.39 (m, 1H), 6.96 (s, 1H); ¹³C-NMR (125 MHz, CDC1₃): δ 22.75, 27.89, 30.17, 46.90, 107.32, 116.76, 120.83, 120.97, 135.93, 138.33; HRMS (ESI): Calcd. for C₁₀H₁₂NOBr₂ [M+H]⁺, 319.9286; found 319.9261; HPLC (OJ-H, elute: Hexanes / z^'-PrOH = 99 / 1, detector: 254 nm, flow rate: 1.0 mL / min), (S) ti = 19.08 min, (R) t₂= 20.45 min.

[28] Optical pure 5,7-Dibromo-l,2,3,4-tetrahydro-2-methylquinolin-8-ol (+)-(2b)/ (-)-(2b) was prepared by preparative HPLC with daicel OJ-H chiral preparative column (elute: Hexanes / z^'-PrOH = 95 / 5, detector: 254 nm, flow rate: 5.0 mL / min), (S) ti = 37.6 min, (R) t₂= 43.8 min.

[29] d) 8-Hydroxy-2-quinolinecarboxaldehyde (4a): 8-Hydroxy-2- methylquinoline la (12.4mmol, 1.97g), selenium dioxide (15.8mmol, 1.74g), 300 ml of pre-dried 1,4-dioxane, and 1.5 ml of water were mixed and stirred in a 1-L round bottom flask. The resulting solution was refluxed for 24 h. The workup procedure can refer to step (b) in order to obtain pure, ¾-NMR (500 MHz, C₆D₆): δ 6.76-6.79 (m, IH), 7.05 (d, IH, / = 4.0 Hz), 7.12 (s, IH), 7.33 (d, IH, / = 9.0 Hz), 7.63 (d, IH, / = 9.0 Hz ), 8.02 (s, IH), 9.79 (s, IH); ¹³C-NMR (125 MHz, C₆D₆): δ 111.81, 118.33, 118.49, 130.98, 131.35, 137.81, 138.54, 150.99, 154.19, 192.58; LRMS (ESI): 174.05 [M+H]⁺; Melting point: 99.7°C

[30] e) l,2,3,4-Tetrahydro-2-(hydroxymethyl)quinolin-8-ol (5b): A mixture of 10 % Pd/C (500 mg), 8-hydroxy-2-quinolinecarboxaldehyde (500 mg, 2.89 mmol), and acetic acid (10 ml) was stirred in an autoclave under 100 bar hydrogen pressure at room temperature for 20 h. The mixture was filtered through a short pad of Celite, which was subsequently washed with MeOH (20 ml). Hydrochloric acid was added, and the solvent was removed under reduced pressure to give the crude product. Purification by a silica gel column eluted with hexane/ E A gave the pure product, ¾-NMR (500 MHz, CDC1₃): δ 1.60-1.67 (m, IH), 1.92-1.98 (m, IH), 2.71-2.80 (m, IH), 2.81-2.87 (m, IH), 3.51-3.54 (m, IH), 3.66-3.69 (m, IH), 6.45-6.54 (m, 3H); ¹³C-NMR (125 MHz, CDC1₃): δ 26.75, 27.59, 55.11, 67.92, 113.52, 119.16, 122.14, 124.57, 134.98, 146.30; HRMS (ESI): Calcd. for C₁₀H_nNO₂Na [M+Na]⁺, 200.0687; found 200.0685.

Synthesis of Alkoxy-Substituted Quinaldine

[31] To a solution of hydroxyl-substituted halogenated or non-halogenated quinoline (3 mmol), alkyl halide (RX, 3 mmol, where X = Br^" or CI) and K₂C0₃ were stirred in 10 mL DMF. The reaction was run at room temperature and monitored by TLC. After the reaction was complete, the mixture was washed with Na₂C0₃ and extracted with EA and then dried over anhydrous sodium sulfate. Then the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography to give the pure product.

[32] 6-Propoxyquinoline (6a)

[33] H-NMR (500 MHz, CDC1₃): 51.03 (t, 3H, / = 7.5 Hz), 1.79-1.86 (m, 2H), 3.96 (t, 2H, / = 6.5 Hz), 6.98 (d, 1H, / = 2.5 Hz), 7.25-7.27 (m, 1H), 7.31-7.34 (m, 1H), 7.94-7.96 (m, 2H), 8.70-8.71 (m, 1H); ¹³C-NMR (125 MHz, CDC1₃): δ 11.12, 23.07, 70.31, 106.37, 121.82, 123.10, 129.89, 131.33, 135.23, 144.92, 148.36, 157.79; Yield = 82.6 %.

[34] 6-Butoxyquinoline (7a)

[35] H-NMR (500 MHz, CDC1₃): δ 0.96 (t, 3H, / = 7.5 Hz), 1.47-1.51 (m, 2H), 1.76- 1.81 (m, 2H), 4.00 (t, 2H, / = 7.0 Hz), 6.99 (d, IH, / = 3.0 Hz), 7.25-7.27 (m, IH), 7.31- 7.34 (m, IH), 7.94-7.97 (m, 2H), 8.70-8.71 (m, IH); ¹³C-NMR (125 MHz, CDC1₃): δ 14.42, 19.85, 31.78, 68.52, 106.35, 121.82, 123.12, 129.90, 131.33, 135.23, 144.93, 148.36, 157.81; Yield = 93.7%.

[36] 8-(2-(Piperidin-l-yl)ethoxy)-2-methylquinoline (8a)

[37] H-NMR (500 MHz, CDC1₃): δ 1.46 (bs, 2H), 1.70 (bs, 4H), 2.71 (bs, 7H), 3.04 (bs, 2H), 4.34 (bs, 2H), 6.99 (d, IH, / = 7.0 Hz), 7.24 (d, IH, / = 9.0 Hz), 7.28-7.33 (m, 2H), 7.95 (d, IH, / = 8.5 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 23.81, 24.88, 25.31, 54.46, 57.31, 64.31, 109.36, 120.26, 122.95, 125.94, 127.98, 136.58, 139.62, 153.83, 158.46; LRMS (ESI): 271.21 [M+H]⁺

[38] 8-(3-nitrobenzyloxy)-2-methylquinoline (9a)

[39] H-NMR (500 MHz, CDC1₃): δ 2.82 (s, 3H), 5.52 (s, 2H), 7.00 (d, IH, / = 7.5 Hz), 7.32 (q, 2H, / = 9.0 Hz), 7.39 (d, IH, / = 8.0 Hz), 7.54 (t, IH, / = 7.5 Hz), 7.89 (d, IH, / = 7.5 Hz), 8.02 (d, 1H, / = 8.5 Hz), 8.16 (d, 1H, / = 8.5 Hz), 8.44 (s, 1H); -NMR (125 MHz, CDC1₃): δ 26.45, 70.59, 111.57, 121.40, 122.60, 123.41, 126.07, 128.52, 130.22, 133.57, 136.78, 140.26, 140.73, 149.11, 154.02, 159.18; HRMS (ESI): Calcd. for

C₁₇H₁₅N₂0₃ [M+H]⁺, 295.1083; found 295.1078; Melting Point = 94.4-95.2°C; Yield = 80.1 %.

[40] 8-(4-nitrobenzyloxy)-2-methylquinoline (10a)

[41] H-NMR (500 MHz, CDC1₃): δ 2.81 (s, 3H), 5.53 (s, 2H), 6.94 (d, 1H, / = 7.5 Hz), 7.26-7.39 (m, 3H), 7.69 (d, 2H, / = 8.5 Hz), 8.02 (d, 1H, / = 8.5 Hz), 8.22 (d, 2H, / = 9.0 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 26.40, 70.34, 111.18, 121.26, 123.38, 124.42, 125.60, 127.89, 128.46, 136.76, 140.56, 145.49, 148.05, 153.82, 159.10; HRMS (ESI): Calcd. for C₁₇H₁₅N₂0₃ [M+H]⁺, 295.1083; found 295.1089; Melting Point = 144.1-145.7°C; Yield = 50 %.

[42] 8-(4-methoxybenzyloxy)-2-methylquinoline (11a)

[43] H-NMR (500 MHz, CDC1₃): δ 2.80 (s, 3H), 3.80 (s, 3H), 5.38 (s, 2H), 6.90 (d, 2H, / = 8.0 Hz), 7.03 (d, 1H, / = 7.0 Hz), 7.26-7.34 (m, 3H), 7.45 (d, 2H, / = 8.5 Hz), 8.00 (d, 1H, / = 8.5 Hz); "C-NMR (125 MHz, CDC1₃): δ 25.95, 55.50, 70.86, 110.71, 114.18, 119.98, 122.75, 125.78, 127.96, 128.89, 129.46, 136.31, 140.32, 154.15, 158.36, 159.45; HRMS (ESI): Calcd. for C₁₈H₁₈N0₂ [M+H]⁺, 280.1338; found 280.1343; Melting Point = 130.8-131.5°C; Yield = 67.3 %.

[44] 8-(3-methoxybenzyloxy)-2-methylquinoline (12a)

[45] H-NMR (500 MHz, CDC1₃): δ 2.81 (s, 3H), 3.79 (s, 3H), 5.44 (s, 2H), 6.84 (d, 1H, / = 8.0 Hz), 7.01 (d, 1H, / = 8.0 Hz), 7.08-7.11 (m, 2H), 7.15-7.38 (m, 4H), 8.01 (d, 1H, / = 8.0 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 26.42, 55.90, 71.43, 111.20, 112.85, 113.99, 119.71, 120.53, 123.21, 126.21, 128.39, 130.25, 136.74, 139.67, 140.73, 154.52, 158.81, 160.53; HRMS (ESI): Calcd. for C₁₈H₁₈N0₂ [M+H]⁺, 280.1338; found 280.1337; Melting Point = 104.1-104.8^°C ; Yield = 86 %.

[46] 4-((2-methylquinolin-8-yloxy)methyl)benzonitrile (13a)

[47] H-NMR (500 MHz, CDC1₃): δ 2.81 (s, 3H), 5.49 (s, 2H), 6.93 (d, 1H, / = 8.0 Hz), 7.28-7.39 (m, 3H), 7.63-7.67 (m, 4H), 8.03 (d, 1H, / = 8.5 Hz); ¹³C-NMR (125 MHz, CDCI3): δ 26.03, 45.01, 70.15, 110.75, 111.72, 119.02, 120.80, 123.00, 125.64, 127.47, 128.08, 132.65, 136.39, 140.20, 143.09, 153.51, 158.71; HRMS (ESI): Calcd. for

C₁₈H₁₅N₂0 [M+H]⁺, 275.1184; found 275.1187; Melting Point = 124.1-125.3°C; Yield = 85.7 %.

[48] 8-(biphenyl-3-ylmethoxy)-2-methylquinoline (14a)

[49] H-NMR (500 MHz, CDC1₃): δ 2.82 (s, 3H), 5.53 (s, 2H), 7.05 (d, 1H, / = 7.5 Hz), 7.26-7.35 (m, 4H), 7.41-7.46 (m, 3H), 7.50-7.54 (m, 2H), 7.59-7.61 (m, 2H), 7.78 (s, 1H), 8.01 (d, 1H, / = 8.0 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 26.01, 71.24, 110.87, 120.18, 122.81, 125.80, 125.92, 126.08, 126.74, 127.46, 127.58, 128.00, 128.96, 129.24, 136.33, 138.12, 141.20, 141.72, 154.15, 158.43; HRMS (ESI): Calcd. for C₂₃H₂₀NO [M+H]⁺, 326.1545; found 326.1557; Melting Point = 89.8-99.4°C ; Yield = 85.7 %.

[50] 8-(4-(trifluoromethoxy)benzyloxy)-2-methylquinoline (15a)

[51] H-NMR (500 MHz, CDC1₃): δ 2.81 (s, 3H), 5.43 (s, 2H), 6.99 (d, 1H, / = 6.5 Hz), 7.22 (d, 2H, / = 7.5 Hz), 7.29-7.37 (m, 3H), 7.56 (d, 2H, / = 9.0 Hz), 8.01 (d, 1H, / = 8.5 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 26.00, 70.28, 110.72, 119.68, 120.43, 121.30, 121.31, 121.72, 122.88, 125.71, 128.02, 128.62, 136.21, 136.34, 140.26, 148.91, 153.84, 158.56; HRMS (ESI): Calcd. for C₁₈H₁₅N0₂F₃ [M+H]⁺, 334.1055; found 334.1056; Melting Point = 103.9-104.6°C; Yield = 73.1 %.

[52] 8-(4-fluorobenzyloxy)-2-methylquinoline (16a)

[53] H-NMR (500 MHz, CDC1₃): δ 2.80 (s, 3H), 5.40 (s, 2H), 6.99 (d, 1H, / = 6.5 Hz), 7.05 (t, 2H, / = 6.5 Hz), 7.28-7.36 (m, 3H), 7.48-7.51 (m, 2H), 8.01 (d, 1H, / = 8.5 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 25.98, 70.47, 110.75, 115.59, 115.76, 120.29, 122.83, 125.72, 128.00, 129.02, 129.09, 133.17, 136.33, 140.28, 153.92, 158.48, 161.61, 163.56; HRMS (ESI): Calcd. for C₁₇H₁₅NOF [M+H]⁺, 268.1138; found 268.1144; Melting Point = 130-130.6°C; Yield = 80.5 %.

[54] 8-(4-(trifluoromethyl)benzyloxy)-2-methylquinoline (17a)

[55] H-NMR (500 MHz, CDC1₃): δ 2.82 (s, 3H), 5.50 (s, 2H), 6.95 (d, 1H, / = 8.0 Hz), 7.26-7.37 (m, 3H), 7.61-7.65 (m, 4H), 8.02 (d, 1H, / = 8.5 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 26.01, 70.30, 110.72, 120.55, 122.55, 125.62, 127.16, 128.05, 130.09, 136.37, 140.23, 141.65, 153.69, 158.62; HRMS (ESI): Calcd. for C₁₈H₁₅NOF₃ [M+H]⁺, 318.1106; found 318.1118; Melting Point = 130.8-131.5^°C; Yield = 82 %.

[56] 8-(4-chlorobenzyloxy)-2-methylquinoline (18a)

[57] H-NMR (500 MHz, CDC1₃): δ 2.80 (s, 3H), 5.41 (s, 2H), 6.96 (d, 1H, / = 6.5 Hz), 7.27-7.36 (m, 5H), 7.45 (d, 2H, / = 8.5 Hz), 8.01 (d, 1H, / = 8.5 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 26.01, 70.35, 110.76, 120.36, 122.86, 125.70, 128.01, 128.52, 128.96, 133.64, 136.01, 136.34, 140.27, 153.82, 158.52; HRMS (ESI): Calcd. for C₁₇H₁₅NOCl [M+H]⁺, 284.0842; found 284.0841; Melting Point = 118.7-119°C; Yield = 90.5 %.

[58] 2-Methylquinolin-8-yl(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-l- yl)methanesulfonate (19a)

[59] H-NMR (500 MHz, CDC1₃): δ 0,95 (s, 3H), 1.19 (s, 3H), 1.41-1.47 (m, 1H), 1.70- 1.76 (m, 1H), 1.95 (d, 1H, / = 18.5 Hz), 2.05-2.13 (m, 2H), 2.39-2.44 (m, 1H), 2.57-2.63 (m, 1H), 2.77 (s, 3H), 3.91 (d, 1H, / = 15.5 Hz), 4.44 (d, 1H, / = 15.0 Hz), 7.35 (d, 1H, / = 8.5 Hz), 7.48 (t, 1H, / = 8.0 Hz), 7.67 (d, 1H, / = 7.5 Hz), 7.73 (d, 1H, / = 8.0 Hz), 8.08 (d, 1H, / = 8.5 Hz); "C-NMR (125 MHz, CDC1₃): δ 19.99, 20.32, 25.42, 25.66, 27.16, 42.75, 43.20, 48.12, 49.71, 58.68, 123.18, 123.92, 125.60, 127.00, 128.37, 136.42, 141.24, 145.50, 160.15, 214.64; HRMS (ESI): 374.1438 [M+H]⁺; Yield = 65%.

[60] l-(4-fluorophenyl)-2-(2-methylquinolin-8-yloxy)ethanone (20a)

[61] H-NMR (500 MHz, CDC1₃): δ 2.77 (s, 3H), 5.56 (s, 2H), 6.97 (d, 1H, / = 7.5 Hz), 7.15 (t, 2H, / = 8.5 Hz), 7.32 (t, 2H, / = 7.5 Hz), 7.39 (d, 1H, / = 8.0 Hz); 8.01 (d, 1H, / = 8.0 Hz), 8.18-8.21 (m, 2H); ¹³C-NMR (125 MHz, CDC1₃): δ 26.17, 72.88, 105.32, 111.38, 116.51, 121.49, 123.24, 125.94, 128.44, 131.77, 136.67, 140.37, 153.77, 158.88, 165.64, 167.68, 193.97; HRMS (ESI): Calcd. for C₁₈H₁₅N0₂F [M+H]⁺, 296.1087; found 296.1090; Yield = 77.7%.

[62] 5,7-Dibromo-8-ethoxy-2-methylquinoline (21a)

[63] H-NMR (500 MHz, CDC1₃): δ 1.53 (t, 3H, / = 7.0 Hz), 2.77 (s, 3H), 4.45 (q, 2H, / = 7.0 Hz), 7.36 (d, 1H, / = 8.5 Hz), 7.88 (s, 1H), 8.30 (d, 1H, / = 8.5 Hz); ¹³C-NMR (125 MHz, CDCI3): δ 16.45, 26.13, 71.74, 116.44, 117.24, 123.93, 126.97, 133.12, 136.54, 144.09, 152.99, 160.44; HRMS (ESI): Calcd. for C₁₂H₁₂NOBr₂ [M+H]⁺, 343.9286; found 343.9288; Yield = 83.5%.

[64] 2-(5,7-dibromo-2-methylquinolin-8-yloxy)-l-phenylethanone (22a)

[65] H-NMR (500 MHz, CDC1₃): δ 2.54 (s, 3H), 5.79 (s, 2H), 7.30 (d, 1H, / = 9.0 Hz), 7.48 (t, 2H, / = 8.0 Hz), 7.58 (t, 1H, / = 7.0 Hz), 7.89 (s, 1H), 8.13 (d, 2H, / = 8.0 Hz), 8.27 (d, 1H, / = 9.0 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 25.53, 77.05, 115.78, 116.17, 123.94, 126.88, 129.04, 129.30, 133.22, 134.08, 135.67, 136.65, 142.63, 151.55, 159.92, 195.12; HRMS (ESI): Calcd. for C₁₈H₁₄N0₂Br₂ [M+H]⁺, 433.9391; found 433.9398; Yield = 87.7%.

Synthesis of 2,8-Bis(benzyloxy)quinoline and l-Benzyl-8-(benzyloxy)quinolin- 2(lH)-one

[66] 2,8-Bis(benzyloxy)quinoline (23a)

[67] H-NMR (500 MHz, CDC1₃): δ 5.26 (s, 2H), 5.51 (s, 2H), 6.90 (d, IH, / = 9.0 Hz), 7.04 (d, IH, / = 8.0 Hz), 7.16-7.20 (m, IH), 7.22-7.32 (m, 7H), 7.48 (q, 4H, / = 8.0 Hz), 7.89 (d, IH, / = 9.0 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 67.96, 71.60, 112.65, 113.70, 120.58, 124.21, 126.69, 127.52, 127.99, 128.09, 128.63, 128.72, 128.90, 137.66, 137.77, 138.68, 139.19, 153.56, 161.35; LRMS (ESI): 342.07 [M+H]⁺ ; Yield = 53.4%.

[68] l-Benzyl-8-(benzyloxy)quinolin-2(lH)-one (24a)

[69] H-NMR (500 MHz, CDC1₃): δ 4.88 (s, 2H), 5.94 (s, 2H), 6.79 (d, IH, / = 9.0 Hz), 6.90 (d, 2H, / = 7.5 Hz), 7.02 (d, IH, / = 8.0 Hz), 7.06-7.19 (m, 7H), 7.26-7.31 (m, 3H), 7.69 (d, IH, / = 7.5 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 49.70, 72.05, 115.22, 122.15, 122,33, 123.07, 123.52, 125.85, 126.28, 127.82, 128.37, 128.42, 128.83, 130.95, 136.14, 139.37, 140.14, 147.49, 163.80; LRMS (ESI): 342.07 [M+H]⁺ ; Yield = 31.4%.

Synthesis of l-Acetyl-2-methyl-l,2,3,4-tetrahydroquinolin-8-yl acetate and 2- Methyl-l,2,3,4-tetrahydroquinolin-8-yl acetate

[70] Add slowly 100 mg (0.6mmol) of l,2,3,4-tetrahydro-2-methylquinolin-8-ol into a preheated solution of ZnCl₂ (4%) (0.5g anhydrous ZnCl₂ inl2.5 ml acetic anhydride) in a 50 ml round flask bottom which was attached with an air condenser. Then the mixture was heated on a water bath for another one hour. After the reaction was completed, cool the solution with cold water, and then pour into ice water (10 ml) and stir vigorously to assist the hydrolysis of unreacted acetic anhydride. Then the product was extracted with EA and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography to give the pure product.

[71] 2-Methyl-l,2,3,4-tetrahydroquinolin-8-yl acetate (25b)

[72] H-NMR (500 MHz, CDCL): δ 2.50 (s, 3H), 2.73 (s, 3H), 7.30 (d, 1H, / = 9.0 Hz), 7.40 (d, 1H, / = 7.5 Hz), 7.46 (t, 1H, / = 8.0 Hz), 7.67 (d, 1H, / = 8.5 Hz), 8.05(d, 1H, / = 9.0 Hz); ¹³C-NMR (125 MHz, CDCL): δ 21.23, 25.96, 31.15, 121.54, 122.89, 125.43, 125.80, 128.01, 136.22, 140.89, 147.24, 159.64, 170.21; LRMS (ESI): 202.09 [M+H]⁺ ; Yield = 91.1%.

[73] l-Acetyl-2-methyl-l,2,3,4-tetrahydroquinolin-8-yl acetate (26b)

[74] H-NMR (500 MHz, CDC1₃): δ 1.05 (d, 3H, / = 6.5 Hz), 1.20-1.26 (m, 1H), 2.01(s, 3H), 2.27 (s, 3H), 2.37-2.45 (m, 2H), 2.59-2.62 (m, 1H), 4.81 (q, 1H, / = 7.5 Hz), 7.02 (d, 1H, / = 8.5 Hz), 7.10 (d, 1H, / = 7.5 Hz), 7.21 (t, 1H, / = 8.0 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 20.96, 21.40, 22.19, 27.28, 33.63, 49.52, 121.59, 124.99, 126.99, 131.13, 139.60, 145.68, 168.93, 170.93; LRMS (ESI): 270.10 [M+Na]⁺

[75] Synthesis of 8-Benzyloxy Substituted Quinoline

[76] To a solution of 8-(Benzyloxy)-2-methylquinoline (3 mmol, 790 mg) in 15 mL ether was added a 1.6M solution of n-butyllithium in hexane (3.5 mmol, 2.2 mL) at 0 °C over 30 minutes. This solution was allowed to warm to room temperature and stirred for 1 h. The above mixture, a solution of BnBr (3 mmol) in 15 mL ether was added dropwise over 15 minutes with vigorous stirring while the temperature was cooled to 0 °C. The mixture was then stirred overnight and hydrolysed with a saturated aqueous ammonium chloride solution. The organic layer was separated and the aqueous layer was further extracted with ether (3 x 50 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography to give the pure product.

[77] 8-(Benzyloxy)-2-ethylquinoline (27a)

[78] H-NMR (500 MHz, CDC1₃): δ 1.43 (t, 3H, / = 7.5 Hz), 3.10 (q, 2H, / = 7.5 Hz), 5.47(s, 2H), 7.02 (d, 1H, / = 7.5 Hz), 7.30 (t, 2H, / = 7.5 Hz), 7.36 (t, 4H, / = 8.0 Hz), 7.54 (d, 2H, / = 7.5 Hz), 8.04 (d, 1H, / = 8.5 Hz); ¹³C-NMR (125 MHz, CDC1₃): 514.32, 32.62, 71.17, 110.97, 120.18, 121.49, 125.79, 127.18, 127.87, 128.24, 128.76, 136.47, 137.59, 140.32, 154.25, 163.34; LRMS (ESI): 264.10 [M+H]⁺.

[79] 8-(Benzyloxy)-2-phenethylquinoline (28a)

[80] H-NMR (500 MHz, CDC1₃): δ 3.22 (t, 2H, / = 7.0 Hz), 3.19 (t, 2H, / = 7.5 Hz), 5.47(s, 2H), 7.06 (d, 1H, / = 7.5 Hz), 7.30 (t, 2H, / = 7.5 Hz), 7.36 (t, 4H, / = 8.0 Hz), 7.56 (d, 2H, / = 7.5 Hz), 8.02 (d, 1H, / = 8.5 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 35.99, 41.03, 71.29, 111.22, 120.27, 122.22, 125.96, 126.16, 127.21, 127.90, 128.33, 128.59, 128.76, 128.83, 136.37, 137.59, 140.49, 141.98, 154.30, 161.05; HRMS (ESI):340.17 [M+H]⁺; Yield = 47.8%. Synthesis of Alcohol Protected Quinoline

[81] To a stirred solution of 5,7-dibromo-8-hydroxyquinoline-2-carbaldehyde (200mg, 0.60 mmol) in dry MeOH (20 ml), hydrochloride gas was bubbled at room temperature, after complete reaction the result mixture was stirring for overnight. Then MeOH was removed under reduced pressure to give the designed product 5,7- Dibromo-2-(dimethoxymethyl)quinolin-8-ol (29a) ¾-NMR (500 MHz, CD₃OD): δ 3.20 (s, 6H), 5.64 (s, 1H), 7.83 (d, 1H, / = 8.5 Hz), 7.91 (s, 1H), 8.63 (d, 1H, / = 9.0 Hz); ¹³C-NMR (125 MHz, CD₃OD): δ 103.68, 110.12, 112.02, 123.21, 129.38, 137.27, 137.56, 142.59, 151.35, 158.59; HRMS (ESI): Calcd. for C₁₂H₁₂NO₃Br₂ [M+H]⁺, 375.9197; found 375.9184 ; Yield = 88.2%.

Asymmetric Synthesis of 1,2,3,4-Tetrahydroquinoline

[82] L* = Chiral P-Phos and its derivatives, C₂-symmetric bidendate chiral diphosphines ligands or any other possible ligands; M = Any metal or non-metal complex. [83] A mixture of metal for example of [Ir(COD)Cl]₂ (1.0 mg, 0.0015 mmol) and the ligand (0.003 mmol) in dried solvent (1.0 mL) was stirred at room temperature for 30 minutes in a glovebox. The mixture was then transferred by a syringe to stainless steel autoclave, in which I₂ (4 mg, 0.015 mmol) and substrate (0.3 mmol) in 0.5 mL dried solvent were placed beforehand. The hydrogenation was performed at room temperature under H₂ for 20 h. After carefully releasing the hydrogen, the reaction mixture was quenched with saturated sodium carbonate solution (2.0 mL) for 15 minutes. The aqueous layer was extracted with EtOAc (3 x 3 mL). The combined organic layer was dried with sodium sulfate and concentrated in vacuo to give the crude product. Purification by a silica gel column eluted with hexane/ EtOAc gave the heterocyclic compound in pure state. The enantiomeric excesses (ee) were determined by chiral HPLC with chiral column (OJ-H, OD-H or OJ) [21].

[84] 8-(2-(Piperidin-l-yl)ethoxy)-l,2,3,4-tetrahydro-2-methylquinoline (8b)

[85] H-NMR (500 MHz, CDC13): δ 0.1 (s, 2H), 1.18 (d, 6H, J = 6.5 Hz), 2.11 (s, 4H), 2.53 (bs, 3H), 2.64-2.69 (m, 2H), 2.72-2.81 (m, 3H), 3.30-3.34 (m, 1H), 4.08 (bs, 2H), 6.46 (t, 1H, J = 8.0 Hz), 6.56 (t, 2H, J = 8.5 Hz); ¹³C-NMR (125 MHz, CDCL): δ 22.84, 24.20, 25.82, 26.60, 26.73, 30.26, 46.89, 55.03, 58.05, 66.03, 70.84, 109.38, 115.89, 121.57, 122.11, 135.24, 145,28; LRMS (ESI): 275.21 [M+H]⁺; 47% ee; HPLC (OD-H, elute: Hexanes / i- PrOH = 90 / 10, detector: 254 nm, flow rate: 1.0 mL / min), (S) tj = 8.3 min, (R) t₂= 7.1 mm.

[86] 8-(Benzyloxy)-l,2,3,4-tetrahydro-2-methylquinoline (30b)

[87] H-NMR (500 MHz, CDC1₃): δ 1.25 (d, 3H, / = 6.5 Hz), 1.62-1.68 (m, IH), 1.93- 1.98 (m, IH), 2.75-2.80 (m, IH), 2.85-2.89 (m, IH), 3.39-3.43 (m, IH), 4.21 (bs, IH), 5.08 (q, 2H, / = 6 Hz), 6.56 (t, IH, / = 8.0 Hz), 6.68 ( q, 2H, / = 8.0 Hz), 7.35(t, IH, / = 7.0 Hz), 7.42 (t, 2H, / = 8.0 Hz), 7.46 ( d, 2H, / = 7.0 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 23.25, 27.04, 30.70, 47.34, 71.04, 109.63, 116.31, 121.96, 122.50, 128.29, 128.57, 129.20, 135.47, 138.06, 145.88; HRMS (ESI): Calcd. for C₁₇H₂₀NO [M+H]⁺, 254.1545; found 254.1542;

[a = +321 (c 0.0048, CHC1₃), 93% ee; HPLC (OD-H, elute: Hexanes / z-PrOH = 90 / 10, detector: 254 nm, flow rate: l.Oml/min), ti = 5.4 min (minor), (R) t₂= 6.7 min (major).

[88] 8-(3-Nitrobenzyloxy)-l,2,3,4-tetrahydro-2-methylquinoline (9b)

[89] Ή-NMR (500 MHz, CDC1₃): δ 1.28 (d, 3H, / = 6.5 Hz), 1.61-1.68 (m, IH), 1.95- 2.00 (m, IH), 2.76-2.81 (m, IH), 2.85-2.92 (m, IH), 3.42-3.48 (m, IH), 4.17 (br, IH), 5.16 (q, 2H, / = 13 Hz), 6.56 (t, IH, / = 7.5 Hz), 6.65 ( d, 2H, / = 8.0 Hz), 6.70 (d, IH, / = 7.5 Hz), 7.58 (t, IH, / = 8.0 Hz), 7.78 (d, IH, / = 7.5 Hz), 8.20 (d, IH, / = 8.0 Hz), 8.32 (s, IH); ¹³C-NMR (125 MHz, CDC1₃): δ 23.18, 26.97, 30.51, 47.31, 69.70,109.66, 116.28, 122.27, 122.84, 122.99, 123.47, 130.17, 133.92, 135.37, 140.15, 145.15, 148,99; HRMS

(ESI): Calcd. for C₁₇H₁₉N₂0₃ [M+H]⁺, 299.1396; found 299.1405; [a = +33 (c 0.003, CHC1₃), 93% ee; HPLC (AD-H, elute: Hexanes / z^'-PrOH = 99 / 1, detector: 254 nm, flow rate: 1.0 mL / min), ti = 14.0 min (minor), t₂= 15.5 min (major).

[90] 8-(4-Nitrobenzyloxy)-l,2,3,4-tetrahydro-2-methylquinoline (10b)

[91] H-NMR (500 MHz, CDC1₃): δ 1.29 (d, 3H, / = 6.5 Hz), 1.62-1.69 (m, IH), 1.96- 2.01 (m, IH), 2.76-2.81 (m, IH), 2.86-2.93 (m, IH), 3.43-3.47 (m, IH), 4.16 (br, IH), 5.18 (q, 2H, / = 13 Hz), 6.55 (t, IH, / = 7.5 Hz), 6.61 ( d, 2H, / = 7.5 Hz), 6.70 (d, IH, / = 7.5 Hz), 7.60 (d, 2H, / = 8.5 Hz), 8.24 (d, 2H, / = 8.5 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 23.18, 26.95, 30.50, 47.32, 69.60, 109.54, 116.30, 122.29, 122.97, 124.37, 128.27, 135.31, 145.08, 145.44, 148.08; HRMS (ESI): Calcd. for C₁₇H₁₉N₂0₃ [M+H]⁺, 299.1396; found

299.1405; [a = +76 (c 0.0032, CHC1₃), 90% ee; HPLC (AD-H, elute: Hexanes / i- PrOH = 90 / 10, detector: 254 nm, flow rate: 1.0 mL / min), ti = 9.5 min (minor), t₂ = 11.6 min (major).

[92] 8-(4-Methoxybenzyloxy)-l,2,3,4-tetrahydro-2-methylquinoline (1 lb)

[93] H-NMR (500 MHz, CDC1₃): δ 1.28 (d, 3H, / = 6.0 Hz), 1.64-1.72 (m, IH), 1.96- 2.01 (m, IH), 2.79-2.84 (m, IH), 2.89-2.95 (m, IH), 3.41-3.46 (m, IH), 3.87 (s, IH), 4.23 (br, IH), 5.03 (q, 2H, / = 11 Hz), 6.52 (t, IH, / = 8.0 Hz), 6.71 (d, IH, / = 7.5 Hz), 6.75 (d, IH, / = 8.0 Hz), 6.98 (d, 2H, / = 9.0 Hz), 7.42 (d, 2H, / = 8.5 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 23.18, 26.98, 30.65, 47.25, 55.86, 70.71, 109.54, 114.51, 116.25, 121.80, 122.34, 129.99, 130.01, 135.38, 145.88, 160.02; HRMS (ESI): Calcd. for

[M+H]⁺,

284.1651; found 284.1657; [a = +277 (c 0.0033, CHC1₃) , 92% ee; HPLC (OD-H, elute: Hexanes / z-PrOH = 90 / 10, detector: 254 ran, flow rate: 1.0 mL / min), ti = 6.6 min (minor), t₂= 9.2 min (major).

[94] 8-(3-Methoxybenzyloxy)-l,2,3,4-tetrahydro-2-methylquinoline (12b)

[95] H-NMR (500 MHz, CDC1₃): δ 1.26 (d, 3H, / = 6.5 Hz), 1.61-1.69 (m, IH), 1.93- 1.98 (m, IH), 2.75-2.80 (m, IH), 2.85-2.92 (m, IH), 3.40-3.44 (m, IH), 3.84 (s, IH), 4.22 (br, IH), 5.05 (q, 2H, / = 11.5 Hz), 6.56 (t, IH, / = 8.0 Hz), 6.68 (t, 2H, / = 8.5 Hz), 6.90 (d, IH, / = 7.5 Hz), 7.03 (t, 2H, / = 8.0 Hz), 7.33 (t, IH, / = 8.5 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 23.26, 27.03, 30.69, 47.32, 55.90, 70.96, 109.66, 113.71, 114.07, 116.31, 120.47, 121.95, 122.52, 130.24, 135.46, 139.66, 145.83, 160.44; HRMS (ESI): Calcd. for

C₁₈H22N0₂, 284.1651; found 284.1657 [M+H]⁺; [a = +543 (c 0.0028, CHC1₃) , 95% ee; HPLC (OD-H, elute: Hexanes / z^'-PrOH = 90 / 10, detector: 254 nm, flow rate: 1.0 mL / min), ti = 6.5 min (minor), t₂= 8.1 min (major).

[96] 4-((l,2,3,4-Tetrahydro-2-methylquinolin-8-yloxy)methyl)benzonitrile (13b)

[97] H-NMR (500 MHz, CDC1₃): δ 1.28 (d, 3H, / = 6.5 Hz), 1.61-1.69 (m, IH), 1.96- 2.00 (m, IH), 2.76-2.81 (m, IH), 2.86-2.92 (m, IH), 3.42-3.46 (m, IH), 4.20 (br, IH), 5.14 (q, 2H, / = 13.5 Hz), 6.55 (t, IH, / = 8.0 Hz), 6.61 ( d, 2H, / = 8.0 Hz), 6.70 (d, IH, / = 7.5 Hz), 7.55 (d, 2H, / = 8.0 Hz), 7.68 (d, 2H, / = 8.0 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 23.16, 26.90, 30.47, 47.25, 69.80,109.50, 112.15, 116.24, 119.28, 122.17, 122.86, 128,20, 132.92, 135,26, 143.38, 145.09; HRMS (ESI): Calcd. for C₁₈H₁₉N₂0 [M+H]⁺, 279.1497; found 279.1510; [a = +294 (c 0.0012, CHC1₃) , 93% ee; HPLC (OD-H, elute: Hexanes / z^'-PrOH = 90 / 10, detector: 254 nm, flow rate: 1.0 mL / min), ti = 12.2 min (minor), t₂ = 20.5 min (major). [98] 8-(Biphenyl-3-ylmethoxy)-2-methyl-l,2,3,4-tetrahydroquinoline (14b)

[99] H-NMR (500 MHz, CDC1₃): 51.30 (d, 3H, / = 6.0 Hz), 1.66-1.74 (m, IH), 1.98- 2.03 (m, IH), 2.81-2.86 (m, IH), 2.91-2.98 (m, IH), 3.44-3.50 (m, IH), 4.30 (br, IH), 5.18 (q, 2H, / = 11.5 Hz), 6.64 (t, IH, / = 8.0 Hz), 6.74 ( d, IH, / = 7.5 Hz), 6.79 (d, IH, / = 8.5 Hz), 7.43 (t, IH, / = 8.0 Hz), 7.48-7.55 (m, 4H), 7.64 (d, IH, / = 7.5 Hz), 7.69 (d, 2H, / = 7.0 Hz), 7.75 (s, IH); ¹³C-NMR (125 MHz, CDC1₃): δ 23.22, 27.02, 30.66, 47.30, 71.12, 109.74, 116.34, 121.94, 122.56, 127.08, 127.21, 127.36, 127.81, 128.06, 129.43, 129.64, 135.46, 138.56, 141.50, 142.12, 145.87; HRMS (ESI): Calcd. for C₂₃H₂₄NO [M+H]⁺,

330.1858; found 330.1874; [a = +131 (c 0.009, CHC1₃) , 94% ee; HPLC (OD-H, elute: Hexanes / z-PrOH = 90 / 10, detector: 254 ran, flow rate: 1.0 mL / min), tj = 7.1 min (minor), t₂= 8.5 min (major).

[100] 8-(4-(Trifluoromethoxy)benzyloxy)-l,2,3,4-tetrahydro-2-methylquinoline (15b)

[101] H-NMR (500 MHz, CDC1₃): δ 1.29 (d, 3H, / = 6.0 Hz), 1.64-1.72 (m, IH), 1.97- 2.02 (m, IH), 2.79-2.84 (m, IH), 2.89-2.95 (m, IH), 3.42-3.48 (m, IH), 4.22 (br, IH), 5.09 (q, 2H, / = 12.0 Hz), 6.60 (t, IH, / = 7.5 Hz), 6.71 ( t, 2H, / = 8.5 Hz), 7.29 (d, 2H, / = 7.5 Hz), 7.50 (d, 2H, / = 9.0 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 23.19, 27.01, 30.62, 47.35, 70.10, 109.61, 116.34, 121.70, 122.12, 122.17, 122.74, 129.60, 135.41, 136.75, 145.57,

149.49; HRMS (ESI): Calcd. for C₁₈H₁₉N0₂F₃ [M+H]⁺, 338.1368; found 338.1367; [a }²° = +30 (c 0.0039, CHC1₃), 94% ee; HPLC (OD-H, elute: Hexanes / z-PrOH = 90 / 10, detector: 254 ran, flow rate: 1.0 mL / min), ti = 5.0 min (minor), t₂= 6.8 min (major).

[102] 8-(4-Fluorobenzyloxy)-l,2,3,4-tetrahydro-2-methylquinoline (16b)

[103] H-NMR (500 MHz, CDC1₃): δ 1.28 (d, 3H, / = 6.0 Hz), 1.63-1.71 (m, IH), 1.96- 2.01 (m, IH), 2.78-2.84 (m, IH), 2.88-2.95 (m, IH), 3.41-3.48 (m, IH), 4.22 (br, IH), 5.06 (q, 2H, / = 11.5 Hz), 6.60 (t, IH, / = 7.5 Hz), 6.71 (d, 2H, / = 8.0 Hz), 7.12 (t, 2H, / = 8.5 Hz), 7.45 (t, 2H, / = 8.0 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 23.19, 26.99, 30.62, 47.31, 70.29, 109.57, 116.13, 122.01, 122.59, 130.06, 130.13, 133.72, 133.75, 135.37, 145.66, 162.13, 164.09; HRMS (ESI): Calcd. for C₁₇H₁₉NOF [M+H]⁺, 272.1451; found 272.1458;

[a = +74 (c 0.0042, CHC1₃), 94% ee; HPLC (OD-H, elute: Hexanes / z-PrOH = 90 / 10, detector: 254 nm, flow rate: 1.0 mL / min), ti = 5.4 min (minor), t₂= 7.1 min (major).

[104] 8-(4-(Trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro-2-methylquinoline (17b)

[105] Ή-NMR (500 MHz, CDC1₃): δ 1.30 (d, 3H, / = 6.0 Hz), 1.64-1.72 (m, IH), 1.97- 2.02 (m, IH), 2.79-2.84 (m, IH), 2.88-2.95 (m, IH), 3.44-3.48 (m, IH), 4.23 (br, IH), 5.16 (q, 2H, / = 12.5 Hz), 6.59 (t, IH, / = 8.0 Hz), 6.67 (d, IH, / = 8.0 Hz), 6.72 (d, IH, / = 7.5 Hz), 7.58 (d, 2H, / = 8.0 Hz), 7.69 (d, 2H, / = 8.5 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 23.22, 27.02, 30.61, 47.37, 70.11, 109.58, 116.35, 122.20, 122.83, 126.16, 128.14, 130.70, 135.39, 142.11, 145.44; HRMS (ESI): Calcd. for C₁₈H₁₉NOF₃ [M+H]⁺, 322.1419; found

322.1417; [a = +60 (c 0.002, CHC1₃), 95% ee; HPLC (OD-H, elute: Hexanes / z-PrOH = 90 / 10, detector: 254 ran, flow rate: 1.0 mL / min), ti = 5.4 min (minor), t₂= 7.7 min

(mojor).

[106] 8-(4-Chlorobenzyloxy)-l,2,3,4-tetrahydro-2-methylquinoline (18b)

[107] H-NMR (500 MHz, CDC1₃): δ 1.27 (d, 3H, / = 6.5 Hz), 1.61-1.69 (m, IH), 1.94- 1.99 (m, IH), 2.76-2.81 (m, IH), 2.86-2.93 (m, IH), 3.39-3.46 (m, IH), 4.18 (br, IH), 5.04 (q, 2H, / = 12.0 Hz), 6.57 (t, IH, / = 7.5 Hz), 6.68 (dd, 2H, / = 8.0 Hz), 7.39 (s, 4H); ¹³C- NMR (125 MHz, CDC1₃): δ 23.24, 27.01, 30.63, 47.33, 70.21, 109.58, 116.31, 122.07, 122.66, 129.36, 129.58, 134.34, 135.39, 136.50, 145.57; HRMS (ESI): Calcd. for C₁₇H₁₉NOCl [M+H]⁺, 288.1155; found 288.1161; [a = +254 (c 0.0024, CHC1₃), 95% ee; HPLC (OD-H, elute: Hexanes / z^'-PrOH = 90 / 10, detector: 254 nm, flow rate: 1.0 mL / min), ti = 5.5 min (minor), (t₂= 7.4 min (major).

[108] 8-(Benzyloxy)-l,2,3,4-tetrahydro-2-phenethylquinoline (28b)

[109] H-NMR (500 MHz, CDC1₃): δ 1.74-1.78 (m, 1H), 1.79-1.97 (m, 2H), 2.06-2.11 (m, 1H), 2.78-2.94 (m, 4H), 3.33-3.38 (m, 1H), 4.41 (ds, 1H), 5.13 (q, 2H, / = 6.0 Hz), 6.62 (t, 1H, / = 8.0 Hz), 6.74 (dd, 2H, / = 8.0 Hz), 7.23-7.27 (m, 3H), 7.34 (t, 2H, / = 7.5 Hz), 7.39 (t, 1H, / = 7.0 Hz), 7.46 (t, 2H, / = 7.0 Hz), 7.51 (d, 2H, / = 7.0 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 26.59, 28.43, 32.77, 38.79, 51.05, 71.06, 109.80, 116.32, 122.05, 122.48, 126.54, 128.13, 128.54, 129.01, 129.08, 129.20, 135.25, 138.10, 142.52, 145.93; HRMS (ESI): Calcd. for C₂₄H₂₆NO[M+H]⁺, 344.2014; found 344.2029; HPLC (OD-H, elute: Hexanes / z^'-PrOH = 90/10, detector: 254 nm, flow rate: 1.0 mL / min), ti = 8.15 min, t₂= 11.38 min.

[110] 2-(3,4-Dimethoxyphenethyl)-l,2,3,4-tetrahydroquinoline (31b)

[111] H-NMR (500 MHz, CDC1₃): δ 1.67-1.75 (m, 1H), 1.82-1.87 (m, 2H), 2.00-2.05 (m, IH), 2.71-2.79 (m, 2H), 2.80-2.88 (m, 2H), 3.31-3.36 (m, IH), 3.90 (d, 6H, / = 8.0 Hz), 6.48 (d, IH, / = 7.5 Hz), 6.64 (t, IH, / = 7.5 Hz), 6.78 (d, 2H, / = 8.5 Hz), 6.84 (d, IH, / = 8.5 Hz), 6.99 (t, 2H, / = 7.0 Hz); ¹³C-NMR (125 MHz, CDC1₃): δ 26.79, 28.59, 32.40, 38.99, 51.79, 56.44, 56.54, 111.97, 112.28, 114.72, 117.59, 120.73, 121.84, 127.31, 129.82, 135.08, 145.11, 147.91, 149.56; HRMS (ESI): Calcd. for C₁₉H₂₄N0₂[M+H]⁺, 298.1807; found 298.1808.

[112] 5,7-dibromo-2-methyl-8-(4-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydroquinoline (32b)

[113] H-NMR (500 MHz, CDC1₃): δ 1.13 (d, 3H, / = 6.0 Hz), 1.46-1.54 (m, IH), 1.93- 1.97 (m, IH), 2.57-2.64 (m, IH), 2.78-2.83 (m, IH), 3.22-3.26 (m, IH), 4.20 (bs, IH), 4.98 (q, 2H, / = 11 Hz), 7.06 (s, IH), 7.61 (d, 2H, / = 8.0 Hz), 7.67 (d, 2H, / = 8.5 Hz); ¹³C- NMR (125 MHz, CDC1₃): δ 22.62, 27.91, 29.94, 46.80, 73.62, 114.77, 121.42, 121.49, 122.64, 126.17, 126.20, 126.23, 126.26, 128.97, 131.07, 141.19, 141.51, 141.55; HRMS (ESI): Calcd. for C₁₈H₁₇NOF₃Br₂[M+H]⁺, 477.9629; found 477.9651; HPLC (OD-H, elute: Hexanes / z-PrOH = 90 / 10, detector: 254 ran, flow rate: 1.0 mL / min), (S) ti = 3.99 min, (R) t₂= 4.89 min. [114] 5,7-dibromo-2-methyl-8-(4-(trifluoromethoxy)benzyloxy)-l,2,3,4- tetrahydroquinoline (33b)

[115] H-NMR (500 MHz, CDC1₃): δ 1.13 (d, 3H, / = 6.0 Hz), 1.45-1.53 (m, IH), 1.92- 1.96 (m, IH), 2.56-2.63 (m, IH), 2.78-2.83 (m, IH), 3.19-3.24 (m, IH), 4.20 (bs, IH), 4.92 (q, 2H, / = 11 Hz), 7.05 (s, IH), 7.26 (d, 2H, / = 8.0 Hz), 7.52 (d, 2H, / = 8.5 Hz); ¹³C- NMR (125 MHz, CDC1₃): δ 22.58, 27.92, 29.95, 46.77, 73.69, 114.80, 120.10, 121.32, 121.39, 121.78, 122.15, 122.58, 130.56, 136.28, 141.19, 141.61, 149.91; HRMS (ESI): Calcd. for C₁₈H₁₇N0₂F₃Br₂[M+H]⁺, 493.9578; found 493.9572; HPLC (OD-H, elute: Hexanes / z^'-PrOH = 90 / 10, detector: 254 nm, flow rate: 1.0 mL / min), (S) tj = 3.83 min, (R) t₂= 4.54 min.

Synthesis of quinoline dimer

[116] A mixture of 2-methylquinolin-8-ol (2.4 g, 15 mmol) and dihaioalkyi (5 mmol) in ACN was added K₂C0₃ (2.28 g, 16.5 mmol) and refluxed overnight. Then the ACN was removed and hydrolysed with water. The organic product was extracted with EA (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography to give the pure product.

[117] l,6-bis(2-methylquinolin-8-yloxy)hexane (34a)

[118] H-NMR (500 MHz, CDCL): δ 1.52-1.55 (m, 4H), 1.94-1.97 (m, 4H), 2.64 (s, 6H), 4.13 (t, 4H, / = 7.0 Hz), 6.90 (d, 2H, / = 7.5 Hz), 7.14 (d, 2H, / = 8.5 Hz), 7.18 (d, 2H, / = 8.0 Hz), 7.23 (t, 2H, / = 8.0 Hz), 7.84 (d, 2H, / = 8.5 Hz); ¹³C-NMR (100 MHz, CDCL): δ 26.29, 26.51, 29.44, 69.52, 109.66, 119.88, 122.96, 126.22, 128.26, 136.56, 140.53, 154.89, 158.55; Yield = 41.8 %.

[119] Synthesis of soluble salts of quinoline compounds

[120] To a stirred solution of quinolines or tetrahydroquinolines (0.57 mmol) in dichloromethane (20 ml), hydrochloride gas was bubbled at room temperature. The precipitate was collected by filtration to give the designed product.

[121] H-NMR (500 MHz, DMSO): δ 3.73 (s, IH), 7.27 (d, IH, / = 7.5 Hz), 7.55 (d, IH, / = 8.5 Hz), 7.66 (t, IH, / =8.0 Hz), 8.00 (d, IH, / = 8.5 Hz), 8.55 (d, IH, / = 8.0 Hz), 10.19 (s, IH); ¹³C-NMR (125 MHz, DMSO): δ 113.49, 117.89, 118.55, 131.33, 131.46, 138.40, 138.91, 151.03, 155.15, 194.13; yield = 96.5%; Melting point: 185°C

[122] IH NMR (500 MHz, DMSO) : δ 1.46 (d, 3H, / = 6.5), 1.78-1.86 (m, IH), 2.03-2.06 (m, IH), 2.78-2.90 (m, 2H), 3.41-3.46 (m, IH), 6.73 (d, IH, / = 7.5), 7.00 (d, IH, / = 8.0), 7.16 (t, IH, / = 8.0), 10.59 (s, IH) , 11.06 (s, IH); ¹³C-NMR (125 MHz, DMSO): δ 18.97, 25.92, 27.43, 51.52, 114.45, 120.11, 120.94, 129.60, 133.43, 152.07; yield = 92.8%; Melting point: 252.6 ^°C .

[123] Ή NMR (500 MHz, DMSO) : δ 1.34 (d, 3H, / = 5.0), 1.63-1.71 (m, 1H), 1.98-2.03 (m, 1H), 2.59-2.66 (m, 1H), 2.69-2.74 (m, 1H), 3.37-3.41 (m, 1H), 6.42 (bs, 4H), 7.41 (s, 1H); ¹³C-NMR (125 MHz, DMSO): δ 20.52, 27.93, 28.30, 49.23, 110.22, 115.93, 126.81, 128.86, 131.33, 145.05.

[124] Lung carcinoma cell line (A549) and hepatocellular carcinoma (HCC) cell line (Hep3B) were obtained from American Type of Culture Collection (ATCC).

Esophageal squamous cell carcinoma cell line KYSE150 was purchased from DSMZ (Braunschweig, Germany) [13]. Esophageal squamous cell carcinoma (ESCC) cell line HKESC1 was kindly provided by Professor Gopesh Srivastava of the

Department of Pathology, The University of Hong Kong [14]. ESCC cell line HKESC- 4 was kindly provided by Professor Simon Law of the Department of Surgery, The University of Hong Kong [15]. Hep3B HCC and A549 lung carcinoma cell lines were maintained in DMEM and F12-K medium respectively with 10% of heat inactivated fetal bovine serum (Hy clone) together with antibiotics involving penicillin and streptomycin. All the ESCC cell lines (KYSE150, HKESC-1 and HKESC-4) were maintained in MEM supplemented with 10% of heat inactivated fetal bovine serum together with antibiotics involving penicillin and streptomycin. Cells were allowed to grow in a humidified cell culture incubator keeping at 5% carbon dioxide.

In Vitro Cytotoxicity against Cancer Cell Lines

[125] Human liver cancer cell line Hep3B was used for purpose of preliminary anticancer screening for the selected alkaloids. Cancer cells (lxl0⁴per well) seeded in the 96 wells microtitre plates for 24 hours were prepared for the alkaloid screening. The selected compounds were prepared as a stock concentration of 50mg/ml in

dimethylsulf oxide (DMSO) and were added at a concentration of 5C^g/ml and incubated for a further of 48 hours. Untreated control received either total complete medium or 0.1% of DMSO. Cisplatin (CDDP, also at 50μg/ml) was the positive reference which induced more than 95% in Hep3B. Afterwards, the evaluation of possible antiproliferative or cytotoxicity of those alkaloids was examined by the One Step ATP lite assay purchased from PerkinElmer according to the technical manual provided. Table 1 showed some preliminary results on antitumor activities. The relative MTS activities were compared with the untreated control and illustrated using symbols "+" (more cell death) and "-" (no cytotoxicity).

Table 1 Relative anticancer activity among quinoline compounds (50ug/ml)

Compound Rj R₂ R3 R4 R5 R6 R7 Rs Relative

Formula B activity to

control

27a H H H OBn H CH₂CH₃

28a H H H OBn H CH₂CH₂Ph

Compound Relative Formula A activity to

2b Br H Br OH H CH₃ H H +++++

5b H H H OH H CH₂OH H H +++++

8b H H H N H CH₃ H H +

b H H H OAc H CH₃ H H + b H H H OAc Ac CH₃ H H + a H H H OBn H CH₂CH₂Ph H H ++++

In Table 1, Formulas A and B are more clearly shown as follows.

Formula B

Formula A

MTS ([3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophen- yl)-H-tetrazoliuml ) Assay

[126] Changes in the cellular viability of compound ll-17a, 9-18b and enantioselective (+)-2b and (-)-2b treated cells were monitored using the MTS activity assay which is known and was reported previously (see reference number 16 below). Results were tabulated in Table 2 and Table 3. Briefly, 1 x 10⁴ carcinoma cells were seeded at day 0. After 24 hours, medium was changed and various compounds were added at different concentrations. Cisplatin (CDDP), a commonly used anticancer agent, was also used as the positive control. After 48 hours of incubation, the medium was removed and MTS/PMS solution was added and they were incubated further for exactly 30 minutes. Afterwards, optical absorbance was determined at 490nm according to the user manual (Promega). All the assays were done in triplicates.

Table 2 Relative anticancer activity among quinoline compounds

Comp'd Relative MTS Activity at 50μg/mL Concentration

Hep3B A549 HKESC-1 HKESC-4 HKESC150 11a 0.320±0.017 0.527±0.018 0.817±0.076 0.488±0.017 0.797±0.083

12a 0.209±0.030 n.d. 0.535±0.032 0.794±0.005 0.648±0.013

14a 0.370±0.214 0.244±0.003 n.d. n.d. n.d.

15a 0.777±0.130 0.629±0.081 n.d. n.d. n.d.

17a 0.878±0.073 0.920±0.042 n.d. n.d. n.d.

9b 0.688±0.027 0.706±0.184 0.453±0.012 0.698±0.096 0.619±0.025

10b 1.264±0.030 1.659±0.173 1.337±0.145 1.056±0.050 1.097±0.036 lib 0.554±0.114 0.759±0.079 0.917±0.023 0.777±0.019 0.764±0.001

12b 0.726±0.065 n.d. 0.682±0.001 0.716±0.022 0.845±0.010

13b 0.842±0.024 n.d. 0.754±0.017 0.424±0.062 0.470±0.087

14b 0.510±0.068 1.238±0.066 n.d. n.d. n.d.

15b 0.760±0.090 0.840±0.029 n.d. n.d. n.d.

16b 0.412±0.017 0.908±0.063 n.d. n.d. n.d.

17b 0.734±0.024 0.983±0.001 n.d. n.d. n.d.

18b 0.609±0.042 1.089±0.039 n.d. n.d. n.d.

CDDP 0.116±0.031 0.216±0.075 0.135±0.017 0.158±0.081 0.205±0.032

In vitro studies of (+)-2b and (-)-2b

[128] We screened (+)-2b and (-)-2b for their effects on cell proliferation and potential cytotoxicity in different cell lines. As shown in FIG. 1, both (+)-2b and (-)-2b showed considerable suppressing effects on cancer cell growth with MTS₅₀ ranging from 4 tolC^g/mL.

[129] In the present invention, studies of cytotoxic activity of (+)-2b and (-)-2b (example 11) were carried out on the five carcinoma cell lines (Hep3B, A549, HKESC- 1, HKESC-4 and KYSE150) by means of MTS assay. In vitro studies, the (+)-2b showed similar MTS₅₀ activity (50% of MTS reduction ability by the chemical treated cell as compared with control) to (-)-2b against the cancer cell lines (MTS₅₀ = ~5 μg/mL). Our preliminary results showed that the (+)-2b exhibited a more than 2-fold cytotoxic activity to the cell line KYSE150 than CDDP, and (+)-2b also exhibited a 1.5- fold cytotoxic activity to the cell lines Hep3B, HKESC-1 and HKESC-4 than CDDP. (+)-2b and (-)-2b showed similar cytotoxic effects on Hep3B, HKESC-4 and A549. These interesting results prompt us to further investigate the underlying molecular mechanisms of antiproliferation.

In Vivo Anti-cancer effects of (-)-2b

[130] Optically pure compound (-)-2b (ee up 99%) was tested for their anti-cancer effects against the subcutaneous xenograft tumors of human esophageal cancer derived from the cell line KYSE150, which was purchased from DSMZ

(Braunschweig, Germany) and was cultured in a known way as previously described (for details see reference number 17).

[131] Each group of three mice received intra-peritoneal (i.p.) injection daily with lOmg/kg of optically pure isomers with 6% polyethylene glycol (PEG Mn 8000) for 19 days. The control group of two mice was injected daily with 6% PEG only. Tumor dimensions were measured regularly with calipers, and tumor volumes were estimated using two-dimensional measurements of length and width and calculated with the formula [1 x (w)²] x 0.52 (1 is length and w is width) as previously described. As shown in FIG. 2, the overall results demonstrated that the compound (-)-2b

(lOmg/kg/day) is effective in suppressing the volume growth of the KYSE150 xenograft tumors in nude mice compared with the negative control. [132] Histological examination of liver, heart, lung and kidney sections of the mice after sacrifice showed no observable damage.

While there have been described and pointed out fundamental novel features of the invention as applied to a preferred embodiment thereof, it will be understood that various omissions and substitutions and changes, in the form and details of the embodiments illustrated, may be made by those skilled in the art without departing from the spirit of the invention. The invention is not limited by the embodiments described above which are presented as examples only but can be modified in various ways within the scope of protection defined by the appended patent claims.

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Claims

WHAT IS CLAIMED IS:

1. A quinoline derivative, comprising a structure of formula selected from formula I, II, III and IV:

wherein each of A, B, C, D,W, X, Y and Z is independently C, N, P or S, and each of Ri, R₂, R3, R4, R5, R6_/ R7 and R₈ is independently H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkoxy or substituted alkoxy, hydroxyl or substituted hydroxyl, amino or substituted amino, thio or substituted thio, sulfonyl or substituted sulfonyl, sulfinyl or substituted sulfinyl, sulfonylamino or substituted sulfonylamino, halo, SO3H, amine, CN, CF₃, acyl or substituted acyl, aryl or substituted aryl, heterocyclyl or substituted heterocyclyl, alkoxy or substituted alkoxy, aldehyde or substituted aldehyde or substituted phosphine; COR^a, CSR^a and CONHR^a where R^a is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, hydroxyl or substituted hydroxyl, aryl or substituted aryl, optionally heterocyclyl ring or substituted heterocyclyl ring; OR^b, SR^b or NR^bR^c where R^b and R^c are H or independently each other, alkyl or substituted alkyl, alkenyl or substituted alkenyl, acyl or substituted acyl, heterocyclyl ring or substituted heterocyclyl ring, CN; Q to C₄NR^dR^e, HCNNR^dR^e or HCNOR^d where R^d and R^e are H or independently each other, alkyl or substituted alkyl, alkenyl or substituted alkenyl, acyl or substituted acyl, heterocyclyl ring or substituted heterocyclyl ring; SR^f, OR^f or NR^fR^g, where R^f and R^g are H or independently each other, alkyl or substituted alkyl, alkenyl or substituted alkenyl, acyl or substituted acyl, heterocyclyl ring or substituted heterocyclyl ring; SOzNR^ where R^h and R' are H or independently each other, alkyl or substituted alkyl, alkenyl or substituted alkenyl, acyl or substituted acyl, heterocyclyl ring or substituted heterocyclyl ring; and wherein connection between any two of A, B, C, D,W, X, Y and Z is of a single bond or a double bond.

2. The quinoline derivative of claim 1, wherein each of said A, B, C, D,W, X, Y and Z is independently C, N, O, P or S.

3. The quinoline derivative of claim 2, wherein said structure is of the following formula:

wherein Rj, R₂ and R₃ are each independently H or Br; R₅, R₇ and R₈ are H; R₆ is selected from the group consisting of CH₃, CH₂CH₃, OBn, CH₂CH₂Ph, CH₂OH; and R₄ IS a substituted phenyl group, OBn, OH or OAc.

4. The quinoline derivative of claim 3, wherein said structure is of formula A:

5. The quinoline derivative of claim 3, wherein said structure is of formula B:

6. The quinoline derivative of claim 2, having a structure of the following formula:

7. The quinoline derivative of claim 3, wherein said phenyl group is of the following formula:

wherein Ra is COH_2/ Rb is H, and Rc is Ph, F, CI, OCF₃, CF_3/ CN, OMe or N0₂; or Ra is CO ^ Rb is Ph, F, CI, OCF₃, CN, OMe or NO₂, and Rc is H.

8. The quinoline derivative of claim 7, wherein said structure is of formula B; Rj, R₂ and R₃ are H; R₅, R₇ and R₈ are H; R₆ is CH₃, and R₄ is a phenyl group wherein Ra is COH₂, Rb is H, OMe, or Ph.

9. The quinoline derivative of claim 8, wherein Rb is H and Rc is OCF₃or CF₃.

10. The quinoline derivative of claim 3, wherein said structure is of formula B; R₄ is OBn; and R₆ is OBn, CH₂CH₂Ph or CH₂CH_{3 .}

11. The quinoline derivative of claim 3, wherein said structure is of formula A; R₄ is OH and R₆ is CH₂OH or CH_{3 .}

12. The quinoline derivative of claim 3, wherein said structure is of formula A; R₄ is OAc; and R₆ is CH₂CH₂Ph or CH_{3 .}

13. The quinoline derivative of claim 7, wherein said structure is of formula A; Ri, R₂ and R₃ are H; R₅, R₇ and R₈ are H; R₆ is CH₃, and R₄ is a phenyl group wherein Ra is COH_{2 /} Rb is H, OMe, NO₂ or Ph.

14. The quinoline derivative of claim 13, wherein Rb is H and Rc is OMe, NO^ F, CI, CF₃ or OCF₃.

15. The quinoline derivative of claim 11, wherein Rj, R₃ are Br, R₂ is H, and R₆ is CH₃.

16. A method of treating cancer in mammals, comprising a step of administering a quinoline derivative of claim 1 in an amount from about 8 to about 12 mg/kg/day body weight with a pharmaceutically acceptable.

The method of Claim 16, wherein said quinoline derivative is administered over a continuous period of between 5 to 10 days.

18. The method of Claim 16, wherein said cancer is breast carcinoma, hepatocellulor carcinoma, or chronic myelogenous leukemia.

19. The method of claim 16, wherein said quinoline derivative is a chiral chiral tetrahydroquinoline derivative.